curcumin and Neoplasms

The Notch signaling pathway is an evolutionarily conserved pathway that modulates normal biological processes involved in cellular differentiation, apoptosis, and stem cell self-renewal in a context-dependent fashion. Attributed to its pleiotropic physiological roles, both overexpression and silencing of the pathway are associated with the emergence, progression, and poorer prognosis in various types of cancer. To decrease disease incidence and promote survival, targeting Notch may have chemopreventive and anti-cancer effects. Natural products with profound historical origins have distinguished themselves from other therapies due to their easy access, high biological compatibility, low toxicity, and reliable effects at specific physiological sites in vivo. This review describes the Notch signaling pathway, particularly its normal activation process, and some main illnesses related to Notch signaling pathway dysregulation. Emphasis is placed on the effects and mechanisms of natural products targeting the Notch signaling pathway in diverse cancer types, including curcumin, ellagic acid (EA), resveratrol, genistein, epigallocatechin-3-gallate (EGCG), quercetin, and xanthohumol and so on. Existing evidence indicates that natural products are feasible solution to fight against cancer by targeting Notch signaling, either alone or in combination with current therapeutic agents.

Topics: Biological Products; Curcumin; Humans; Neoplasms; Receptors, Notch; Signal Transduction

Cancer is one of the most common diseases throughout the world, with many treatment modalities currently being used, and new treatment strategies being sought. Most chemotherapeutic molecules have shown extensive toxicity for normal cells, which leads to severe adverse effects. Chemotherapy may also lead to drug resistance, which is one of the major obstacles to the clinical treatment of cancer. Curcumin, a polyphenolic natural compound, has long been considered a therapeutic molecule for a variety of diseases and possesses anti-cancer, anti-oxidant, and anti-inflammatory properties. However, its use is limited due to its hydrophobic nature, poor solubility in water at acidic or neutral pH, and limited bioavailability at the tumor site. Cyclodextrin complexes of curcumin increase curcumin's water solubility, as well as its physicochemical stability to hydrolysis and photochemical decomposition. The most common type of cyclodextrin used for pharmaceutical preparations is β-cyclodextrin. This review focuses on different curcumin-cyclodextrin formulations and compares their pharmacokinetic parameters and efficacy.

Topics: Curcumin; Cyclodextrins; Drug Compounding; Humans; Neoplasms; Solubility; Water

Hydrogels have emerged as a versatile platform for a numerous biomedical application due to their ability to absorb a huge quantity of biofluids. In order to design hydrogels, natural polymers are an attractive option owing to their biocompatibility and biodegradability. Due to abundance in occurrence, cost effectiveness, and facile crosslinking approaches, alginate has been extensively investigated to fabricate hydrogel matrix. Management of cancer and chronic wounds have always been a challenge for pharmaceutical and healthcare sector. In both cases, curcumin have been shown significant improvement and effectiveness. However, the innate restraints like poor bioavailability, hydrophobicity, and rapid systemic clearance associated with curcumin have restricted its clinical translations. The current review explores the cascade of research around curcumin encapsulated alginate hydrogel matrix for wound healing and cancer therapy. The focus of the review is to emphasize the mechanistic effects of curcumin with its fate inside the cells. Further, the review discusses different approaches to designed curcumin loaded alginate hydrogels along with the parameters that regulates their release behavior. Finally, the review is concluded with emphasize on some key aspect on increasing the efficacy of these hydrogels along with novel strategies to further develop curcumin loaded alginate hydrogel matrix with multifacet applications.

Topics: Alginates; Curcumin; Hydrogels; Neoplasms; Polymers; Wound Healing

The immune network is an effective network of cell types and chemical compounds established to maintain the body's homeostasis from foreign threats and to prevent the risk of a wide range of diseases; hence, its proper functioning and balance are essential. A dysfunctional immune system can contribute to various disorders, including cancer. Therefore, there has been considerable interest in molecules that can modulate the immune network. Curcumin, the active ingredient of turmeric, is one of these herbal remedies with many beneficial effects, including modulation of immunity. Curcumin is beneficial in managing various chronic inflammatory conditions, improving brain function, lowering cardiovascular disease risk, prevention and management of dementia, and prevention of aging. Several clinical studies have supported this evidence, suggesting curcumin to have an immunomodulatory and anti-inflammatory function; nevertheless, its mechanism of action is still not clear. In the current review, we aim to explore the modulatory function of curcumin through interferons in cancers.

Topics: Anti-Inflammatory Agents; Curcuma; Curcumin; Humans; Immune System; Interferons; Neoplasms

As the greatest defense organ of the body, the skin is exposed to endogenous and external stressors that produce reactive oxygen species (ROS). When the antioxidant system of the body fails to eliminate ROS, oxidative stress is initiated, which results in skin cellular senescence, inflammation, and cancer. Two main possible mechanisms underlie oxidative stress-induced skin cellular senescence, inflammation, and cancer. One mechanism is that ROS directly degrade biological macromolecules, including proteins, DNA, and lipids, that are essential for cell metabolism, survival, and genetics. Another one is that ROS mediate signaling pathways, such as MAPK, JAK/STAT, PI3K/AKT/mTOR, NF-κB, Nrf2, and SIRT1/FOXO, affecting cytokine release and enzyme expression. As natural antioxidants, plant polyphenols are safe and exhibit a therapeutic potential. We here discuss in detail the therapeutic potential of selected polyphenolic compounds and outline relevant molecular targets. Polyphenols selected here for study according to their structural classification include curcumin, catechins, resveratrol, quercetin, ellagic acid, and procyanidins. Finally, the latest delivery of plant polyphenols to the skin (taking curcumin as an example) and the current status of clinical research are summarized, providing a theoretical foundation for future clinical research and the generation of new pharmaceuticals and cosmetics.

Topics: Antioxidants; Carcinogenesis; Cellular Senescence; Curcumin; Humans; Inflammation; Neoplasms; Oxidative Stress; Phosphatidylinositol 3-Kinases; Polyphenols; Reactive Oxygen Species

Natural plant phytochemicals are effective against different types of diseases, including cancer. Curcumin, a powerful herbal polyphenol, exerts inhibitory effects on cancer cell proliferation, angiogenesis, invasion, and metastasis through interaction with different molecular targets. However, the clinical use of curcumin is limited due to poor solubility in water and metabolism in the liver and intestine. The synergistic effects of curcumin with some phytochemicals such as resveratrol, quercetin, epigallocatechin-3-gallate, and piperine can improve its clinical efficacy in cancer treatment. The present review specifically focuses on anticancer mechanisms related to the co-administration of curcumin with other phytochemicals, including resveratrol, quercetin, epigallocatechin-3-gallate, and piperine. According to the molecular evidence, the phytochemical combinations exert synergistic effects on suppressing cell proliferation, reducing cellular invasion, and inducing apoptosis and cell cycle arrest. This review also emphasizes the significance of the co-delivery vehicles-based nanoparticles of such bioactive phytochemicals that could improve their bioavailability and reduce their systemic dose. Further high-quality studies are needed to firmly establish the clinical efficacy of the phytochemical combinations.

Topics: Curcumin; Humans; Neoplasms; Phytochemicals; Quercetin; Resveratrol

Treatment of metastatic cancer is one of the biggest challenges in anticancer therapy. Curcumin is interesting nature polyphenolic compound with unique biological and medicinal effects, including repression of metastases. High impact studies imply that curcumin can modulate the immune system, independently target various metastatic signalling pathways, and repress migration and invasiveness of cancer cells. This review discusses the potential of curcumin as an antimetastatic agent and describes potential mechanisms of its antimetastatic activity. In addition, possible strategies (curcumin formulation, optimization of the method of administration and modification of its structure motif) to overcome its limitation such as low solubility and bioactivity are also presented. These strategies are discussed in the context of clinical trials and relevant biological studies.

Topics: Antineoplastic Agents; Curcumin; Humans; Neoplasms

Curcumin, a natural polyphenol compound, has been identified as an effective therapeutic agent against cancer that exerts its anti-tumor activities by up/downregulating signaling mediators and modulating various cellular processes, including angiogenesis, autophagy, apoptosis, metastasis, and epithelial-mesenchymal transition (EMT). Since almost 98% of genomic transcriptional production is noncoding RNAs in humans, there is evidence that curcumin exerts therapeutic effects through the alterations of noncoding RNAs in various types of cancers. Circular RNAs (circRNAs) are formed by the back-splicing of immature mRNAs and have several functions, including functioning as miRNA sponges. It has been shown that curcumin modulated various circRNAs, including circ-HN1, circ-PRKCA, circPLEKHM3, circZNF83, circFNDC3B, circ_KIAA1199, circRUNX1, circ_0078710, and circ_0056618. The modulation of these circRNAs targeted the expression of mRNAs and modified various signaling pathways and hallmarks of cancer. In this article, we reviewed the pharmacokinetics of curcumin, its anti-cancer activities, as well as the biology and structure of circRNAs. Our main focus was on how curcumin exerts anti-cancer functions by modulating circRNAs and their target mRNAs and pathways.

Topics: Curcumin; Humans; MicroRNAs; Neoplasms; RNA, Circular; RNA, Messenger

Short non-coding RNAs called microRNAs (miRNAs) control gene expression by either inhibiting translation or degrading messenger RNA. MiRNAs are crucial for many biological functions, and the deregulation of their expression is strongly linked to the emergence of cancer. A single miRNA controls several gene expressions, allowing it to simultaneously control a number of cellular signaling pathways. As a result, miRNAs may be used as therapeutic targets as well as biomarkers for the prognosis and diagnosis of different cancers. Recent research has shown that natural compounds like curcumin, resveratrol and quercetin exert their pro-apoptotic and/or anti-proliferative impacts by modulating one and/or more miRNAs, which inhibits the growth of cancer cells, induces apoptosis, or increases the effectiveness of conventional cancer therapies. Here, we summarize the most recent developments in curcumin's control over the expression of miRNAs and emphasize the significance of these herbal remedies as a viable strategy in the treatment and prevention of cancer.

Topics: Curcumin; Female; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Ovarian Neoplasms; Signal Transduction

Curcumin is the principal curcuminoid found in the rhizomes of turmeric. Due to its therapeutic action against cancer, depression, diabetes, some bacteria, and oxidative stress, it has been used widely in medicine since ancient times. Due to its low solubility, the human organism cannot completely absorb it. Advanced extraction technologies, followed by encapsulation in microemulsion and nanoemulsion systems, are currently being used to improve bioavailability. This review discusses the different methods available for curcumin extraction from plant material, methods for the identification of curcumin in the resulting extracts, its beneficial effects on human health, and the encapsulation techniques into small colloidal systems that have been used over the past decade to deliver this compound.

Topics: Curcumin; Emulsions; Humans; Neoplasms; Solubility

Curcumin, derived from turmeric, has a strong anticancer potential known for millennia. The development of this phytochemical as a medicine has been hampered by several significant deficiencies, including its poor water solubility and low bioavailability. This review article discusses possibilities to overcome these bottlenecks by focusing on this natural polyphenol's nanoformulation. Moreover, preparation of curcumin conjugates containing folates as ligands for folic acid receptors can add a new important dimension in this field, allowing specific targeting of cancer cells, considering the significantly higher expression of these receptors in malignant tissues compared to normal cells. It is highly expected that simultaneous improvement of different aspects of curcumin in fighting against such a complex and multifaceted disease like cancer. Therefore, we can better comprehend cancer biology by developing a mechanistic understanding of curcumin, which will also inspire the scientific community to develop new pharmacological models, and exploration of emerging directions to revitalize application of natural products in cancer therapy.

Topics: Curcumin; Folic Acid; Humans; Neoplasms; Solubility

Polyphenols derived from fruits, vegetables, and plants are bioactive compounds potentially beneficial to human health. Notably, compounds such as quercetin, curcumin, epigallocatechin-3-gallate (EGCG), and resveratrol have been highlighted as antiproliferative agents for cancer. Due to their low solubility and limited bioavailability, some alternative nanotechnologies have been applied to encapsulate these compounds, aiming to improve their efficacy against cancer. In this comprehensive review, we evaluate the main nanotechnology approaches to improve the therapeutic potential of polyphenols against cancer using in vitro studies and in vivo preclinical models, highlighting recent advancements in the field. It was found that polymeric nanomaterials, lipid-based nanomaterials, inorganic nanomaterials, and carbon-based nanomaterials are the most used classes of nanocarriers for encapsulating polyphenols. These delivery systems exhibit enhanced antitumor activity and pro-apoptotic effects, particularly against breast, lung, prostate, cervical, and colorectal cancer cells, surpassing the performance of free bioactive compounds. Preclinical trials in xenograft animal models have revealed decreased tumor growth after treatment with polyphenol-loaded delivery systems. Moreover, the interaction of polyphenol co-delivery systems and polyphenol-drug delivery systems is a promising approach to increase anticancer activity and decrease chemotherapy side effects. These innovative approaches hold significant implications for the advancement of clinical cancer research.

Topics: Animals; Antineoplastic Agents; Curcumin; Humans; Male; Nanoparticles; Nanotechnology; Neoplasms; Polyphenols

Cancer poses a significant global health burden, necessitating the widespread use of chemotherapy and radiotherapy as conventional frontline interventions. Although targeted therapy and immunotherapy have shown remarkable advancements, the challenges of resistance development and severe side effects persist in cancer treatment. Consequently, researchers have actively sought more effective alternatives with improved safety profiles. In recent years, curcumin, a natural polyphenolic phytoalexin, has garnered considerable attention due to its broad spectrum of biological effects. This concise review provides valuable insights into the role of curcumin in cancer therapy, with a focus on elucidating its molecular mechanisms in inducing programmed cell death of tumor cells and suppressing tumor cell metastasis potential. Additionally, we discuss the challenges associated with the clinical application of curcumin and explore current endeavors aimed at overcoming these limitations. By shedding light on the promising potential of curcumin, this review contributes to the advancement of cancer treatment strategies.

Topics: Apoptosis; Curcumin; Humans; Immunotherapy; Neoplasms

Due to the progressive ageing of the human population, the number of cancer cases is increasing. For this reason, there is an urgent need for new treatments that can prolong the lives of cancer patients or ensure them a good quality of life. Although significant progress has been made in the treatment of cancer in recent years and the survival rate of patients is increasing, limitations in the use of conventional therapies include the frequent occurrence of side effects and the development of resistance to chemotherapeutic agents. These limitations are prompting researchers to investigate whether combining natural agents with conventional drugs could have a positive therapeutic effect in cancer treatment. Several natural bioactive compounds, especially polyphenols, have been shown to be effective against cancer progression and do not exert toxic effects on healthy tissues. Many studies have investigated the possibility of combining polyphenols with conventional drugs as a novel anticancer strategy. Indeed, this combination often has synergistic benefits that increase drug efficacy and reduce adverse side effects. In this review, we provide an overview of the studies describing the synergistic effects of curcumin, a polyphenol that has been shown to have extensive cytotoxic functions against cancer cells, including combined treatment. In particular, we have described the results of recent preclinical and clinical studies exploring the pleiotropic effects of curcumin in combination with standard drugs and the potential to consider it as a promising new tool for cancer therapy.

Topics: Combined Modality Therapy; Curcumin; Drug-Related Side Effects and Adverse Reactions; Humans; Neoplasms; Polyphenols; Quality of Life

Curcuminoids, flavoring, and coloring agents in food have potent antioxidant, anti-tumor activity, and anti-inflammatory effects. However, they are rapidly metabolized to lesser active metabolites. Therefore, various studies have been conducted to synthesize new and stable curcumin analogues with enhanced therapeutic activity.. Fluorinated curcumin compounds (2a-2f) were synthesized by Knoevenagel condensation between fluorobenzaldehydes (1a-1f) with curcumin. Fluorinated demethoxycurcumin (3a) was synthesized by condensation between demethoxycurcumin and 3,4-difluorobenzaldehyde (1f). The structures of these compounds were confirmed by FTIR, 1H-NMR, 13C-NMR, 19FNMR, and mass spectroscopy. Antiproliferative activities of these synthetic compounds were evaluated against breast cancer cells (4T1), melanoma cancer cells (B16F10), and normal cell lines (NIH 3T3) using MTT assay. The interaction of curcumin, 2f and 3a with several proteins (1HCL, 2ZOQ, 3D94, 5EW3, 4WA9, 1XKK, 6CCY) was investigated. The structural preservation of the epidermal growth factor receptor (EGFR) was investigated by molecular dynamics simulation.. The spectroscopic data obtained confirmed the proposed structure of fluorinated analogues. The results showed that compounds 2f and 3a inhibited cancer cells proliferation significantly more than other compounds. Compounds 2f and 3a showed the highest affinity and lowest binding energy with EGFR. The binding energies were -7.8, -10, and - 9.8 kcal/mol for curcumin, 2f and 3a with EGFR, respectively. The molecular docking results demonstrated that compounds 2f and 3a were firmly bound in a complex with EGFR via the formation of a hydrogen bond.. In summary, we found that fluorinated demethoxycurcumin and fluorinated curcumin induces cancer cell death and binds to EGFR with high affinity.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Humans; Molecular Docking Simulation; Neoplasms; Structure-Activity Relationship

Curcumin is a phytochemical isolated from Curcuma longa with potent tumor-suppressor activity, which has shown significant efficacy in pre-clinical and clinical studies. Curcumin stimulates cell death, triggers cycle arrest, and suppresses oncogenic pathways, thereby suppressing cancer progression. Cisplatin (CP) stimulates DNA damage and apoptosis in cancer chemotherapy. However, CP has adverse effects on several organs of the body, and drug resistance is frequently observed. The purpose of the present review is to show the function of curcumin in decreasing CP's adverse impacts and improving its antitumor activity. Curcumin administration reduces ROS levels to prevent apoptosis in normal cells. Furthermore, curcumin can inhibit inflammation via down-regulation of NF-κB to maintain the normal function of organs. Curcumin and its nanoformulations can reduce the hepatoxicity, neurotoxicity, renal toxicity, ototoxicity, and cardiotoxicity caused by CP. Notably, curcumin potentiates CP cytotoxicity via mediating cell death and cycle arrest. Besides, curcumin suppresses the STAT3 and NF-ĸB as tumor-promoting pathways, to enhance CP sensitivity and prevent drug resistance. The targeted delivery of curcumin and CP to tumor cells can be mediated nanostructures. In addition, curcumin derivatives are also able to reduce CP-mediated side effects, and increase CP cytotoxicity against various cancer types.

Topics: Antineoplastic Agents; Apoptosis; Cisplatin; Curcumin; Humans; Neoplasms

Nanoparticles have emerged as promising drug delivery systems for the treatment of several diseases. Novel cancer therapies have exploited these particles as alternative adjuvant therapies to overcome the traditional limitations of radio and chemotherapy. Curcumin is a natural bioactive compound found in turmeric, that has been reported to show anticancer activity against several types of tumors. Despite some biological limitations regarding its absorption in the human body, curcumin encapsulation in poly(lactic-co-glycolic acid) (PLGA), a non-toxic, biodegradable and biocompatible polymer, represents an effective strategy to deliver a drug to a tumor site. Furthermore, PLGA nanoparticles can be engineered with targeting moieties to reach specific cancer cells, thus enhancing the antitumor effects of curcumin. We herein aim to bring an up-to-date summary of the recently developed strategies for curcumin delivery to different types of cancer cells through encapsulation in PLGA nanoparticles, correlating their effects with those of curcumin on the biological capabilities acquired by cancer cells (cancer hallmarks). We discuss the targeting strategies proposed for advanced curcumin delivery and the respective improvements achieved for each cancer cell analyzed, in addition to exploring the encapsulation techniques employed. The conjugation of correct encapsulation techniques with tumor-oriented targeting design can result in curcumin-loaded PLGA nanoparticles that can successfully integrate the elaborate network of development of alternative cancer treatments along with traditional ones. Finally, the current challenges and future demands to launch these nanoparticles in oncology are comprehensively examined.

Topics: Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers

Curcumin, a phytochemical derived from the rhizome of turmeric (Curcuma longa L.), has a broad group of substances with antibacterial, anti-inflammatory, anti-oxidant, anticancer activities. The anticancer activity of curcumin and its derivatives are mainly related to its regulation of signal transduction pathways. However, due to the low oral availability of curcumin, fast metabolism and other pharmacokinetic properties limit the application of curcumin in the treatment of cancer. Evidence suggests that curcumin combined with photodynamic therapy can overcome the limitation of curcumin's low bioavailability by acting on apoptosis pathways, such as B-cell lymphoma 2 (Bcl-2) and caspase family, and affecting cell cycle. This paper reviews the structure and pharmacokinetics of curcumin, focusing on the anticancer activity of curcumin combined with photodynamic therapy and the effects on cancer-related signal pathways.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Neoplasms; Photochemotherapy; Proto-Oncogene Proteins c-bcl-2

Chemotherapeutic drugs are used to treat advanced stages of cancer or following surgery. However, cancers often develop resistance against drugs, leading to failure of treatment and recurrence of the disease. Polyphenols are a family of organic compounds with more than 10,000 members which have a three-membered flavan ring system in common. These natural compounds are known for their beneficial properties, such as free radical scavenging, decreasing oxidative stress, and modulating inflammation. Herein, we discuss the role of polyphenols (mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG]) in different aspects of cancer drug resistance. Increasing drug uptake by tumor cells, decreasing drug metabolism by enzymes (e.g. cytochromes and glutathione-S-transferases), and reducing drug efflux are some of the mechanisms by which polyphenols increase the sensitivity of cancer cells to chemotherapeutic agents. Polyphenols also affect other targets for overcoming chemoresistance in cancer cells, including cell death (i.e. autophagy and apoptosis), EMT, ROS, DNA repair processes, cancer stem cells, and epigenetics (e.g. miRNAs).

Topics: Antineoplastic Agents; Catechin; Curcumin; Drug Resistance, Neoplasm; Neoplasms; Polyphenols; Resveratrol

Curcumin is a phytochemical achieved from the plant turmeric. It is extensively utilized for the treatment of several types of diseases such as cancers. Nevertheless, its efficiency has been limited because of rapid metabolism, low bioavailability, poor water solubility, and systemic elimination. Scientists have tried to solve these problems by exploring novel drug delivery systems such as lipid-based nanoparticles (NPs) (e.g., solid lipid NPs, nanostructured lipid carriers, and liposomes), polymeric NPs, micelles, nanogels, cyclodextrin, gold, and mesoporous silica NPs. Among these, liposomes have been the most expansively studied. This review mainly focuses on the different curcumin nanoformulations and their use in cancer therapy in vitro, in vivo, and clinical studies. Despite the development of curcumin-containing NPs for the treatment of cancer, potentially serious side effects, including interactions with other drugs, some toxicity aspects of NPs may occur that require more high-quality investigations to firmly establish the clinical efficacy.

Topics: Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Micelles; Nanomedicine; Nanoparticles; Neoplasms

Natural compounds, primarily derived from plants, have been isolated and evaluated as alternative and complementary treatments for cancer. Curcumin has been proven to be beneficial in cancer therapy due to its multiple effects on cell signaling pathways, although the application of curcumin is limited due to its low oral bioavailability. Nanotechnology-based drug delivery systems have been used to overcome limited bioavailability and ensure greater biodistribution after administration. Nano-formulations of curcumin have shown more significant anticancer activity than free curcumin. Among the various nanocarriers, polymeric micelles with inherent stability and ease of formulation are ideal for tumor targeting via the enhanced permeation and retention (EPR) effect. The structure of polymeric micelles is suitable for the encapsulation of hydrophobic or low water-soluble drugs. Additionally, the outer shell of polymeric micelles provides protection against the normal uptake of foreign compounds by the reticuloendothelial system (RES). This review discusses the recent developments in curcumin delivery using polymeric micelles for various cancers.

Topics: Antineoplastic Agents; Curcumin; Drug Carriers; Humans; Micelles; Neoplasms; Tissue Distribution

Cancer-induced mortality is increasingly prevalent globally, which skyrocketed the necessity to discover new/novel, safe and effective anticancer drugs. Cancer is characterized by the continuous multiplication of cells in the human, which is unable to control. Scientific research is drawing its attention toward naturally-derived bioactive compounds as they have fewer side effects compared to the current synthetic drugs used for chemotherapy.. Drugs isolated from natural sources and their role in the manipulation of epigenetic markers in cancer are discussed briefly in this review article.. With advancing medicinal plant biotechnology and microbiology in the past century, several anticancer phytomedicines were developed. Modern pharmacopeia contains at least 25% herbal-based remedies, including clinically used anticancer drugs. These drugs mainly include the podophyllotoxin derivatives vinca alkaloids, curcumin, mistletoe plant extracts, taxanes, camptothecin, combretastatin, and colchicine artesunate, homoharringtonine, ellipticine, roscovitine, maytansine, tapsigargin,and bruceantin.. Compounds (psammaplin, didemnin, dolastin, ecteinascidin, and halichondrin) isolated from marine sources and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates. They have been evaluated for their anticancer activity on cells and experimental animal models and used chemotherapy.Drug-induced manipulation of epigenetic markers plays an important role in the treatment of cancer.. The development of a new drug from isolated bioactive compounds of plant sources has been a feasible way to lower the toxicity and increase their effectiveness against cancer. Potential anticancer therapeutic leads obtained from various ethnomedicinal plants, foods, marine, and microorganisms are showing effective yet realistically safe pharmacological activity. This review will highlight important plant-based bioactive compounds like curcumin, stilbenes, terpenes, other polyphenolic phyto-compounds, and structurally related families that are used to prevent/ ameliorate cancer. However, a contribution from all possible fields of science is still a prerequisite for discovering safe and effective anticancer drugs.

Topics: Animals; Antineoplastic Agents; Biological Products; Curcumin; Neoplasms; Plants, Medicinal

Notch signaling is often aberrantly activated in solid and hematological cancers and regulates cell fate decisions and the maintenance of cancer stem cells. In addition, increased expression of Notch pathway components is clinically associated with poorer prognosis in several types of cancer. Targeting Notch may have chemopreventive and anti-cancer effects, leading to reduced disease incidence and improved survival. While therapeutic agents are currently in development to achieve this goal, several researchers have turned their attention to dietary and natural agents for targeting Notch signaling. Given their natural abundance from food sources, the use of diet-derived agents to target Notch signaling offers the potential advantage of low toxicity to normal tissue. In this review, we discuss several dietary agents including curcumin, EGCG, resveratrol, and isothiocyanates, which modulate Notch pathway components in a context-dependent manner. Dietary agents modulate Notch signaling in several types of cancer and concurrently decrease in vitro cell viability and in vivo tumor growth, suggesting a potential role for their clinical use to target Notch pathway components, either alone or in combination with current therapeutic agents.

Topics: Antineoplastic Agents; Curcumin; Diet; Humans; Neoplasms; Neoplastic Stem Cells; Receptors, Notch; Signal Transduction

Turmeric, or Curcuma longa as it is formally named, is a multifunctional plant with numerous names. It was dubbed "the golden spice" and "Indian saffron" not only for its magnificent yellow color, but also for its culinary use. Turmeric has been utilized in traditional medicine since the dawn of mankind. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which are all curcuminoids, make up turmeric. Although there have been significant advancements in cancer treatment, cancer death and incidence rates remain high. As a result, there is an increasing interest in discovering more effective and less hazardous cancer treatments. Curcumin is being researched for its anti-inflammatory, anti-cancer, anti-metabolic syndrome, neuroprotective, and antibacterial properties. Turmeric has long been used as a home remedy for coughs, sore throats, and other respiratory problems. As a result, turmeric and its compounds have the potential to be used in modern medicine to cure a variety of diseases. In this current review, we highlighted therapeutic potential of curcumin and its multiple health benefits on various diseases.

Topics: Anti-Inflammatory Agents; Curcuma; Curcumin; Humans; Neoplasms; Spices

Photodynamic therapy (PDT) is a therapeutic intervention that can be applied to cancer treatment. The interaction between a photosensitizer (PS), ideal wavelength radiation, and tissue molecular oxygen triggers a series of photochemical reactions responsible for producing reactive oxygen species. These highly reactive species can decrease proliferation and induce tumor cell death. The search for PS of natural origin extracted from plants becomes relevant, as they have photoactivation capacity, preferentially targeting tumor cells and because they do not present any or little toxicity to healthy cells.. Our work aimed to carry out a qualitative systematic review to investigate the effects of curcumin (CUR), a molecule considered as PS of natural origin, on PDT, using red light or near-infrared radiation in tumor models.. A systematic search was performed in three databases (PubMed, Scopus, and Web of Science) using the PICOT method, retrieving a total of 1,373 occurrences. At the end of the peer screening, 25 eligible articles were included in this systematic review using inclusion, exclusion, and eligibility criteria.. CUR, whether in its free state, associated with metal complexes or other PS and in a nanocarrier system, was considered a relevant PS for PDT using red light or near-infrared against tumoral models in vitro and in vivo, acting by increasing cytotoxicity, inhibiting proliferation, inducing cell death mainly by apoptosis, and changing oxidative parameters.. The results found in this systematic review suggest the potential use of CUR as a PS of natural origin to be applied in PDT against many neoplasms, encouraging further search in PDT against cancer and serving as an investigative basis for upcoming pre-clinical and clinical applications.

Topics: Cell Line, Tumor; Curcumin; Humans; Light; Neoplasms; Photochemotherapy; Photosensitizing Agents

Cancer is a leading risk of death globally. According to the World Health Organization, it is presently the second most important disease that causes death in both developing and developed countries. Remarkable progress has been made in the war against cancer with the development of numerous novel chemotherapy agents. However, it remains an immense challenge to discover new efficient therapeutic potential candidates to combat cancer.. The majority of the currently used anticancer drugs are of natural origins, such as curcumin, colchicine, vinca alkaloid, paclitaxel, bergenin, taxols, and combretastatin. Concerning this, this review article presents the structure of the most potent molecules along with IC50 values, structure-activity relationships, mechanistic studies, docking studies, in silico studies of phytomolecules, and important key findings on human cancer cell lines.. A viewpoint of drug design and development of antiproliferative agents from natural phytomolecules has been established by searching peer-reviewed literature from Google Scholar, PubMed, Scopus, Springer, Science Direct, and Web of Science over the past few years.. Our analysis revealed that this article would assist chemical biologists and medicinal chemists in industry and academia in gaining insights into the anticancer potential of phytomolecules.. In vitro and in silico studies present phytomolecules, such as curcumin, colchicine, vinca alkaloids, colchicine, bergenin, combretastatin, and taxol encompassing anticancer agents, offerings abundant sanguinity and capacity in the arena of drug discovery to inspire the investigators towards the continual investigations on these phytomolecules. It is extremely expected that efforts in this track will strengthen and grant some budding cancer therapeutics candidates in the near future.

Topics: Antineoplastic Agents; Bibenzyls; Colchicine; Curcumin; Humans; Molecular Docking Simulation; Neoplasms; Paclitaxel

Plant extracts comprise a complex mixture of natural compounds with diverse biological activities including anticancer activities. This has made the use of plant extracts a trending strategy in cancer treatment. In addition, plants' active constituents such as polyphenols could confer protective effects on normal cells against damage by free radicals as well as lessen the toxicity of chemotherapeutic drugs. Recently, many emerging studies revealed the combinatory uses of plant extracts and individual therapeutic compounds that could be a promising panacea in hampering multiple signaling pathways involved in cancer development and progression. Besides enhancing the therapeutic efficacy, this has also been proven to reduce the dosage of chemotherapeutic drugs used, and hence overcome multiple drug resistance and minimize treatment side effects. Notably, combined use of plant extracts with chemotherapeutics drugs was shown to enhance anticancer effects through modulating various signaling pathways, such as P13K/AKT, NF-κB, JNK, ERK, WNT/β-catenin, and many more. Hence, this review aims to comprehensively summarize both In Vitro and In Vivo mechanisms of actions of well-studied plant extracts, such as

Topics: Curcumin; Humans; Neoplasms; NF-kappa B; Plant Extracts; Polyphenols

Throughout the United States, cancer remains the second leading cause of death. Traditional treatments induce significant medical toxic effects and unpleasant adverse reactions, making them inappropriate for long-term use. Consequently, anticancer-drug resistance and relapse are frequent in certain situations. Thus, there is an urgent necessity to find effective antitumor medications that are specific and have few adverse consequences. Curcumin is a polyphenol derivative found in the turmeric plant (

Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Antineoplastic Agents; Biological Availability; Curcumin; Humans; Nanoparticles; Neoplasms

The effects of plant-derived active compounds on cancer cells have been intensively investigated, leading to the possibility of dietary-based cancer prevention regimens and recommendations for patients with cancer. Many studies have revealed that several compounds can attenuate oxidative stress, suppress survival and proliferative signals, and diminish or suppress cancer stem cells (CSCs). These may provide novel lead compounds for drug development and benefit cancer therapy. The important pharmacological shift in anticancer therapy is the transition of drug discovery for cytotoxic drugs toward targeted therapy and more specific therapy like CSC-targeted therapy. Cancer-driven signaling, as well as survival pathways, have become vital targets for targeted therapeutic drug action. Furthermore, in aggressive cancers, such as lung cancer, it was shown that CSCs drive cancer initiation, progression, metastasis, and therapeutic failure. Moreover, plant-derived compounds are found as a component in diet and are considered safe. Here, we review cancer-protective elements found in plants, including phenolic compounds such as curcumin, carotenoids (β-carotene and lycopene), epigallocatechin-3-gallate, ginsenoside Rg3, resveratrol, and sulforaphane, for their possible anticancer, anti-metastasis, and cancer-preventive actions against lung cancer, especially in clinical and molecular pharmacological approaches. This review comprehensively summarizes the anticancer properties, target proteins, and CSC suppression capabilities of these plant-derived compounds that may potentially benefit the development of novel anticancer drugs or dietary recommendations for patients with lung cancer.

Topics: Antineoplastic Agents; Curcumin; Humans; Lung Neoplasms; Neoplasms; Neoplastic Stem Cells; Phytochemicals

Conventional cancer treatment is mainly based on the surgical removal of the tumor followed by radiotherapy and/or chemotherapy. When surgical removal is not possible, radiotherapy and, less often, chemotherapy is the only way to treat patients. However, despite significant progress in understanding the molecular mechanisms of carcinogenesis and developments in modern radiotherapy techniques, radiotherapy (alone or in combination) does not always guarantee treatment success. One of the main causes is the radioresistance of cancer cells. Increasing the radiosensitivity of cancer cells improves the processes leading to their elimination during radiotherapy and prolonging the survival of cancer patients. In order to enhance the effect of radiotherapy in the treatment of radioresistant neoplasms, radiosensitizers are used. In clinical practice, synthetic radiosensitizers are commonly applied, but scientists have recently focused on using natural products (phytocompounds) as adjuvants in radiotherapy. In this review article, we only discuss naturally occurring radiosensitizers currently in clinical trials (paclitaxel, curcumin, genistein, and papaverine) and those whose radiation sensitizing effects, such as resveratrol, have been repeatedly confirmed by many independent studies.

Topics: Biological Products; Curcumin; Genistein; Humans; Neoplasms; Paclitaxel; Papaverine; Radiation Tolerance; Radiation-Sensitizing Agents; Radiation, Ionizing; Resveratrol

Human diseases such as cancer can be caused by aberrant epigenetic regulation. Polyphenols play a major role in mammalian epigenome regulation through mechanisms and proteins that remodel chromatin. In fruits, seeds, and vegetables, as well as food supplements, polyphenols are found. Compounds such as these ones are powerful anticancer agents and antioxidants. Gallic acid, kaempferol, curcumin, quercetin, and resveratrol, among others, have potent anti-tumor effects by helping reverse epigenetic changes associated with oncogene activation and tumor suppressor gene inactivation. The role dietary polyphenols plays in restoring epigenetic alterations in cancer cells with a particular focus on DNA methylation and histone modifications was summarized. We also discussed how these natural compounds modulate gene expression at the epigenetic level and described their molecular targets in cancer. It highlights the potential of polyphenols as an alternative therapeutic approach in cancer since they modulate epigenetic activity.

Topics: Animals; Antineoplastic Agents; Chromatin; Curcumin; DNA Methylation; Epigenesis, Genetic; Gallic Acid; Histones; Humans; Kaempferols; Mammals; MicroRNAs; Neoplasms; Polyphenols; Quercetin; Resveratrol

Nowadays, one of the leading causes of death in humans is cancer, which is still on the rise globally and is in great need of intense study on the pathogenic mechanism and effective therapy. Epigenetics is a discipline that studies heritable changes in gene expression without alteration of DNA sequence. Epigenetic changes mainly involve DNA methylation, histone modifications and non-coding RNA (ncRNA) expression, which are interconnected to play a crucial role in the initiation and progression of various malignancies. Curcumin is a type of plant-derived polyphenolic compound with strong bioactivity against various disorders, particularly cancer. Retrieving commonly used databases such as PubMed, Google Scholar and CNKI, we summarized recent advances in the efficacy of curcumin on cancer and its epigenetic regulation in terms of DNA methylation, histone modifications and ncRNA expression. Furthermore, we also focused on improving the bioavailability of curcumin by development of novel curcumin analogs with high bioavailability, nanoparticles-loaded drug delivery system for curcumin, and combination therapy of curcumin with other agents. This review provides comprehensive insights into the molecular mechanisms, on the basis of epigenetic regulation, underlying the clinical application of curcumin in cancer.

Topics: Curcumin; DNA Methylation; Epigenesis, Genetic; Humans; Neoplasms; Protein Processing, Post-Translational

Polyphenols are considered popular ingredients in the pharmaceutical and medical fields due to their preventive and therapeutic properties. However, the potential effects and mechanisms of action of individual polyphenols remain largely unknown. Herein, we analyzed recent data on the synthetic pathways, features, and similarity of the properties of quercetin, as the most famous flavonoid, and curcumin, a representative of curcuminoids that despite their anti-oxidant activity, also have a pro-oxidant effect, depending on the concentration and the cellular environment. This review focuses on an analysis of their anti-cancer efficacy against various cancer cell lines via cell cycle arrest (regulation of p53/p21 and CDK/cyclins) and by triggering the mitochondrial intrinsic (Bcl-2/Bax/caspase 9) apoptotic pathway, as well as through the modulation of the signaling pathways (PI3K/Akt, Wnt/β-catenin, JAK/STAT, MAPK, p53, and NF-ĸB) and their influence on the non-coding RNAs involved in angiogenesis, invasion, migration, and metastasis. The therapeutic potential of quercetin and curcumin is discussed not only on the basis of their anti-cancer effects, but also with regard to their anti-diabetic, anti-obesity, anti-inflammatory, and anti-bacterial actions.

Topics: Apoptosis; Curcumin; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Quercetin; Tumor Suppressor Protein p53

Herein, I present an updated and contextualized literature review of functional genomic studies of natural phenols in the context of cancer. I suggest multilevel chemopreventive and anticancer mechanisms of action, which are shared by multiple dietary natural phenols. Specifically, I cite evidence that curcumin and resveratrol have multilevel anti-cancer effects through: (1) inducing either p53-dependent or p53-independent apoptosis in cancer cell lines, (2) acting as potent regulators of expression of oncogenic and anti-oncogenic microRNAs, and (3) inducing complex epigenetic changes that can switch off oncogenes/switch on anti-oncogenes. There is no simple reductionist explanation for anti-cancer effects of curcumin and resveratrol. More generally, multilevel models of chemoprevention are suggested for related natural phenols and flavonoids such as genistein, quercetin, or luteolin.

Topics: Curcumin; Genistein; Genomics; Humans; Luteolin; Neoplasms; Phenols; Quercetin; Resveratrol; Tumor Suppressor Protein p53

Cancer is considered as the major public health scourge of the 21st century. Although remarkable strides were made for developing targeted therapeutics, these therapies suffer from lack of efficacy, high cost, and debilitating side effects. Therefore, the search for safe, highly efficacious, and affordable therapies is paramount for establishing a treatment regimen for this deadly disease. Curcumin, a known natural, bioactive, polyphenol compound from the spice turmeric (Curcuma longa), has been well documented for its wide range of pharmacological and biological activities. A plethora of literature indicates its potency as an anti-inflammatory and anti-cancer agent. Curcumin exhibits anti-neoplastic attributes via regulating a wide array of biological cascades involved in mutagenesis, proliferation, apoptosis, oncogene expression, tumorigenesis, and metastasis. Curcumin has shown a wide range of pleiotropic anti-proliferative effect in multiple cancers and is a known inhibitor of varied oncogenic elements, including nuclear factor kappa B (NF-κB), c-myc, cyclin D1, Bcl-2, VEGF, COX-2, NOS, tumor necrosis factor alpha (TNF-α), interleukins, and MMP-9. Further, curcumin targets different growth factor receptors and cell adhesion molecules involved in tumor growth and progression, making it a most promising nutraceutical for cancer therapy. To date, curcumin-based therapeutics have completed more than 50 clinical trials for cancer. Although creative experimentation is still elucidating the immense potential of curcumin, systematic validation by proper randomized clinical trials warrant its transition from lab to bedside. Therefore, this review summarizes the outcome of diverse clinical trials of curcumin in various cancer types.

Topics: Anti-Inflammatory Agents; Apoptosis; Curcumin; Dietary Supplements; Humans; Neoplasms; NF-kappa B

Despite significant advancements made in the treatment of cancer during the past several decades, it remains one of the leading causes of death worldwide killing approximately 9.6 million people annually. The major challenge for therapeutic success is the development of chemoresistance in cancer cells against conventional chemotherapeutic agents via modulation of numerous survival and oncogenic signaling pathways. Therefore, sensitization of cancer cells to conventional drugs using multitargeted agents that suppress the survival and oncogenic pathways, in single or in combination, is an emerging strategy to overcome drug-resistance. During the last couple of decades, phytochemicals such as curcumin, resveratrol, tocotrienol and quercetin have emerged as potential chemosensitizing agents in cancer cells due to their less toxic and multitargeted properties. Numerous preclinical and clinical studies enumerated their potential to prevent drug resistance and sensitize cancer cells to chemotherapeutic agents by modulating several genes/proteins or pathways that regulate the key factors during the growth and progression of tumors such as inhibition of anti-apoptotic proteins, activation of pro-apoptotic proteins, reduced expression of different transcription factors, chemokines, enzymes, cell adhesion molecules, protein tyrosine kinases and cell cycle regulators. Therefore, natural chemosensitizing agents will have a special place in cancer treatment in the near future. This comprehensive review summarizes data obtained from various in vitro, in vivo and clinical studies to provide a new perspective for the application of agents obtained from "Mother Nature" as potential chemosensitizers for further cancer drug research and development.

Topics: Antineoplastic Agents; Curcumin; Humans; Neoplasms; Phytochemicals; Signal Transduction

In spite of all the investigations in the past 20 years that established a great body of knowledge in cancer therapy, utilizing some elderly methods such as plant compound administration might still be useful. Curcumin is a bioactive polyphenol, which has many anticancer properties but its capability in modulating miRNA expression has opened new doors in the field of cancer-targeted therapy. MiRNAs are a class of small noncoding RNAs that are able to regulate gene expression and signaling. In addition, some other effects of these RNAs such as modulating cell differentiation and regulation of cell cycle have made miRNAs great candidates for personalized cancer treatment. In this review, we try to find some answers to the questions on how curcumin exerts its impacts on cancer hallmarks through miRNAs and whether chemotherapy can be replaced by this beneficial plant compound.

Topics: Aged; Curcumin; Humans; MicroRNAs; Neoplasms; Polyphenols; Signal Transduction

Accumulating evidence has demonstrated that cancer stem cells (CSCs) play an essential role in tumor progression and reoccurrence and drug resistance. Multiple signaling pathways have been revealed to be critically participated in CSC development and maintenance. Emerging evidence indicates that numerous chemopreventive compounds, also known as nutraceuticals, could eliminate CSCs in part via regulating several signaling pathways. Therefore, in this review, we will describe the some natural chemopreventive agents that target CSCs in a variety of human malignancies, including soy isoflavone, curcumin, resveratrol, tea polyphenols, sulforaphane, quercetin, indole-3-carbinol, 3,3'-diindolylmethane, withaferin A, apigenin, etc. Moreover, we discuss that eliminating CSCs by nutraceuticals might be a promising strategy for treating human cancer via overcoming drug resistance and reducing tumor reoccurrence.

Topics: Curcumin; Dietary Supplements; Humans; Neoplasms; Neoplastic Stem Cells; Signal Transduction

Curcuma kwangsiensis root tuber is a widely used genuine medicinal material in Guangxi, with the main active components of terpenoids and curcumins. It has the effects of promoting blood circulation to relieve pain, moving Qi to relieve depression, clearing heart and cooling blood, promoting gallbladder function and anti-icterus. Modern research has proved its functions in liver protection, anti-tumor, anti-oxidation, blood lipid reduction and immunosuppression. Considering the research progress of C. kwangsiensis root tubers and the core concept of quality marker(Q-marker), we predicted the Q-markers of C. kwangsiensis root tubers from plant phylogeny, chemical component specificity, traditional pharmacodynamic properties, new pharmacodynamic uses, chemical component measurability, processing methods, compatibility, and components migrating to blood. Curcumin, curcumol, curcumadiol, curcumenol, curdione, germacrone, and β-elemene may be the possible Q-markers. Based on the predicted Q-markers, the mechanisms of the liver-protecting and anti-tumor activities of C. kwangsiensis root tubers were analyzed. AKT1, IL6, EGFR, and STAT3 were identified as the key targets, and neuroactive ligand-receptor interaction signaling pathway, nitrogen metabolism pathway, cancer pathway, and hepatitis B pathway were the major involved pathways. This review provides a basis for the quality evaluation and product development of C. kwangsiensis root tubers and gives insights into the research on Chinese medicinal materials.

Topics: China; Curcuma; Humans; Liver; Neoplasms; Terpenes

Cancer is known as a second major cause of death globally. Nowadays, several modalities have been developed for the treatment of cancer. Radiotherapy and chemotherapy are the most common modalities in most countries. However, newer modalities such as immunotherapy and targeted therapy drugs can kill cancer cells with minimal side effects. All anticancer agents work based on the killing of cancer cells. Numerous studies are ongoing to kill cancer cells more effectively without increasing side effects to normal tissues. The combination modalities with low toxic agents are interesting for this aim. Curcumin is one of the most common herbal agents that has shown several anticancer properties. It can regulate immune system responses against cancer. Furthermore, curcumin has been shown to potentiate cell death signalling pathways and attenuate survival signalling pathways in cancer cells. The knowledge of how curcumin induces cell death in cancers can improve therapeutic efficiency. In this review, the regulatory effects of curcumin on different cell death mechanisms and their signalling pathways will be discussed. Furthermore, we explain how curcumin may potentiate the anticancer effects of other drugs or radiotherapy through modulation of apoptosis, mitotic catastrophe, senescence, autophagy and ferroptosis.

Topics: Animals; Antineoplastic Agents; Cell Death; Curcumin; Humans; Neoplasms; Signal Transduction

The last decade has seen an unprecedented rise in the prevalence of chronic diseases worldwide. Different mono-targeted approaches have been devised to treat these multigenic diseases, still most of them suffer from limited success due to the off-target debilitating side effects and their inability to target multiple pathways. Hence a safe, efficacious, and multi-targeted approach is the need for the hour to circumvent these challenging chronic diseases. Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, has been under intense scrutiny for its wide medicinal and biological properties. Curcumin is known to manifest antibacterial, antiinflammatory, antioxidant, antifungal, antineoplastic, antifungal, and proapoptotic effects. A plethora of literature has already established the immense promise of curcuminoids in the treatment and clinical management of various chronic diseases like cancer, cardiovascular, metabolic, neurological, inflammatory, and infectious diseases. To date, more than 230 clinical trials have opened investigations to understand the pharmacological aspects of curcumin in human systems. Still, further randomized clinical studies in different ethnic populations warrant its transition to a marketed drug. This review summarizes the results from different clinical trials of curcumin-based therapeutics in the prevention and treatment of various chronic diseases.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Chronic Disease; Curcuma; Curcumin; Humans; Neoplasms

Cancer is the second leading cause of death in the world. Chemotherapy and radiotherapy (RT) are the common cancer treatments. In addition to these limitations, the development of adverse effects from chemotherapy and RT reduces the quality of life for cancer patients. Cellular radiosensitivity, or the ability to resist and overcome cell damage caused by ionizing radiation (IR), is directly related to cancer cells' response to RT. Therefore, radiobiological research is emphasizing chemical compounds 'radiosensitization of cancer cells so that they are more reactive in the IR spectrum. Recent years researchers have seen an increase in interest in natural products that have antitumor effects with minimal side effects. Natural products, on the other hand, are easy to recover and therefore less expensive. There have been several scientific studies done based on these compounds that have tested their ability in vitro and in vivo to induce tumor radiosensitization. The role of natural products in RT, as well as their usefulness and potential applications, is the goal of this current review.

Topics: Berberine; Biological Products; Curcumin; Emodin; Genistein; Humans; Neoplasms; Pentacyclic Triterpenes; Radiation-Protective Agents; Radiation-Sensitizing Agents; Radiotherapy; Resveratrol; Sesquiterpenes; Triterpenes; Ursolic Acid; Vitamin D; Withanolides

Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the nucleus and heterodimerizes with the tiny Maf or Jun proteins. It then attaches to certain DNA locations in the nucleus, such as electrophile response elements (EpRE) or antioxidant response elements (ARE), to start the transcription of cytoprotective genes. Many neoplasms have been shown to have over activated Nrf2, strongly suggesting that it is responsible for tumors with a poor prognosis. Exactly like curcumin, Zinc-curcumin Zn (II)-curc compound has been shown to induce Nrf2 activation. In the cancer cell lines analyzed, Zinc-curcumin Zn (II)-curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1 and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1) protein.As a result, the crosstalk between p62/SQSTM1 and Nrf2 could be used to improve cancer patient response to treatments. The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on Nrf2 signaling pathway have been shown to improve insulin resistance. Curcumin exerts its anti-inflammatory impact through suppressing metabolic reactions and proteins such as Keap1 that provoke inflammation and oxidation. A rational amount of curcumin-activated antioxidant Nrf2 HO-1 and Nrf2-Keap1 pathways and upregulated the modifier subunit of glutamate-cysteine ligase involved in the production of the intracellular antioxidant glutathione. Enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). A variety of in vivo, in vitro and clinical studies has been done so far to confirm the protective role of curcumin via Nrf2 regulation. This manuscript is designed to provide a comprehensive review on the molecular aspects of curcumin and its derivatives/analogs via regulation of Nrf2 regulation.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carrier Proteins; Curcumin; Drug Evaluation, Preclinical; Gene Expression Regulation; Humans; Neoplasms; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Protein Binding; Signal Transduction; Transcriptional Activation

Cancer continues to be one of the deadliest diseases that adversely impacts the large population of the world. A stack of scientific documents reflects a huge number of potent plant-based anticancer drugs such as curcumin (CUR), podophyllotoxin, camptothecin (CPT), vincristine, vinblastine, paclitaxel (PTX), etc. that have been integrated into the modern practice of cancer treatment. The demand for natural products raises exponentially as they are generally considered to be safe, and devoid of critical toxic effects at the therapeutic dose when compared to their synthetic counterparts. Despite rising interest towards the potent phytoconstituents, formulation developer faces various challenges in drug development processes such as poor water solubility, low bioavailability, marginal permeability, and nonspecific drug delivery at the target site, etc. Further, adverse drug reaction and multidrug resistance are other critical issues that need to be addressed. Nanomedicines owing to their unique structural and functional attributes help to fix the above challenges for improved translational outcomes. This review summarises the prospects and challenges of a nanotechnology-based drug delivery approach for the delivery of plant-based anticancer drugs.

Topics: Curcumin; Drug Delivery Systems; Nanomedicine; Nanoparticles; Nanotechnology; Neoplasms

Curcumin is a major curcuminoid present in turmeric. The compound is attributed to various therapeutic properties, which include anti-oxidant, anti-inflammatory, anti-bacterial, anti-malarial, and neuroprotection. Due to its therapeutic potential, curcumin has been employed for centuries in treating different ailments. Curcumin has been investigated lately as a novel therapeutic agent in the treatment of cancer. However, the mechanisms by which curcumin exerts its cytotoxic effects on malignant cells are still not fully understood. One of the main limiting factors in the clinical use of curcumin is its poor bioavailability and rapid elimination. Advancements in drug delivery systems such as nanoparticle-based vesicular drug delivery platforms have improved several parameters, namely, drug bioavailability, solubility, stability, and controlled release properties. The use of curcumin-encapsulated niosomes to improve the physical and pharmacokinetic properties of curcumin is one such approach. This review provides an up-to-date summary of nanoparticle-based vesicular drug carriers and their therapeutic applications. Specifically, we focus on niosomes as novel drug delivery formulations and their potential in improving the delivery of challenging small molecules, including curcumin. Overall, the applications of such carriers will provide a new direction for novel pharmaceutical drug delivery, as well as for biotechnology, nutraceutical, and functional food industries.

Topics: Curcumin; Drug Delivery Systems; Humans; Liposomes; Neoplasms; Solubility

Curcumin is a major active principle of Curcuma longa. There are more than 1700 citations in the Medline, reflecting various biological effects of curcumin. Most of these biological activities are associated with the antioxidant, anti-inflammatory and antitumor activity of the molecule. Several reports suggest various targets of natural curcumin that include growth factors, growth factor receptor, cytokines, enzymes and gene regulators of apoptosis. This review focuses on the improved curcumin derivatives that target the cancer and inflammation.. In this present review, we explored the anticancer drugs with curcumin-based drugs under pre-clinical and clinical studies with critical examination. Based on the strong scientific reports of patentable and non-patented literature survey, we have investigated the mode of the interactions of curcumin-based molecules with the target molecules.. Advanced studies have added new dimensions of the molecular response of cancer cells to curcumin at the genomic level. However, poor bioavailability of the molecule seems to be the major limitation of the curcumin. Several researchers have been involved to improve the curcumin derivatives to overcome this limitation. Sufficient data of clinical trials to various cancers that include multiple myeloma, pancreatic cancer and colon cancer, have also been discussed.. The detailed analysis of the structure-activity relationship (SAR) and common synthesis of curcumin-based derivatives have been discussed in the review. Utilising the predictions of in silico coupled with validation reports of in vitro and in vivo studies have concluded many targets for curcumin. Among them, cancer-related inflammation genes regulating curcumin-based molecules are a very promising target to overcome hurdles in the multimodality therapy of cancer.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Curcumin; Drug Design; Humans; Inflammation; Neoplasms

Curcumin, an active compound of turmeric spice, is one of the most-studied natural compounds and has been widely recognized as a chemopreventive agent. Several molecular mechanisms have proven that curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as in the inhibition of the carcinogenesis process.. To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents.. A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed Central, and Google scholar for the implication of curcumin in cancer management, along with a special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com, and www.freshpatents.com.. Recent studies based on cancer cells have proven that curcumin has potential effects against cancer cells as it prevents the growth of cancer and acts as a cancer therapeutic agent. Besides, curcumin exerted anti-cancer effects by inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion, and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells.. Accumulating evidences suggest that curcumin has the potential to inhibit cancer growth, induce apoptosis, and modulate various cell signaling pathway molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy, and safe dose in the management of various cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Curcuma; Curcumin; Humans; Neoplasms; Patents as Topic; Signal Transduction

The frequent inefficiency of conventional cancer therapies due to drug resistance, non-targeted drug delivery, chemotherapy-associated toxic side effects turned the focus to bioactive phytochemicals. In this context, curcumin and resveratrol have emerged as potent chemopreventive and chemoprotective compounds modulating apoptotic and autophagic cell death pathways in cancer in vitro and in vivo. As synergistic agents in combination with clinically established anticancer drugs, the enhanced anticancer activity at reduced chemotherapy-associated toxicity towards normal organs can be explained by improved pharmacokinetics, pharmacodynamics, bioavailability and metabolism. With promising preclinical and clinical applications, the design of drug-loaded nanoparticles, nanocarriers, liposomes and micelles have gained much attention to improve target specificity and drug efficacy. The present review focuses on the molecular modes of chemoprevention, chemoprotection and drug synergism with special emphasis to preclinical and clinical applications, pharmacokinetics, pharmacodynamics and advanced drug delivery methods for the development of next-generation personalized cancer therapeutics.

Topics: Animals; Antineoplastic Agents, Phytogenic; Chemoprevention; Curcumin; Drug Synergism; Humans; Neoplasms; Phytochemicals; Resveratrol

Substances present in nature have been a continuous source for the development of drugs for cardiovascular and infectious diseases, cancer, and many other diseases. As the literature concerning these natural products grows, it becomes more difficult for a reader to quickly grasp the essential facts and develop a well-informed impression of this field of research. Until now, it has also been difficult to determine which natural products and research objectives were gaining the most attention as measured by a number of citations.. The current study of all published articles concerned with natural products sought to identify which natural products and which research objectives are connected with the major contributors to scientific journals based on the number of relevant publications and the number of times each publication was cited elsewhere.. Bibliometric data, including citation data, were extracted from the Web of Science database using the search string TS=("natural product*)" and analyzed by the VOSviewer software.. The search yielded 63,194 articles, with more than half of the manuscripts published since 2012. The ratio of original articles to reviews was 5.8:1. The major contributing countries were the United States, China, Germany, Japan, and India. Articles were published mainly in journals focused on chemistry, pharmacology or biochemistry. Curcumin, resveratrol, and terpenoids were the most frequently cited natural products.. The results of the current study provide researchers from different backgrounds and healthcare professionals with a brief overview of the major trends in natural-product research in the form of a citation-based summary of the relevant literature.

Topics: Bibliometrics; Biological Products; Curcumin; Humans; Neoplasms; Software; United States

Despite the dramatic advances in cancer research over the decades, effective therapeutic strategies are still urgently needed. Increasing evidence indicates that connective tissue growth factor (CTGF), a multifunctional signaling modulator, promotes cancer initiation, progression, and metastasis by regulating cell proliferation, migration, invasion, drug resistance, and epithelial-mesenchymal transition (EMT). CTGF is also involved in the tumor microenvironment in most of the nodes, including angiogenesis, inflammation, and cancer-associated fibroblast (CAF) activation. In this review, we comprehensively discuss the expression of CTGF and its regulation, oncogenic role, clinical relevance, targeting strategies, and therapeutic agents. Herein, we propose that CTGF is a promising cancer therapeutic target that could potentially improve the clinical outcomes of cancer patients.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Movement; Cell Proliferation; Clinical Trials as Topic; Connective Tissue Growth Factor; Curcumin; Disease Progression; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mice; Neoplasms; Oncogene Proteins; Prognosis; Signal Transduction; Survival Rate; Tumor Microenvironment; Xenograft Model Antitumor Assays

Medicinal plants are being used for therapeutic purposes since the dawn of human civilization. The therapeutic efficacy of medicinal plants is due to the presence of wide range phytochemical constituents or secondary metabolites. The medicinal plants are traditionally used for several types of ailments. Even in those pathological conditions where other methods of treatment fail to work. Curcuma longa Linn is very common ingredient used as spice in foods as preservative and coloring material in different part of the world. It has been used as a home remedy for a variety of diseases. Curcuma longa and its isolated constituent curcumin are widely evaluated for anticancer activity. Curcumin possesses broad remedial potential due to its multi-targeting effect against many different carcinoma including leukemia, genitourinary cancers, gastrointestinal cancers and breast cancer etc. Hence, Curcumin has potential for the development of new medicine for the treatment of several diseases.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neoplasms; Phytochemicals; Signal Transduction

Curcuma longa has been mentioned in the Indian system of medicine for the management of a wide range of diseases. C. longa and its metabolites like curcumin, ar-turmerone, methylcurcumin, demethoxy-curcumin, and bisdemethoxycurcumin have also been reported to be beneficial in various types of cancer. Curcumin elicits anticancer properties chiefly by triggering apoptotic pathways in cancer cells. The properties are facilitated through diverse signaling pathways viz. pathways mediated by NF-kB, WNT/β-catenin pathway COX-2, LOX, STAT3, prostaglandin E2, phosphorylase kinase, VEGF, AKT, AP1, STAT3, PI3K, Akt, mTOR, ERK5, AP-1, TGF-b, PPARc, EBPa, NLRP3 inflammasome, p38MAPK, Nrf2, Notch-1, AMPK, TLR-4, etc. The present article highlights curcumin biosynthesis, phytochemistry and diverse molecular pathways involved in regulating several types of secondary messengers to exhibit anticancer activity in almost all the forms of cancer.

Topics: Curcumin; Humans; Neoplasms; Signal Transduction

Curcumin, a potent phytochemical, has been a significant lead compound and has been extensively investigated for its multiple bioactivities. Owing to its natural origin, non-toxic, safe, and pleiotropic behavior, it has been extensively explored. However, several limitations such as its poor stability, bioavailability, and fast metabolism prove to be a constraint to achieve its full therapeutic potential. Many approaches have been adopted to improve its profile, amongst which, structural modifications have indicated promising results. Its symmetric structure and simple chemistry have prompted organic and medicinal chemists to manipulate its arrangement and study its implications on the corresponding activity. One such recurring and favorable modification is at the diketo moiety with the aim to achieve isoxazole and pyrazole analogues of curcumin. A modification at this site is not only simple to achieve, but also has indicated a superior activity consistently. This review is a comprehensive and wide-ranged report of the different methods adopted to achieve several cyclized curcumin analogues along with the improvement in the efficacy of the corresponding activities observed.

Topics: Animals; Antineoplastic Agents; Chemistry Techniques, Synthetic; Curcumin; Cyclization; Heterocyclic Compounds; Humans; Neoplasms

Curcumin is a polyphenolic compound that exhibited good anticancer potential against different types of cancers through its multi-targeted effect like the termination of cell proliferation, inflammation, angiogenesis, and metastasis, thereby acting as antiproliferative and cytotoxic in nature. The present review surveys the various drug combination tried with curcumin or its synthetic analogues and also the mechanism by which curcumin potentiates the effect of almost every drug. In addition, this article also focuses on aromatherapy which is gaining much popularity in cancer patients. After thoroughly studying several articles on combination therapy of curcumin through authenticated book chapters, websites, research, and review articles available at PubMed, ScienceDirect, etc., it has been observed that multi-targeted curcumin possess enormous anticancer potential and, with whatever drug it is given in combination, has always resulted in enhanced effect with reduced dose as well as side effects. It is also capable enough in overcoming the problem of chemoresistance. Besides this, aromatherapy also proved its potency in reducing cancer-related side effects. Combining all the factors together, we can conclude that combination therapy of drugs with curcumin should be explored extensively. In addition, aromatherapy can be used as an adjuvant or supplementary therapy to reduce the cancer complications in patients.

Topics: Antineoplastic Agents; Cell Proliferation; Curcumin; Humans; Neoplasms

Curcumin (CUR) is a phenolic compound present in some herbs, including Curcuma longa Linn. (turmeric rhizome), with a high bioactive capacity and characteristic yellow color. It is mainly used as a spice, although it has been found that CUR has interesting pharmaceutical properties, acting as a natural antioxidant, anti-inflammatory, antimicrobial, and antitumoral agent. Nonetheless, CUR is a hydrophobic compound with low water solubility, poor chemical stability, and fast metabolism, limiting its use as a pharmacological compound. Smart drug delivery systems (DDS) have been used to overcome its low bioavailability and improve its stability. The current work overviews the literature from the past 10 years on the encapsulation of CUR in nanostructured systems, such as micelles, liposomes, niosomes, nanoemulsions, hydrogels, and nanocomplexes, emphasizing its use and ability in cancer therapy. The studies highlighted in this review have shown that these nanoformulations achieved higher solubility, improved tumor cytotoxicity, prolonged CUR release, and reduced side effects, among other interesting advantages.

Topics: Biological Availability; Curcumin; Humans; Micelles; Nanostructures; Neoplasms

Cancer is the second-leading cause of death worldwide. Till date, many such effective treatments are available, for example chemotherapy, surgery, and radiation therapy, but there are severe associated side effects, such as increased infection risk, constipation, hair loss, anaemia, among others. Thus, the need for effective therapeutic strategies and screening methodology arises. Researchers around the world are increasingly trying to discover anticancer therapies with as few side effects as possible and many are now focusing on phytochemicals, like curcumin. Curcumin is a bright yellow substance isolated from the plant rhizomes of Curcuma longa L. To this molecule a high therapeutic benefit has been underlined, being able to alter the development of cancer by different mechanisms, such as regulating multiple microRNA expression, modifying a series of signalling pathways, that is, Akt, Bcl-2, PTEN, p53, Notch, and Erbb. Another major pathway that curcumin targets is the matrix metalloproteinase (MMP) gene expression. In fact, MMPs are responsible for the degradation of the cell-extracellular matrix, which can lead to the diseased condition and many different pathways contribute to its activity, such as JAK/STAT, NF-κB, MAPK/ERK, COX-2, ROS, TGF-β, among others. In this review, we have attempted to describe the curcumin regulatory effect on different cell signalling pathways involved in the progression of different types of cancers.

Topics: Curcumin; Humans; Neoplasms; Signal Transduction

Cancer is a multi-factorial health condition involving uncontrolled cell divisions. The disease has its roots in genetic mutation. This disease affects men, women, and even children. Chemotherapy, photodynamic, photothermal, and hormonal therapies have been used to treat this deadliest disease, but a huge percentage of patients have chances of disease recurrence or resistance. Nowadays, dysregulation in miRNAs is considered one of the key factors for the development and progression of different types of cancers as they control the expression of genes responsible for cell proliferation, growth, differentiation, and apoptosis. Dietary phytochemicals with anticancer properties have been gaining focus for cancer treatment since they have been found more effective in targeting cancer via regulating miRNAs expression. These phytochemicals have no side effects and are readily available at a low cost. Several dietary phytochemicals with regulatory effects on the expression of miRNAs have been reported, including curcumin, diallyl disulfide, 3, 30-diindolylmethane, ellagic acid, genistein, indole-3-carbinol, quercetin, resveratrol, and sulforaphane. They exert their regulatory effects against different cancers either by upregulating or downregulating different cancer signalling pathways and inhibiting their progression. Curcumin down-regulates SHH pathways, epigallocatechin-3-gallate regulates the Notch pathway and inhibits TGFβ1/SMAD signalling, and resveratrol regulates the Wnt/β-catenin pathway and carnosic acid-induced apoptosis in colon cancer cell via JAK2/STAT3 signalling pathway. The miRNAs are used for the treatment of cancer as essential modulators in cellular pathways. Therefore, identifying the miRNAs and their targets and countering them with specific phytochemicals provide a safe and effective mechanism for the treatment of cancer.

Topics: Curcumin; Diet; Female; Humans; MicroRNAs; Neoplasm Recurrence, Local; Neoplasms; Phytochemicals; Signal Transduction

Despite significant signs of progress in cancer treatment over the past decade, either cancer prevalence or mortality continuously grow worldwide. Current anti-cancer agents show insignificant effectiveness, followed by serious side effects. It is important to find new, highly efficient pharmacological agents to increase cancer patients' clinical outcomes. Curcumin, a polyphenolic compound, has gained growing attention because of its anti-cancer properties. Curcumin can hinder the development, migration, and metastasis of cancer cells. The anti-cancer effects of curcumin are principally attributed to the regulation of several cellular signaling pathways, including MAPK/PI3K/Akt, Wnt/β-catenin, JAK/STAT, and NF-ĸB signaling pathways. Furthermore, curcumin can affect the expression and function of tumor-suppressive and oncogenic long non-coding RNAs (lncRNAs). In this study, we briefly reviewed the modulatory effect of curcumin on dysregulated tumor-supportive and tumor-suppressive lncRNAs in several cancers. It is hoped that a better understanding of curcumin's anti-cancer properties would pave the way for the development of a therapeutic approach in cancer.

Topics: Antineoplastic Agents; Curcumin; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; RNA, Long Noncoding

Aging increases the susceptibility to a diverse set of diseases and disorders, including neurodegeneration, cancer, diabetes, and arthritis. Natural compounds are currently being explored as alternative or complementary agents to treat or prevent aging-related malfunctions. Curcumin, a phytochemical isolated from the spice turmeric, has garnered great interest in recent years. With anti-oxidant, anti-inflammatory, anti-microbial, and other physiological activities, curcumin has great potential for health applications. However, the benefits of curcumin are restricted by its low bioavailability and stability in biological systems. Curcumin nanoformulations, or nano-curcumin, may overcome these limitations. This review discusses different forms of nano-curcumin that have been evaluated in vitro and in vivo to treat or prevent aging-associated health impairments. We describe current barriers for the routine use of curcumin nanoformulations in the clinic. Our review highlights outstanding questions and future work that is needed to ensure nano-curcumin is efficient and safe to lessen the burden of aging-related health problems.

Topics: Aging; Anti-Inflammatory Agents; Biological Availability; Curcumin; Humans; Neoplasms

There is extensive pre-clinical evidence for utility of curcuminoids across many diseases with a particular focus on cancer prevention, yet there remains a paucity of clinical evidence for its approved use. To assess current knowledge on the broader potential for clinical efficacy of curcumin and in particular, in cancer prevention strategies, this study undertook a systematic review determining the number and quality of randomized controlled trials (RCTs) undertaken across any pathology.. Search strategies for RCTs using a quantifiable amount of curcuminoids, are applied across Medline (Medical Literature Analysis and Retrieval System Online), Embase (Excerpta Medica dataBASE), Cochrane and clinicaltrials.gov. There are 314 curcuminoid-based RCTs, with 100 of these revealing significant within- and between-group changes relating to the primary outcome. Twenty three studies are conducted in a setting where there is an increased risk of cancer. Fifteen of these meet all prescribed quality criteria, and 10 reveal positive outcomes.. A substantial number of studies reveal positive outcomes following curcumin use. However, despite the vast array of preclinical data, there are relatively few RCTs conducted in the prevention setting. Future approaches to trials must deliver improved robustness and credibility of curcumin-related research to facilitate approvals for use in clinical settings.

Topics: Curcumin; Humans; Neoplasms; Randomized Controlled Trials as Topic

Despite a potential drug with multiple pharmacological activities, curcumin has disadvantages of the poor water solubility, rapid metabolism, low bioavailability, which considerably limit its clinical application. Currently, polymeric micelles (PMs) have gained widespread concern due to their advantageous physical and chemical properties, easy preparation, and biocompatibility. They can be used to improve drug solubility, prolong blood circulation time, and allow passive targeted drug delivery to tumor through enhanced penetration and retention effect. Moreover, studies focused on tumor microenvironment offer alternatives to design stimulus-responsive smart PMs based on low pH, high levels of glutathione, altered enzyme expression, increased reactive oxygen species production, and hypoxia. There are various external stimuli, such as light, ultrasound, and temperature. These endogenous/exogenous stimuli can be used for the research of intelligent micelles. Intelligent PMs can effectively load curcumin with improved solubility, and intelligently respond to release the drug at a controlled rate at targeted sites such as tumors to avoid early release, which markedly improves the bioavailability of curcumin. The present review is aimed to discuss and summarize recent developments in research of curcumin-loaded intelligent PMs based on endogenous and exogenous stimuli, and facilitates the development of novel delivery systems for future research.

Topics: Antineoplastic Agents; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Micelles; Neoplasms; Polymers; Tumor Microenvironment

The increasing prevalence of cancer has led to expanding traditional medicine objectives for developing novel drug delivery systems. A wide range of plant-derived polyphenol bioactive substances have been investigated in order to explore the anti-cancer effects of these natural compounds and to promote the effective treatment of cancer through apoptosis induction. In this regard, plant-derived polyphenol compounds, including curcumin, silibinin, quercetin, and resveratrol, have been the subject of intense interest for anti-cancer applications due to their ability to regulate apoptotic genes. However, some limitations of pure polyphenol compounds, such as poor bioavailability, short-term stability, low-cellular uptake, and insufficient solubility, have restricted their efficiency. Nanoscale formulations of bioactive agents have provided a novel platform to address these limitations. This paper reviews recent advances in nanoformulation approaches of polyphenolic drugs and their effects on improving the delivery of chemotherapy agents to cancer cells.

Topics: Curcumin; Drug Delivery Systems; Nanoparticles; Neoplasms; Pharmaceutical Preparations; Polyphenols; Transcriptome

Today, due to the prevalence of various diseases such as the novel coronavirus (SARS-CoV-2), diabetes, central nervous system diseases, cancer, cardiovascular disorders, and so on, extensive studies have been conducted on therapeutic properties of natural and synthetic agents. A literature review on herbal medicine and commercial products in the global market showed that curcumin (Cur) has many therapeutic benefits compared to other natural ingredients. Despite the unique properties of Cur, its use in clinical trials is very limited. The poor biopharmaceutical properties of Cur such as short half-life in plasma, low bioavailability, poor absorption, rapid metabolism, very low solubility (at acidic and physiological pH), and the chemical instability in body fluids are major concerns associated with the clinical applications of Cur. Recently, nanoformulations are emerging as approaches to develop and improve the therapeutic efficacy of various drugs. Many studies have shown that Cur nanoformulations have tremendous therapeutic potential against various diseases such as SARS-CoV-2, cancer, inflammatory, osteoporosis, and so on. These nanoformulations can inhibit many diseases through several cellular and molecular mechanisms. However, successful long-term clinical results are required to confirm their safety and clinical efficacy. The present review aims to update and explain the therapeutic potential of Cur nanoformulations.

Topics: Biological Availability; COVID-19; Curcumin; Humans; Nanoparticles; Neoplasms; SARS-CoV-2

Curcumin, a pure compound extracted from the flowering plant, turmeric (Curcuma longa. Zingiberaceae), is a common dietary ingredient found in curry powder. It has been studied extensively for its anti-inflammatory, antioxidant, antimicrobial and anti-tumour activities. Evidence is accumulating demonstrating its potential in chemoprevention and as an anti-tumour agent for the treatment of cancer. Despite demonstrated safety and tolerability, the clinical application of curcumin is frustrated by its poor solubility, metabolic instability and low oral bioavailability. Consequently researchers have tried novel techniques of formulation and delivery as well as synthesis of analogues with enhanced properties to overcome these barriers. This review presents the synthetic analogues of curcumin that have proven their anticancer potential from different studies. It also highlights studies that combined these analogues with approved chemotherapies and delivered them via novel techniques. Currently, there are no reports of clinical studies on any of the synthetic congeners of curcumin and this presents an opportunity for future research. This review presents the synthetic analogues of curcumin and makes a compelling argument for their potential application in the management of cancerous disease.

Topics: Animals; Cell Line, Tumor; Curcumin; Humans; Molecular Structure; Neoplasms; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Curcumin, isolated from Curcuma longa L., is a fat-soluble natural compound that can be obtained from ginger plant tuber roots, which accumulative evidences have demonstrated that it can resist viral and microbial infection and has anti-tumor, reduction of blood lipid and blood glucose, antioxidant and removal of free radicals, and is active against numerous disorders various chronic diseases including cardiovascular, pulmonary, neurological and autoimmune diseases. In this article is highlighted the recent evidence of curcuminoids applied in sevral aspects of medical problem particular in COVID-19 pandemics. We have searched several literature databases including MEDLINE (PubMed), EMBASE, the Web of Science, Cochrane Library, Google Scholar, and the ClinicalTrials.gov website via using curcumin and medicinal properties as a keyword. All studies published from the time when the database was established to May 2021 was retrieved. This review article summarizes the growing confirmation for the mechanisms related to curcumin's physiological and pharmacological effects with related target proteins interaction via molecular docking. The purpose is to provide deeper insight and understandings of curcumin's medicinal value in the discovery and development of new drugs. Curcumin could be used in the prevention or therapy of cardiovascular disease, respiratory diseases, cancer, neurodegeneration, infection, and inflammation based on cellular biochemical, physiological regulation, infection suppression and immunomodulation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; Autoimmune Diseases; Cardiovascular Diseases; Curcumin; Humans; Neoplasms; Protein Structure, Secondary

The rise in cancer cases in recent years is an alarming situation worldwide. Despite the tremendous research and invention of new cancer therapies, the clinical outcomes are not always reassuring. Cancer cells could develop several evasive mechanisms for their survivability and render therapeutic failure. The continuous use of conventional cancer therapies leads to chemoresistance, and a higher dose of treatment results in even greater toxicities among cancer patients. Therefore, the search for an alternative treatment modality is crucial to break this viscous cycle. This paper explores the suitability of curcumin combination treatment with other cancer therapies to curb cancer growth. We provide a critical insight to the mechanisms of action of curcumin, its role in combination therapy in various cancers, along with the molecular targets involved. Curcumin combination treatments were found to enhance anticancer effects, mediated by the multitargeting of several signalling pathways by curcumin and the co-administered cancer therapies. The preclinical and clinical evidence in curcumin combination therapy is critically analysed, and the future research direction of curcumin combination therapy is discussed.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Curcumin; Humans; Neoplasms; Signal Transduction

Signal transducer and activator of transcription 3 (STAT3) plays pivotal role in several cellular processes such as cell proliferation and survival and has been found to be aberrantly activated in many cancers. STAT3 is largely believed to be one of the key oncogenes and crucial therapeutic targets. Much research has suggested the leading mechanisms for regulating the STAT3 pathway and its role in promoting tumorigenesis. Therefore, intensive efforts have been devoted to develop potent STAT3 inhibitors and several of them are currently undergoing clinical trials. Nevertheless, many natural products were identified as STAT3 inhibitors but attract less attention compared to the small molecule counterpart. In this review, the development of natural STAT3 inhibitors with an emphasis on their biological profile and chemical synthesis are detailed. The current state of STAT3 inhibitors and the future directions and opportunities for STAT3 inhibitor are discussed.

Topics: Alkaloids; Biological Products; Cell Proliferation; Curcumin; Humans; Neoplasms; STAT3 Transcription Factor; Terpenes

One of the main current strategies for cancer treatment is represented by combination chemotherapy. More recently, this strategy shifted to the "hybrid strategy", namely the designing of a new molecular entity containing two or more biologically active molecules and having superior features compared with the individual components. Moreover, the term "hybrid" has further extended to innovative drug delivery systems based on biocompatible nanomaterials and able to deliver one or more drugs to specific tissues or cells. At the same time, there is an increased interest in plant-derived polyphenols used as antitumoral drugs. The present review reports the most recent and intriguing research advances in the development of hybrids based on the polyphenols curcumin and resveratrol, which are known to act as multifunctional agents. We focused on two issues that are particularly interesting for the innovative chemical strategy involved in their development. On one hand, the pharmacophoric groups of these compounds have been used for the synthesis of new hybrid molecules. On the other hand, these polyphenols have been introduced into hybrid nanomaterials based on gold nanoparticles, which have many potential applications for both drug delivery and theranostics in chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Biological Products; Curcumin; Drug Delivery Systems; Gold; Humans; Metal Nanoparticles; Neoplasms; Resveratrol; Stilbenes

Cancer is a fatal disease with high mortality and low survival rate worldwide. At present, there is still no known cure for most cancers. Traditional Chinese medicine (TCM) represents a noteworthy reservoir for anticancer agents in drug discovery and development. Curcumae Rhizoma (called Ezhu in Chinese) is widely prescribed in TCM for anticancer therapy owing to its broad-spectrum antineoplastic activities. Especially, the terpenoids isolated from the essential oil of Curcumae Rhizoma form an integral part of cancer research and are well established as a potential anticancer agent. For example, β-elemene has been developed into a new drug for the treatment of solid tumors in China, and is currently undergoing clinical trials in the United States. The review aims to systematically summarize the recent advances on the anticancer effects and related molecular mechanisms of Curcumae Rhizoma, and its terpenoids (β-elemene, Furanodiene, Furanodienone, Germacrone, Curcumol, Curdione). In addition, we evaluated and compared the anticancer efficacy and clinical use of the terpenoids with combination therapies and traditional therapies. Therefore, this review provides sufficient evidence for the anticancer therapeutic potential of Curcumae Rhizoma and its terpenoids, and will contribute to the development of potential anticancer drugs.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Curcuma; Drugs, Chinese Herbal; Humans; Neoplasms; Rhizome; Terpenes

Topics: Animals; Antineoplastic Agents; Enzyme Inhibitors; Gene Regulatory Networks; Humans; Neoplasms; Protein Structure, Secondary; Sarcoplasmic Reticulum Calcium-Transporting ATPases

Turmeric (Curcuma longa) is a popular spice that has been used in Ayurvedic medicine for its ability to treat various common ailments. There have been statistical correlations between turmeric consumption and lower incidences of cancer development, prompting research into its primary component curcumin. Several in vitro and in vivo studies over the last decade into cancer treatment have provided experimental evidence that curcumin contains antiproliferative, antiangiogenic, and apoptotic properties. The results of human clinical trials however, have proven mostly to be inconclusive. This short review provides an insight into the properties of curcumin including its bioavailability, biological activity, and potential usage in clinical trials as a chemotherapeutic drug.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Proliferation; Curcuma; Curcumin; Humans; Molecular Structure; Neoplasms

Over the past decades, studies of phytochemicals as modifiers of radiotherapeutic efficacy have become increasingly popular to improve the treatment outcome of human malignancies. In the current comprehensive review article, radiosensitizing effects of curcumin, a yellow-colored polyphenolic constituent of turmeric, in various preclinical cancer models, both

Topics: Animals; Antineoplastic Agents; Curcumin; Disease Models, Animal; Humans; Neoplasms; Radiation-Sensitizing Agents; Signal Transduction

Curcumin, a controversial "panacea," has been broadly studied. Its bioactivities including antioxidant, anti-inflammatory, and especially antineoplastic activities have been documented. However, due to its extensive bioactivities, some scientists hold a skeptical point of view toward curcumin and described curcumin as a "deceiver" to chemists. The objective of this study was to explore curcumin's another possibility as a potential supplementary leading compound to cancer treatments.. Literature searches were conducted using electronic databases. Search terms such as "curcumin," "curcumin analogues," and so on were used. The literatures were collected and summarized. In this article, reported targets of curcumin are reviewed. The limitations of a curcumin as a therapeutic anticancer product including low bioavailability and poor targeting are mentioned. Furthermore, modified curcumin analogues and antitumor mechanisms are listed and discussed in the aspects of cell death and tumor microenvironment including angiogenesis, tissue hypoxia status, and energy metabolism.. Several possible modification strategies were presented by analyzing the relationships between the antitumor activity of curcumin analogues and their structural characteristics, including the introduction of hydrophilic group, shortening of redundant hydrocarbon chain, the introduction of extra chemical group, and so on.. From our perspective, after structural modification curcumin could be more effective complementary product for cancer therapies by the enhancement of targeting abilities and the improvement of bioavailability.

Topics: Antineoplastic Agents; Biological Availability; Cell Death; Coloring Agents; Complementary Therapies; Curcumin; Humans; Neoplasms; Tumor Microenvironment

Curcumin has been at the center of vigorous research and major debate during the past decade. Inspired by its anti-inflammatory properties, many curcumin-based products are being sold now to manage various forms of arthritis. Parallel preclinical studies have established its role in dissolving beta-amyloid plaques, tau-based neurofibrillary tangles, and also alpha-synuclein-linked protein aggregates typically observed in Parkinson's disease. In cancer research, most cancer cells in culture are eliminated by curcumin at an IC50 of 15-30 µM, whereas the maximum in vivo curcumin concentration achieved in humans is only about 6 µM. Additionally, a decade ago, no improvement over the placebo groups was observed in clinical studies using free curcumin as an anticancer agent. The lack of anticancer efficacy was attributed to its low bioavailability, which results from the low water-solubility and high metabolic rate in vivo. Newer lipid-complexed or antibody-targeted forms have been used and these studies have revealed an exciting property of curcumin, which involves repolarization of the tumor-promoting, tumor-associated microglia/macrophages (TAMs) into a tumoricidal form and recruitment of natural killer cells from the periphery. This review will cover some efforts to explore the effect of appropriately-delivered curcumin to dramatically alter the tumor microenvironment, thereby launching an indirect attack on the tumor cells and the tumor stem cells. Reviewing some aspects of immunotherapy, this article will argue for the use of the innate immune cells in cancer therapy.

Topics: Animals; Antineoplastic Agents; Biological Availability; Curcumin; Disease Models, Animal; Humans; Immunity, Innate; Macrophages; Microglia; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a natural protein expressed in a wide range of tissues in our body. It is a promising anti-cancer agent due to its selective killing of cancer cells, rendering normal cells unharmed. However, resistance occurs either intrinsically or develops over the course of TRAIL treatment. In view of its specificity to cancer cells, there is a pushing need to overcome TRAIL resistance. Curcumin (Cur), a natural active constituent of turmeric, has been evidenced to have anti-cancer properties. However, it is limited by its sparing solubility and low bioavailability. Combinational therapy is one of the most frequently used strategies to overcome these limitations, which has been proved to be more effective than monotherapy by achieving synergistic effects and reducing toxicity. This review aims to discuss TRAIL and its underlying apoptotic mechanisms, the combinational treatment of Cur and TRAIL in view of their respective limitations, and the underlying apoptotic mechanisms activated by the sensitization of cancers by Cur towards TRAIL-induced apoptosis. Finally, this review discusses the research gap and the author's insight into this research area in bridging the research gap from bench to bedside.

Topics: Apoptosis; Curcumin; Drug Resistance, Neoplasm; Drug Synergism; Humans; Neoplasms; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand

Curcumin, isolated from the rhizome of Curcuma longa, is one of the most extensively studied phytochemicals. This natural compound has a variety of pharmacological effects including antioxidant, anti-inflammatory, anti-tumor, cardio-protective, hepato-protective and anti-diabetic. Wnt signaling pathway, one of the potential targets of curcumin through upregulation and/or downregulation, plays a significant role in many diseases, even in embryogenesis and development of various organs and systems. In order to exert an anti-tumor activity in the organism, curcumin seems to inhibit the Wnt pathway. The downstream mediators of Wnt signaling pathway such as c-Myc and cyclin D1 are also modified by curcumin. This review demonstrates how curcumin influences the Wnt signaling pathway and is beneficial for the treatment of neurological disorders (Alzheimer's and Parkinson's diseases), cancers (melanoma, lung cancer, breast cancer, colon cancer, endothelial carcinoma, gastric carcinoma and hepatocellular carcinoma) and other diseases, such as diabetes mellitus or bone disorders.

Topics: Alzheimer Disease; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Curcuma; Curcumin; Humans; Neoplasms; Neuroprotective Agents; Parkinson Disease; Wnt Signaling Pathway

Diarypentanoids are commonly considered as monocarbonyl analogues of curcumin. Since the discovery of this compound in 1962, twenty one diarylpentanoids have been isolated and almost 600 synthetic analogues with antitumor activity have been synthesized. This review reports the exploitation of diarylpentanoids to develop curcumin analogues with improved antitumor activity over the last two decades. The mechanism of action and structure-activity relationship (SAR) studies are also highlighted. More importantly, structural features for the antitumor activity that may guide the design of new and more effective diarylpentanoids are also proposed.

Topics: Antineoplastic Agents; Curcumin; Humans; Molecular Structure; Neoplasms; Structure-Activity Relationship

Malignant tumor endangers seriously the health of all mankind. Multidrug resistance (MDR) is one of the main causes of clinical tumor chemotherapy failure. Curcumin (CUR) has not only antitumor activity but also reversing tumor MDR effect. CUR reverses tumor MDR via regulating related signal pathways or corresponding expressed proteins or gene. When combined with chemotherapeutic agents, CUR can be a chemotherapeutic sensitive agent to enhance chemotherapy efficacy and weaken tumor MDR. On the other hand, to improve the MDR reversal effect of CUR, its derivatives have been extensively studied. Therefore, this article mainly focuses on reviewing the application of CUR and its derivatives in MDR and its mechanism of reversing MDR.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Phytotherapy; Signal Transduction

The mammalian target of rapamycin (mTOR) is a protein kinase that has been considered as a key regulator of a large number of cellular processes, including cell growth, proliferation, differentiation, survival, and motility. Overactivation of mTOR (especially mTORC1) signaling is related to oncogenic cellular processes. Therefore targeting mTORC1 signaling is a new promising strategy in cancer therapy. In this regard, various studies have shown that curcumin, a polyphenol produced from the turmeric rhizome, has anti-inflammatory, antioxidant and anticancer properties. Curcumin may exert its anticancer function, at least in part, by suppressing mTOR-mediated signaling pathway in tumor cells. However, the exact underlying mechanisms by which curcumin blocks the mTORC1 signaling remain unclear. According to literature, curcumin inhibits insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 pathway which leads to apoptosis and cell cycle arrest via suppression of erythroblastosis virus transcription factor 2 and murine double minute 2 oncoprotein. In addition, activation of unc-51-like kinase 1 by curcumin, as a downstream target of IGF-1/PI3K/Akt/mTORC1 axis, enhances autophagy. Curcumin induces AMP-activated protein kinase, a negative regulator of mTORC1, via inhibition of F0F1-ATPase. Interestingly, curcumin suppresses IκB kinase β, the upstream kinase in mTORC1 pathway. Moreover, evidence revealed that curcumin downregulates the E3-ubiquitin ligases NEDD4, neural precursor cell-expressed developmentally downregulated 4. NEDD4 is frequently overexpressed in a wide range of cancers and degrades the phosphatase and tensin homolog, which is a negative regulator of mTORC1. Finally another suggested mechanism is suppression of MAOA/mTORC1/hypoxia-inducible factor 1α signaling pathway by curcumin.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Proliferation; Curcumin; Humans; Mechanistic Target of Rapamycin Complex 1; Neoplasms; Protein Kinase Inhibitors; Signal Transduction; TOR Serine-Threonine Kinases

Studies regarding the uses and biological benefits curcumin have long been paid worldwide attention. Curcumin is a polyphenol found in the turmeric spice, which is derived from the rhizomes of Curcuma longa. Curcumin is a major constituent of the traditional Indian holistic system, Ayurveda, and it is well-known in treating diverse ailments. The aim of this study is to conduct an overview that introduces the traditional uses and therapeutic effects of this valuable phytochemical with more focus on the antitumor results. This review was conducted based on published articles on PubMed, Medline, and Web of Science databases. In this study, the search strategy identified 103 references. Curcumin is found to possess many functions in recent years. It is commonly used for its antioxidant, antimicrobial, anti-inflammatory, antitumor, anti-diabetic, hypolipidemic, hepatoprotective, and neuroprotective effects. Curcumin has been greatly reported to prevent many diseases through modulating several signaling pathways, and the molecular bases of its anti-tumor bioactivities are imputed to the antiproliferative, anti-inflammatory, pro-apoptotic, anti-angiogenesis and anti-metastasis effects. The antitoxic potential of curcumin against various toxin like Aflatoxin B1 is reported. Although curcumin is a safe and promising phytochemical, it suffers from bioavailability problems that limit its therapeutic efficacy. Thus, various promising strategies allowed for the achievement of multiple and effective varieties of curcumin formulations, such as adjuvants, nanoparticles, liposome, micelle and phospholipid complexes, metal complexes, derivatives, and analogues. In conclusion, curcumin is widely used for myriad therapeutic purposes that trigger its significant value. This short review aims to highlight the known biological activities of curcumin and provide evidence for its antitumor effects.

Topics: Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Curcuma; Curcumin; Diabetes Mellitus; Herbal Medicine; Hypoglycemic Agents; Neoplasms

Many dietary polyphenols have been investigated for their therapeutic potential either as single agents or in combinations. Despite the significant anticancer potential of these polyphenols in

Topics: Animals; Catechin; Curcumin; Humans; Neoplasms; Polyphenols; Quercetin; Resveratrol

Chemotherapy is one of the main methods for cancer treatment. However, despite many advances in the design of anticancer drugs, their efficiency is limited due to their high toxicity and resistance of cells to chemotherapeutic drugs. In order to improve the cancer therapy, it is essential to use the compounds that can overcome drug resistance and increase treatment efficiency. Researchers have studied the effects of natural compounds for the controlling various drug resistance mechanisms. Curcumin is a natural phenolic compound which shows potent anticancer activities in different tumors, alone or as an adjuvant with other antitumor drugs to prevent or inhibit the survival and cancer progression by various mechanisms. The role of curcumin in overcoming drug resistance was followed by reviewing different applications of curcumin in cancer therapy. Afterward, the clinical impacts of curcumin, role of curcumin in decreasing drug resistance in different cancer cells and its mechanisms were discussed. It has been demonstrated that curcumin regulates signaling pathways in cancer cells, reduces the expression of proteins related to drug resistance, and increases the performance of antitumor drugs at various levels. Curcumin reverses multidrug resistance mechanisms and increases sensitivity of resistance cells to chemotherapy. This review mainly focuses on different mechanisms of drug resistance and curcumin as a nontoxic natural substance to eliminate the effects of drug resistance through modulation and controlling cell resistance pathways and eventually suggests curcumin as a potent chemosensitizer in cancers.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Signal Transduction

Cancer accounts for the second major cause of death globally. Conventional cancer therapies lead to systemic toxicity that forbids their long term application. Besides, tumor resistance and recurrence have been observed in the majority of cases. Thus, the development of such therapy, which will pose minimum side effects, is the need of the hour. Curcumin or diferuloylmethane (CUR) is a natural polyphenol bioactive (obtained from Curcuma longa) which possesses anti-cancer and chemo-preventive activity. It acts by modulating various components of signaling cascades that are involved in cancer cell proliferation, invasion, and apoptosis process. It interacts with the adaptive and innate immune systems of our body and causes tumor regression. This may be the reason behind the attainment of in vivo anti-tumor activity at a very low concentration. Its ease of availability, safety profile, low cost, and multifaceted role in cancer prevention and treatment has made it a promising agent for chemoprevention of many cancers. Regardless of the phenomenal properties, its clinical utility is haltered due to its low aqueous solubility, poor bioavailability, rapid metabolism, and low cellular uptake. In the last few years, a variety of novel drug carriers have been fabricated to enhance the bioavailability and pharmacokinetic profile of CUR to attain better targeting of cancer. In this review, the recent developments in the arena of nanoformulations, like liposomes, polymeric NPs, solid lipid NPs (SNPs), polymeric micelles, nanoemulsions, microspheres, nanogels, etc. in anticancer therapy have been discussed along with a brief overview of the molecular targets for CUR in cancer therapy and role of CUR in cancer immunotherapy.

Topics: Antineoplastic Agents; Biological Availability; Curcumin; Drug Carriers; Drug Delivery Systems; Micelles; Neoplasms

Curcumin is a poly phenolic compound extracted from turmeric. Over the past years, it has acquired significant interest among researchers due to its numerous pharmacological activities like anti- cancer, anti-alzheimer, anti-diabetic, anti-bacterial, anti-inflammatory and so on. However, the clinical use of curcumin is still obstructed due to tremendously poor bioavailability, rapid metabolism, lower gastrointestinal absorption, and low permeability through cell that makes its pharmacology thrilling. These issues have led to enormous surge of investigation to develop curcumin nano formulations which can overcome these restrictive causes. The scientists all across the universe are working on designing several drug delivery systems viz. liposomes, micelles, magnetic nano carriers, etc. for curcumin and its composites which not only improve its physiochemical properties but also enhanced its therapeutic applications. The review aims to systematically examine the treasure of information about the medicinal use of curcumin. This article delivers a general idea of the current study piloted to overwhelm the complications with the bioavailability of curcumin which have exhibited an enhanced biological activity than curcumin. This article explains the latest and detailed study of curcumin and its conjugates, its phytochemistry and biological perspectives and also proved curcumin as an efficient drug candidate for the treatment of numerous diseases. Recent advancements and futuristic viewpoints are also deliberated, which shall help researchers and foster commercial translations of improved nanosized curcumin combination for the treatment of various diseases.

Topics: Cell Survival; Curcumin; Drug Carriers; Humans; Hydrogels; Liposomes; Micelles; Nanostructures; Neoplasms; Wound Healing

Despite a huge body of research in the past two decades investigating the antioxidant, antiinflammatory, anti-microbial, and anti-carcinogenic properties of curcumin (CUR), a CUR-based antitumor drug is yet to be developed. Lack of success in achieving this goal stems from CUR's unfavorable biophysicochemical features, particularly poor solubility, low bioavailability, and rapid metabolism, coupled with a complex biological profile making it difficult to determine its mechanism of action. A significant body of literature aimed at improving its physicochemical properties through synthesis or by designing delivery methods has been published, and the progress in these areas has been reviewed. The present review aims to summarize recent progress in the synthesis of structurally diverse "curcumin-inspired" compounds along with computational docking and bioassay studies, through which a number of promising analogs have been identified that warrant further study.

Topics: Antineoplastic Agents; Antioxidants; Catalytic Domain; Cell Proliferation; Curcumin; Humans; Molecular Docking Simulation; Neoplasms; Protein Binding; Receptor, ErbB-2

Phytochemicals are a diverse group of compounds found in a variety of fruits, vegetables and herbs, and have been reported to possess a number of health benefits. Marketed as supplements by health food retailers, this group of naturally occurring compounds have been investigated for a number of years to determine if they possess any chemopreventative and/or chemotherapeutic benefits. In this comprehensive review, the phytochemicals resveratrol, berberine and curcumin will be discussed, with particular focus being given to their proposed anticancer applications. The purpose of this review is to help clarify whether there is any truth in the claims that are regularly made regarding the efficacy of these compounds. To this end, a number of significant studies that involved the use of these phytochemicals will be identified, discussed and evaluated, to determine if they show promise in the ongoing fight to reduce the incidence rates and severity of various cancers. Specifically, it is the aim of this review to present and discuss key studies performed over the last two decades using these compounds and to evaluate, compare and contrast their effectiveness as chemopreventatives and chemotherapeutics. This should provide the reader with an overarching picture of how these structurally similar phytochemicals might be used in both clinical and nonclinical settings, as a part of the ongoing effort by clinicians, to help to slow down the increasing rate of cancers observed over the last few decades.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Berberine; Curcumin; Humans; Neoplasms; Phytochemicals; Resveratrol

The biological activities of four aromatic plants, namely frankincense, myrrh, ginger, and turmeric, were reviewed in the current study. The volatile fraction (essential oil) as well as the nonvolatile fraction of these four plants showed different promising biological activities that are displayed in detail. These activities can include protection from and/or alleviation of some ailment, which is supported with different proposed mechanisms of action. This review aimed to finally help researchers to get a handle on the importance of considering these selected aromatic plants, which have not been thoroughly reviewed before, as a potential adjuvant to classical synthetic drugs to enhance their efficiency. Moreover, the results elicited in this review encourage the consumption of these medicinal plants as an integrated part of the diet to boost the body's overall health based on scientific evidence.

Topics: Animals; Curcuma; Curcumin; Frankincense; Humans; Neoplasms; Oils, Volatile; Zingiber officinale

In recent decades, cancer has been one of the leading causes of death worldwide. Despite advances in understanding the molecular basis of tumorigenesis, diagnosis, and clinical therapies, the discovery and development of effective drugs is an active and vital field in cancer research. Tetrahydrocurcumin is a major curcuminoid metabolite of curcumin, naturally occurring in turmeric. The interest in tetrahydrocurcumin research is increasing because it is superior to curcumin in its solubility in water, chemical stability, bioavailability, and anti-oxidative activity. Many in vitro and in vivo studies have revealed that tetrahydrocurcumin exerts anti-cancer effects through various mechanisms, including modulation of oxidative stress, xenobiotic detoxification, inflammation, proliferation, metastasis, programmed cell death, and immunity. Despite the pharmacological similarities between tetrahydrocurcumin and curcumin, the structure of tetrahydrocurcumin determines its distinct and specific molecular mechanism, thus making it a potential candidate for the prevention and treatment of cancers. However, the utility of tetrahydrocurcumin is yet to be evaluated as only limited pharmacokinetic and oral bioavailability studies have been performed. This review summarizes research on the anti-cancer properties of tetrahydrocurcumin and describes its mechanisms of action.

Topics: Antineoplastic Agents; Curcumin; Humans; Neoplasms

Dealing with cancer is of importance due to enhanced incidence rate of this life-threatening disorder. Chemotherapy is an ideal candidate in overcoming and eradication of cancer. To date, various chemotherapeutic agents have been applied in cancer therapy and paclitaxel (PTX) is one of them. PTX is a key member of taxane family with potential anti-tumor activity against different cancers. Notably, PTX has demonstrated excellent proficiency in elimination of cancer in clinical trials. This chemotherapeutic agent is isolated from Taxus brevifolia, and is a tricyclic diterpenoid. However, resistance of cancer cells into PTX chemotherapy has endangered its efficacy. Besides, administration of PTX is associated with a number of side effects such as neurotoxicity, hepatotoxicity, cardiotoxicity and so on, demanding novel strategies in obviating PTX issues. Curcumin is a pharmacological compound with diverse therapeutic effects including anti-tumor, anti-oxidant, anti-inflammatory, anti-diabetic and so on. In the current review, we demonstrate that curcumin, a naturally occurring nutraceutical compound is able to enhance anti-tumor activity of PTX against different cancers. Besides, curcumin administration reduces adverse effects of PTX due to its excellent pharmacological activities. These topics are discussed with an emphasis on molecular pathways to provide direction for further studies in revealing other signaling networks.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Curcumin; Humans; Neoplasms; Paclitaxel

Curcumin is herbal compound that has been shown to have anti-cancer effects in pre-clinical and clinical studies. The anti-cancer effects of curcumin include inhibiting the carcinogenesis, inhibiting angiogenesis, and inhibiting tumour growth. This study aims to determine the Clinical effects of curcumin in different types of cancers using systematic review approach.. A systematic review methodology is adopted for undertaking detailed analysis of the effects of curcumin in cancer therapy. The results presented in this paper is an outcome of extracting the findings of the studies selected from the articles published in international databases including SID, MagIran, IranMedex, IranDoc, Google Scholar, ScienceDirect, Scopus, PubMed and Web of Science (ISI). These databases were thoroughly searched, and the relevant publications were selected based on the plausible keywords, in accordance with the study aims, as follows: prevalence, curcumin, clinical features, cancer.. The results are derived based on several clinical studies on curcumin consumption with chemotherapy drugs, highlighting that curcumin increases the effectiveness of chemotherapy and radiotherapy which results in improving patient's survival time, and increasing the expression of anti-metastatic proteins along with reducing their side effects.. The comprehensive systematic review presented in this paper confirms that curcumin reduces the side effects of chemotherapy or radiotherapy, resulting in improving patients' quality of life. A number of studies reported that, curcumin has increased patient survival time and decreased tumor markers' level.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Chemoradiotherapy; Curcumin; Drug-Related Side Effects and Adverse Reactions; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Oxidative Stress; Quality of Life; Radiation Injuries

Curcumin has attracted much attention for medicinal purposes in wide range of illnesses including cancer. In some studies, its efficacy is evaluated against chemotherapy and radiotherapy induced adverse reaction and also as adjuvant to cancer treatment. Here we have tried to present a comprehensive review on protective and therapeutic effect of curcumin against these side effects. METHOD: The data were collected by searching Scopus, PubMed, Medline, and Cochrane database systematic reviews, using key words "nephrotoxicity", "cardiotoxicity", "genotoxicity", "ototoxicity", "hepatotoxicity", "reproductive toxicity", "myelosuppression", "pulmonary toxicity", "radiotherapy induced side effect" with "turmeric" and "curcumin". Although curcumin has low bioavailability, it has shown brilliant profile on prevention and management of chemotherapy and radiotherapy induced adverse reactions, particularly based on in vitro and in vivo studies and limited number of human studies on radiotherapy adverse reactions. Antioxidant and anti-inflammatory properties of the curcumin are the main proposed mechanism of action for management and prevention of adverse reactions. One of the major points regarding the protective effect of curcumin is its wide tolerable therapeutic range of dose with minimal side effects. Furthermore, new nano-formulations help to improve the bioavailability, increase in efficacy and lower the adverse effects. In conclusion, based on the present knowledge, curcumin has significant supportive potential in patients receiving chemotherapy or radiotherapy and may be suggested as adjutant with cancer treatments. Further well-designed human studies are recommended.

Topics: Animals; Anti-Inflammatory Agents; Curcuma; Curcumin; Drug-Related Side Effects and Adverse Reactions; Humans; Neoplasms; Plant Extracts; Radiotherapy

Most data published on curcumin and curcumin-based formulations are very promising. In cancer research, the majority of data has been obtained in vitro. Less frequently, researchers used experimental animals. The results of several clinical studies are conclusive, and these studies have established a good foundation for further research focusing on implementing curcumin in clinical oncology. However, the issues regarding timely data reporting and lack of disclosure of the exact curcumin formulations used in these studies should not be neglected. This article is a snapshot of the current status of publicly available data on curcumin clinical trials and a detailed presentation of results obtained so far with some curcumin formulations. Phenomena related to the observed effects of curcumin shown in clinical trials are presented, and its modifying effect on gut microbiota and metabolic reprogramming is discussed. Based on available data, there is a strong indication that curcumin and its metabolites present molecules that do not necessarily need to be abundant in order to act locally and benefit systemically. Future clinical studies should be designed in a way that will take that fact into consideration.

Topics: Animals; Antineoplastic Agents; Biological Availability; Clinical Trials as Topic; Curcumin; Gastrointestinal Microbiome; Humans; Interleukin-17; Medical Oncology; National Institutes of Health (U.S.); Neoplasms; Nicotinamide N-Methyltransferase; Precision Medicine; Translational Research, Biomedical; United States

There is compelling evidence that drug molecules isolated from natural sources are hindered by low systemic bioavailability, poor absorption, and rapid elimination from the human body. Novel approaches are urgently needed that could enhance the retention time as well as the efficacy of natural products in the body. Among the various adopted approaches to meet this ever-increasing demand, nanoformulations show the most fascinating way of improving the bioavailability of dietary phytochemicals through modifying their pharmacokinetics and pharmacodynamics. Curcumin, a yellowish pigment isolated from dried ground rhizomes of turmeric, exhibits tremendous pharmacological effects, including anticancer activities. Several in vitro and in vivo studies have shown that curcumin mediates anticancer effects through the modulation (upregulation and/or downregulations) of several intracellular signaling pathways both at protein and mRNA levels. Scientists have introduced multiple modern techniques and novel dosage forms for enhancing the delivery, bioavailability, and efficacy of curcumin in the treatment of various malignancies. These novel dosage forms include nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles. Nanocurcumin has shown improved anticancer effects compared to conventional curcumin formulations. This review discusses the underlying molecular mechanism of various nanoformulations of curcumin for the treatment of different cancers. We hope that this study will make a road map for preclinical and clinical investigations of cancer and recommend nano curcumin as a drug of choice for cancer therapy.

Topics: Biological Availability; Curcumin; Humans; Micelles; Nanoparticles; Neoplasms

Free radicals, generally composed of reactive oxygen species (ROS) and reactive nitrogen species (RNS), are generated in the body by various endogenous and exogenous systems. The overproduction of free radicals is known to cause several chronic diseases including cancer. However, increased production of free radicals by chemotherapeutic drugs is also associated with apoptosis in cancer cells, indicating the dual nature of free radicals. Among various natural compounds, curcumin manifests as an antioxidant in normal cells that helps in the prevention of carcinogenesis. It also acts as a prooxidant in cancer cells and is associated with inducing apoptosis. Curcumin quenches free radicals, induces antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase), and upregulates antioxidative protein markers-Nrf2 and HO-1 that lead to the suppression of cellular oxidative stress. In cancer cells, curcumin aggressively increases ROS that results in DNA damage and subsequently cancer cell death. It also sensitizes drug-resistant cancer cells and increases the anticancer effects of chemotherapeutic drugs. Thus, curcumin shows beneficial effects in prevention, treatment and chemosensitization of cancer cells. In this review, we will discuss the dual role of free radicals as well as the chemopreventive and chemotherapeutic effects of curcumin and its analogues against cancer.

Topics: Animals; Antineoplastic Agents; Antioxidants; Curcumin; Free Radicals; Humans; Neoplasms; Reactive Oxygen Species

Traditional chemotherapy is being considered due to hindrances caused by systemic toxicity. Currently, the administration of multiple chemotherapeutic drugs with different biochemical/molecular targets, known as combination chemotherapy, has attained numerous benefits like efficacy enhancement and amelioration of adverse effects that has been broadly applied to various cancer types. Additionally, seeking natural-based alternatives with less toxicity has become more important. Experimental evidence suggests that herbal extracts such as Solanum nigrum and Claviceps purpurea and isolated herbal compounds (e.g., curcumin, resveratrol, and matairesinol) combined with antitumoral drugs have the potential to attenuate resistance against cancer therapy and to exert chemoprotective actions. Plant products are not free of risks: Herb adverse effects, including herb-drug interactions, should be carefully considered. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.

Topics: Curcumin; Dietary Supplements; Humans; Neoplasms

Complementary and alternative medicine (CAM) plays a critical role in treating cancer patients. Traditional Chinese Medicine (TCM) is the main component of CAM. TCM, especially Chinese Herbal Medicine (CHM), has been increasingly used in China, some other Asian countries and European countries. It has been proven to enhance the efficacy of chemotherapy, radiotherapy, targeted-therapy, and immunotherapy. It lessens the damage caused by these therapies. CHM functions on cancer by inhibiting tumor progression and improving an organism's immune system. Increasing evidence has shown that many CHM exert favorable effects on the immune regulation. We will summarize the role of CHM on patient's immune system when treating cancer patients. Our evidence reveals that single herbs, including their extracts, compound formulations, and preparations, will provide current advances on CHM study, especially from the perspective of immune regulation and novel insights for CHM application in clinic. The main herbs used to treat cancer patients are health-strengthening (

Topics: Angelica sinensis; Astragalus propinquus; Curcuma; Drug Compounding; Drugs, Chinese Herbal; Humans; Lycium; Neoplasms; Panax; Phytotherapy; Plant Extracts; Polyporaceae; Scutellaria; Tumor Microenvironment

Inhibitors of the ubiquitin-proteasome system (UPS) have been the object of research interests for many years because of their potential as anti-cancer agents. Research in this field is aimed at improving the specificity and safety of known proteasome inhibitors. Unfortunately, in vitro conditions do not reflect the processes taking place in the human body. Recent reports indicate that the components of human plasma affect the course of many signaling pathways, proteasome activity and the effectiveness of synthetic cytostatic drugs. Therefore, it is believed that the key issue is to determine the effects of components of the human diet, including effects of chemically active polyphenols on the ubiquitin-proteasome system activity in both physiological and pathological (cancerous) states. The following article summarizes the current knowledge on the direct and indirect synergistic and antagonistic effects between polyphenolic compounds present in the human diet and the efficiency of protein degradation via the UPS.

Topics: Animals; Diet; Humans; Neoplasms; Phenols; Polyphenols; Proteasome Endopeptidase Complex; Ubiquitin

Inflammation is a biological function which triggered after the mechanical tissue disruption or from the responses by the incidence of physical, chemical or biological negotiator in body. These responses are essential act provided by the immune system during infection and tissue injury to maintain normal tissue homeostasis. Inflammation is a quite complicated process at molecular level with the involvement of several proinflammatory expressions. Several health problems are associated with prolonged inflammation, which effects nearly all major to minor diseases. The molecular and epidemiological studies jagged that the inflammation is closely associated with several disorders with their specific targets. It would be great achievement for human health around the world to overcome on inflammation. Mostly used anti-inflammatory drugs are at high risk of side effects and also expensive. Hence, the plant-based formulations gained a wide acceptance by the public and medical experts to treat it. Due to extensive dispersal, chemical diversity and systematically established biological potentials of natural products have induced renewed awareness as a gifted source for medications. However, today's urgent need to search for cheaper, more potent and safe anti-inflammatory medications to overcome on current situation. The goal of this review to compile an update on inflammation, associated diseases, molecular targets, inflammatory mediators and role of natural products. The entire text concise the involvement of various cytokines in pathogenesis of various human disorders. This assignment discussed about 321 natural products with their promising anti-inflammatory potential discovered during January 2009 to December 2018 with 262 citations.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Biological Products; Cardiovascular Diseases; Humans; Inflammation; Neoplasms; Skin Diseases

Curcumin (CU), an edible natural pigment from Curcuma Longa, has demonstrated extensive anti-tumor effect in vivo and in vitro. With the property of reversing drug resistance and low toxicity, CU has been considered to develop a new adjuvant chemotherapy protocol of cancer. However, the poor stability, solubility, in vivo bioavailability and weak activity of CU greatly limit its clinical application. Therefore, CU analogues have been extensively studied. Starting from the study of natural CU analogues, multiple approaches are being sought to obtain more stable, soluble and effective analogues of CU. This review focuses on the progress of these approaches to more potent CU analogues.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Proliferation; Curcumin; Humans; Neoplasms

Curcumin is a natural substance known for ages, exhibiting a multidirectional effect in cancer prevention and adjuvant cancer therapies. The great advantage of using nutraceuticals of vegetable origin in comparison to popular cytostatic drugs is the minimized side effect and reduced toxicity. The targets in oncological therapy are, among others, tyrosine kinases, important mediators of signaling pathways whose impaired expression is observed in many types of cancer. Unfortunately, the hydrophobic nature of the curcumin molecule often limits its bioavailability, which is why many studies focus on the chemical modification of this compound. Current research is aimed at modifying structures that improve the pharmacokinetic parameters of curcumin, e.g. the formation of nanoparticles, complexes with metals or the synthesis of curcumin derivatives with functional substituents that allow tumor targeting. The article is a review and analysis of current literature on the properties of curcumin and its derivatives in the treatment of cancers directed to signaling pathways of tyrosine kinases and confronts the problem of low assimilation of curcumin with potential therapeutic effects.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Proliferation; Curcumin; Humans; Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases

Curcumin is a small organic molecule with pleiotropic biological activities. However, its multiple structural-pharmacokinetic challenges prevent its development into a clinical drug. Various structural modifications have been made to improve its drug profile. In this review, we focus on the methods adopted in the synthesis of asymmetric curcumin derivatives and their biological activities and forecast the future of this exciting class of compounds in the field of medicine.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Curcumin; Humans; Molecular Structure; Neoplasms

Curcumin, a polyphenol extracted from

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biological Availability; Cell Proliferation; Curcumin; Humans; Neoplasms; Signal Transduction; Treatment Outcome

Curcumin is a naturally occurring polyphenol isolated from Curcuma longa that has various pharmacological activities, including, anti-inflammatory, anti-oxidant and anti-cancer properties. The anticancer effect of curcumin is attributed to activation of apoptotic pathways in cancer cells, as well as inhibition of inflammation and angiogenesis in the tumour microenvironment and suppression of tumour metastasis. Angiogenesis, which is the formation of new blood vessels from pre-existing ones, is a fundamental step in tumour growth and expansion. Several reports have demonstrated that curcumin inhibits angiogenesis in a wide variety of tumour cells through the modulation of various cell signaling pathways which involve transcription factors, protein kinases, growth factors and enzymes. This review provides an updated summary of the various pathways and molecular targets that are regulated by curcumin to elicit its anti-angiogenic activity.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Curcumin; Humans; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Treatment Outcome

Curcumin (diferuloylmethane), a yellowish agent extracted from turmeric, is a bioactive compound known for its anti-inflammatory, antiproliferative, antidiabetic, and anticancer activities. Multiple lines of evidence have indicated that curcumin regulates several regulatory proteins in the cellular signal transduction pathway. AMP-activated protein kinase (AMPK) is one of the central regulators of cellular metabolism and energy homeostasis, which is activated in response to increasing cellular adenosine monophosphate/adenosine triphosphate ratio. AMPK plays a critical role in regulating growth and reprogramming metabolism and is linked to several cellular processes including apoptosis and inflammation. Recently, it has been demonstrated that AMPK is a new molecular target affected by curcumin and its derivatives. In this review, we discuss recent findings on the targeting of AMPK signaling by curcumin and the resulting impact on the pathogenesis of proinflammatory diseases. We also highlight the therapeutic value of targeting AMPK by curcumin in the prevention and treatment of proinflammatory diseases, including cancers, atherosclerosis, and diabetes.

Topics: AMP-Activated Protein Kinases; Apoptosis; Curcumin; Diabetes Mellitus; Energy Metabolism; Humans; Inflammation; Neoplasms

Autophagy is a self-degradative process that plays a pivotal role in several medical conditions associated with infection, cancer, neurodegeneration, aging, and metabolic disorders. Its interplay with cancer development and treatment resistance is complicated and paramount for drug design since an autophagic response can lead to tumor suppression by enhancing cellular integrity and tumorigenesis by improving tumor cell survival. In addition, autophagy denotes the cellular ability of adapting to stress though it may end up in apoptosis activation when cells are exposed to a very powerful stress. Induction of autophagy is a therapeutic option in cancer and many anticancer drugs have been developed to this aim. Curcumin as a hydrophobic polyphenol compound extracted from the known spice turmeric has different pharmacological effects in both in vitro and in vivo models. Many reports exist reporting that curcumin is capable of triggering autophagy in several cancer cells. In this review, we will focus on how curcumin can target autophagy in different cellular settings that may extend our understanding of new pharmacological agents to overcome relevant diseases.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Autophagy-Related Proteins; Curcumin; Humans; Neoplasms; Signal Transduction

Cancer is the second cause of death worldwide. Chemotherapy and radiotherapy are the most common modalities for the treatment of cancer. Experimental studies have shown that inflammation plays a central role in tumor resistance and the incidence of several side effects following both chemotherapy and radiotherapy. Inflammation resulting from radiotherapy and chemotherapy is responsible for adverse events such as dermatitis, mucositis, pneumonitis, fibrosis, and bone marrow toxicity. Chronic inflammation may also lead to the development of second cancer during years after treatment. A number of anti-inflammatory drugs such as nonsteroidal anti-inflammatory agents have been proposed to alleviate chronic inflammatory reactions after radiotherapy or chemotherapy. Curcumin is a well-documented herbal anti-inflammatory agents. Studies have proposed that curcumin can help management of inflammation during and after radiotherapy and chemotherapy. Curcumin targets various inflammatory mediators such as cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor κB (NF-κB), thereby attenuating the release of proinflammatory and profibrotic cytokines, and suppressing chronic production of free radicals, which culminates in the amelioration of tissue toxicity. Through modulation of NF-κB and its downstream signaling cascade, curcumin can also reduce angiogenesis, tumor growth, and metastasis. Low toxicity of curcumin is linked to its cytoprotective effects in normal tissues. This protective action along with the capacity of this phytochemical to sensitize tumor cells to radiotherapy and chemotherapy makes it a potential candidate for use as an adjuvant in cancer therapy. There is also evidence from clinical trials suggesting the potential utility of curcumin for acute inflammatory reactions during radiotherapy such as dermatitis and mucositis.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Curcumin; Drug-Related Side Effects and Adverse Reactions; Humans; Inflammation Mediators; Neoplasms; Radiation Injuries; Radiation-Protective Agents; Radiotherapy; Risk Factors; Signal Transduction

A huge surge of research is being conducted on combination therapy with anticancer compounds formulated in the form of nanoparticles (NPs). Numerous advantages like dose minimalization and synergism, reversal of multi drug resistance (MDRs), enhanced efficacy have emerged with nanoencapsulation of chemotherapeutic agents with chemo-sensitizing agent like curcumin. Within last couple of years various nano-sized formulations have been designed and tested both in vitro with cell lines for different types of cancers and in vivo with cancer types and drug resistance models. Despite the combinatorial models being advanced, translation to human trials has not been as smooth as one would have hoped, with as few as twenty ongoing clinical trials with curcumin combination, with less than 1/10th being nano-particulate formulations. Mass production of nano-formulation based on their physico-chemical and pharmacokinetics deficits poses as major hurdle up the ladder. Combination of these nano-sized dosage with poorly bioavailable drugs, unspecific target binding ability and naturally unstable curcumin further complicates the formulation aspects. Emphasis is now therefore being laid on altering natural forms of curcumin and usage of formulations like prodrug or coating of curcumin to overcome stability issues and focus more on enhancing the pharmaceutical and therapeutic ability of the nano-composites. Current studies and futuristic outlook in this direction are discussed in the review, which can serve as the basis for upcoming research which could boost commercial translational of improved nano-sized curcumin combination chemotherapy.

Topics: Animals; Antineoplastic Agents; Curcumin; Drug Combinations; Humans; Nanomedicine; Nanoparticles; Neoplasms

Cancer incidences are growing and cause millions of deaths worldwide. Cancer therapy is one of the most important challenges in medicine. Improving therapeutic outcomes from cancer therapy is necessary for increasing patients' survival and quality of life. Adjuvant therapy using various types of antibodies or immunomodulatory agents has suggested modulating tumor response. Resistance to apoptosis is the main reason for radioresistance and chemoresistance of most of the cancers, and also one of the pivotal targets for improving cancer therapy is the modulation of apoptosis signaling pathways. Apoptosis can be induced by intrinsic or extrinsic pathways via stimulation of several targets, such as membrane receptors of tumor necrosis factor-α and transforming growth factor-β, and also mitochondria. Curcumin is a naturally derived agent that induces apoptosis in a variety of different tumor cell lines. Curcumin also activates redox reactions within cells inducing reactive oxygen species (ROS) production that leads to the upregulation of apoptosis receptors on the tumor cell membrane. Curcumin can also upregulate the expression and activity of p53 that inhibits tumor cell proliferation and increases apoptosis. Furthermore, curcumin has a potent inhibitory effect on the activity of NF-κB and COX-2, which are involved in the overexpression of antiapoptosis genes such as Bcl-2. It can also attenuate the regulation of antiapoptosis PI3K signaling and increase the expression of MAPKs to induce endogenous production of ROS. In this paper, we aimed to review the molecular mechanisms of curcumin-induced apoptosis in cancer cells. This action of curcumin could be applicable for use as an adjuvant in combination with other modalities of cancer therapy including radiotherapy and chemotherapy.

Topics: Animals; Apoptosis; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Neoplasms

Curcumin is a multifunctional phytochemical that has documented anti-oxidant, anti-inflammatory and anti-tumor properties. The anti-tumor effect of curcumin has been widely investigated, both as a single ingredient and in combination with chemotherapeutic agents. Oxaliplatin is a third-generation platinum agent with established effectiveness in multiple malignancies including gastroesophageal, colorectal, pancreas, ovarian, breast and head and neck cancers. The effects of curcumin and its synthetic analogues in combination with oxaliplatin have been studied in a variety of malignant cell lines in vitro and in vivo, providing evidence supporting the beneficial effects of curcumin as an adjunct to oxaliplatin, though dose, combination ratio and the timing of exposure to the agents are covariates that may affect the therapeutic efficacy and need to be determined. This review provides a summary of the studies investigating the effects of curcumin and its analogues, as adjuvants to oxaliplatin treatment in malignant cell lines and experimental tumor models. Addition of curcumin as an adjunct to oxaliplatin enhances oxaliplatin's toxicity in malignant cells, which potentially allows an oxaliplatin dose reduction and decreasing the adverse effects of chemotherapy. Curcumin has also been studied in several nonmalignant cell types and has been shown to exert cytoprotective properties against oxaliplatin's off-target toxicities. Despite all of the promising evidence to date, there is a scarcity of supportive evidence from clinical trials on the adjuvant use of curcumin, which needs future translational and clinical studies.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Curcumin; Drug Synergism; Humans; Neoplasms; Oxaliplatin

Monocytes and macrophages are important cells of the innate immune system that have diverse functions, including defense against invading pathogens, removal of dead cells by phagocytosis, antigen presentation in the context of MHC class I and class II molecules, and production of various pro-inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1. In addition, pro-inflammatory (M1) and anti-inflammatory (M2) macrophages clearly play important roles in the progression of several inflammatory diseases. Therefore, therapies that target macrophage polarization and function by either blocking their trafficking to sites of inflammation, or skewing M1 to M2 phenotype polarization may hold clinical promise in several inflammatory diseases. Dietary-derived polyphenols have potent natural anti-oxidative properties. Within this group of polyphenols, curcumin has been shown to suppress macrophage inflammatory responses. Curcumin significantly reduces co-stimulatory molecules and also inhibits MAPK activation and the translocation of NF-κB p65. Curcumin can also polarize/repolarize macrophages toward the M2 phenotype. Curcumin-treated macrophages have been shown to be highly efficient at antigen capture and endocytosis via the mannose receptor. These novel findings provide new perspectives for the understanding of the immunopharmacological role of curcumin, as well as its therapeutic potential for impacting macrophage polarization and function in the context of inflammation-related disease. However, the precise effects of curcumin on the migration, differentiation, polarization and immunostimulatory functions of macrophages remain unknown. Therefore, in this review, we summarized whether curcumin can influence macrophage polarization, surface molecule expression, cytokine and chemokine production and their underlying pathways in the prevention of inflammatory diseases.

Topics: Alzheimer Disease; Animals; Antigen Presentation; Atherosclerosis; Cell Movement; Cell Polarity; Curcumin; Cytokines; Diet; Humans; Immunologic Factors; Infections; Liver Cirrhosis; Macrophages; Neoplasms; Obesity

Effective drug delivery is one of the most important issues associated with the administration of therapeutic agents that have low oral bioavailability. Curcumin is an active ingredient in the turmeric plant, which has low oral bioavailability due to its poor aqueous solubility. One strategy that has been considered for enhancing the aqueous solubility, and, thus, its oral bioavailability, is the use of chitosan as a carrier for curcumin. Chitosan is a biodegradable and biocompatible polymer that is relatively water-soluble. Therefore, various studies have sought to improve the aqueous solubility of chitosan. The use of different pharmaceutical excipients and formulation strategies has the potential to improve aqueous solubility, formulation processing, and the overall delivery of hydrophobic drugs. This review focuses on various methods utilized for chitosan-based delivery of curcumin.

Topics: Animals; Biological Availability; Chitosan; Curcumin; Drug Carriers; Humans; Nanoparticles; Neoplasms

Cancer is considered a fetal disease caused by uncontrolled proliferation and progression of abnormal cells. The most efficient cancer therapies suppress tumor growth, prevent progression and metastasis, and are minimally toxic to normal cells. Natural compounds have shown a variety of chemo-protective effects alone or in combination with standard cancer therapies. Along with better understanding of the dynamic interactions between our immune system and cancer development, nutritional immunology-the use of natural compounds as immunomodulators in cancer patients-has begun to emerge. Cancer cells evolve strategies that target many aspects of the immune system to escape or even edit immune surveillance. Therefore, the immunesuppressive tumor microenvironment is a major obstacle in the development of cancer therapies. Because interaction between the tumor microenvironment and the immune system is a complex topic, this review focuses mainly on human clinical trials and animal studies, and it highlights specific immune cells and their cytokines that have been modulated by natural compounds, including carotenoids, curcumin, resveratrol, EGCG, and β-glucans. These natural compounds have shown promising immune-modulating effects, such as inhibiting myeloid-derived suppressor cells and enhancing natural killer and cytolytic T cells, in tumor-bearing animal models, but their efficacy in cancer patients remains to be determined.

Topics: Animals; beta-Glucans; Carotenoids; Catechin; Curcumin; Humans; Immune System; Immunologic Factors; Killer Cells, Natural; Mice; Neoplasms; Resveratrol; T-Lymphocytes; Tretinoin; Tumor Microenvironment

Cancer is the second leading cause of death in the world and one of the major public health problems. Despite the great advances in cancer therapy, the incidence and mortality rates of cancer remain high. Therefore, the quest for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Curcumin, the active ingredient of the

Topics: Animals; Antineoplastic Agents; Curcumin; Drug Delivery Systems; Humans; Molecular Targeted Therapy; Neoplasms; Structure-Activity Relationship

The aim of this study was to evaluate the effects of turmeric and curcumin in the management of oral mucositis in cancer patients undergoing chemo and/or radiotherapy. The systematic review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses. The search was performed in the following database: Cochrane Library, LILACS, LIVIVO, PubMed, Scopus, and Web of Science. A gray literature search was undertaken using Google Scholar, Open Grey, and ProQuest. The methodology of included studies was evaluated by the Meta-Analysis of Statistics Assessment and Review Instrument. After a two-step selection process, four randomized and one nonrandomized clinical trials were included in the analysis. Two studies were categorized as low and three as moderate risk of bias. Turmeric/curcumin was applied topically as a gel or as a mouthwash. Patients treated with turmeric/curcumin experienced reduced grade of mucositis, pain, erythema intensity, and ulcerative area. Current evidence suggests that topical application of turmeric or curcumin is effective in controlling signs and symptoms of oral mucositis. Thus, further investigation is required to confirm the promising effect of turmeric and curcumin in oral inflammatory lesions.

Topics: Curcuma; Curcumin; Humans; Neoplasms; Stomatitis

Pleiotropic effects of curcumin have been the subject of intensive research. The interest in this molecule for preventive medicine may further increase because of its potential to modulate inflamm-aging. Although direct data related to its effect on inflamm-aging does not exist, there is a strong possibility that its well-known anti-inflammatory properties may be relevant to this phenomenon. Curcumin's binding to various proteins, which was shown to be dependent on cellular oxidative status, is yet another feature for exploration in depth. Finally, the binding of curcumin to various metabolic enzymes is crucial to curcumin's interference with powerful metabolic machinery, and can also be crucial for metabolic reprogramming of cancer cells. This review offers a synthesis and functional links that may better explain older data, some observational, in light of the most recent findings on curcumin. Our focus is on its modes of action that have the potential to alleviate specific morbidities of the 21st century.

Topics: Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Curcuma; Curcumin; Humans; Inflammation; Neoplasms; Oxidative Stress

Thioredoxin reductase (TrxR) participates in the regulation of redox reactions in organisms. It works mainly via its substrate molecule, thioredoxin, to maintain the redox balance and regulate signal transduction, which controls cell proliferation, differentiation, death, and other important physiological processes. In recent years, increasing evidence has shown that the overactivation of TrxR is related to the development of tumors. The exploration of TrxR-targeted antitumor drugs has attracted wide attention and is expected to provide new therapies for cancer treatment. In this perspective, we highlight the specific relationship between TrxR and apoptotic signaling pathways. The cytoplasm and mitochondria both contain TrxR, resulting in the activation of apoptosis. TrxR activity influences reactive oxygen species (ROS) and further regulates the inflammatory signaling pathway. In addition, we discuss representative TrxR inhibitors with anticancer activity and analyze the challenges in developing TrxR inhibitors as anticancer drugs.

Topics: Antineoplastic Agents; Apoptosis; Biological Products; Curcumin; Enzyme Inhibitors; Humans; Molecular Targeted Therapy; Neoplasms; Thioredoxin-Disulfide Reductase; Thioredoxins

The current study aimed to provide a comprehensive bibliometric overview of the literature on curcumin, complementing the previous reviews and meta-analyses on its potential health benefits. Bibliometric data for the current analysis were extracted from the Web of Science Core Collection database, using the search string TOPIC=("curcumin*"), and analyzed by the VOSviewer software. The search yielded 18,036 manuscripts. The ratio of original articles to reviews was 10.4:1. More than half of the papers have been published since 2014. The major contributing countries were the United States, China, India, Japan, and South Korea. These publications were mainly published in journals representing the following scientific disciplines: biochemistry, chemistry, oncology, and pharmacology. There was a significant positive correlation between the total publication count and averaged citations per manuscript for affiliations, but not for countries/regions and journals. Chemicals that were frequently mentioned in the keywords of evaluated curcumin publications included curcuminoids, resveratrol, chitosan, flavonoids, quercetin, and polyphenols. The literature mainly focused on curcumin's effects against cancer, inflammation, and oxidative stress. Cancer types most frequently investigated were breast, colon, colorectal, pancreatic, and prostate cancers.

Topics: Bibliometrics; Curcumin; Data Mining; Humans; Neoplasms; Software

Epithelial-to-mesenchymal transition (EMT) is involved in tumor progression, invasion, migration and metastasis. EMT is a process by which polarized epithelial cells acquire motile mesothelial phenotypic features. This process is initiated by disassembly of cell-cell contacts through the loss of epithelial markers and replacement of these markers by mesenchymal markers. Reconstruction of the cytoskeleton and degradation of the tumor basement membrane ensures the spread of invasive malignant tumor cells to distant locations. Accumulating evidence indicates that curcumin, as a well-known phytochemical, can inhibit EMT/metastasis through various mechanisms and pathways in human tumors.. In this review, we summarize the mechanisms by which curcumin may affect EMT in cells under pathological conditions to understand its potential as a novel anti-tumor agent. Curcumin can exert chemo-preventive effects by inhibition and reversal of the EMT process through both TGF-β-dependent (e.g. in hepatoma and retinal pigment epithelial cancer) and -independent (e.g. in oral cancer, colorectal cancer, pancreatic cancer, hepatocellular carcinoma, breast cancer, melanoma, prostate cancer, bladder cancer, thyroid cancer and lung cancer) pathways. Curcumin can also mitigate chemoresistance through EMT suppression and promotion of the antiproliferative effects of conventional chemotherapeutics. Therefore, curcumin has the potential to be used as a novel adjunctive agent to prevent tumor metastasis, which may at least partly be attributed to its hampering of the EMT process.

Topics: Animals; Curcumin; Epithelial-Mesenchymal Transition; Humans; Neoplasms; Retinal Pigment Epithelium

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Antioxidants; Cell Line, Tumor; Cell Survival; Clinical Studies as Topic; Curcumin; Drug Evaluation, Preclinical; Drug Interactions; Energy Metabolism; Humans; Neoplasms; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Treatment Outcome

Curcumin [(1E,6E)‑1,7‑bis(4‑hydroxy‑3‑-methoxyphenyl) hepta‑1,6‑diene‑3,5‑dione] is a natural polyphenol that is derived from the turmeric plant (curcuma longa L.). Curcumin is widely used in food coloring, preservatives, and condiments. Curcumin possesses anti‑tumor, anti‑oxidative and anti‑inflammatory efficacy, as well as other pharmacological effects. Emerging evidence indicates that curcumin alters microRNAs (miRNAs) and long non‑coding RNAs (lncRNAs) in various types of cancers. Both miRNAs and lncRNAs are non‑coding RNAs that can epigenetically modulate the expression of multiple genes via post‑transcriptional regulation. In the present review, the interactions between curcumin and non‑coding RNAs are summarized in numerous types of cancers, including lung, colorectal, prostate, breast, nasopharyngeal, pancreatic, blood, and ovarian cancer, and the vital non‑coding RNAs and their downstream targets are described.

Topics: Animals; Curcumin; Epigenesis, Genetic; Female; Gene Expression Regulation; Gene Regulatory Networks; Humans; Male; MicroRNAs; Neoplasms; RNA, Long Noncoding

Topics: Animals; Autoimmune Diseases; Curcumin; Humans; Hypersensitivity; Inflammatory Bowel Diseases; Neoplasms; Organ Transplantation; Psoriasis; T-Lymphocytes, Helper-Inducer

Cancer metastasis represents a multistep process, including alteration of cell adhesion/motility in the microenvironment and sustained angiogenesis, which is essential for supporting cancer growth in tissues that are distant from the primary tumor. There is growing evidence suggesting that heat shock proteins (HSPs) (also known as heat stress proteins), which constitute a family of stress-inducible proteins, may be involved in the pathogenesis of cancer. Curcumin (diferuloylmethane) is a potent anti-inflammatory, antioxidant, antimicrobial, and antitumor agent. Curcumin has been shown to regulate different members of HSPs including HSP27, HSP40, HSP60, HSP70, and HSP90 in cancer. Here, we present extent findings suggesting that curcumin may act as a potential therapeutic agent for the treatment of cancer through its regulation of HSPs.

Topics: Antineoplastic Agents, Phytogenic; Chaperonin 60; Curcumin; Gene Expression Regulation, Neoplastic; Heat-Shock Proteins; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Lymphatic Metastasis; Mitochondrial Proteins; Molecular Chaperones; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Tumor Microenvironment

Despite significant progressions in treatment modalities over the last decade, either cancer incidence or mortality is continuously on the rise throughout the world. Current anticancer agents display limited efficacy, accompanied by severe side effects. In order to improve therapeutic outcomes in patients with cancer, it is crucial to identify novel, highly efficacious pharmacological agents. Curcumin, a hydrophobic polyphenol extracted from turmeric, has gained increasing attention due to its powerful anticancer properties. Curcumin can inhibit the growth, invasion and metastasis of various cancers. The anticancer mechanisms of curcumin have been extensively studied. The anticancer effects of curcumin are mainly mediated through its regulation of multiple cellular signaling pathways, including Wnt/β-catenin, PI3K/Akt, JAK/STAT, MAPK, p53 and NF-ĸB signaling pathways. Moreover, curcumin also orchestrates the expression and activity of oncogenic and tumor-suppressive miRNAs. In this review, we summarized the regulation of these signaling pathways by curcumin in different cancers. We also discussed the modulatory function of curcumin in the downregulation of oncogenic miRNAs and the upregulation of tumor-suppressive miRNAs. An in-depth understanding of the anticancer mechanisms of curcumin will be helpful for developing this promising compound as a therapeutic agent in clinical management of cancer.

Topics: Antineoplastic Agents; Curcumin; Humans; MicroRNAs; Neoplasms; Signal Transduction

While curcumin has a range of therapeutic benefits, its potent anticancer activity remains an attractive avenue for anticancer research owing to the multifactorial nature of cancer itself. The structure of curcumin has thus been used as a lead to design more potent analogues, and diarylpentanoids in particular have shown improved cytotoxicity over curcumin. Investigations of diarylpentanoids have demonstrated that these compounds exert anti-cancer effects through several signalling pathways that are associated with cancer. This review focuses on selected diarylpentanoids and highlights molecular targets that modulate key pathways involved in cancer such as NF-κB, MAPK/ERK, and STAT signalling. Future research will need to focus on drug interactions to explore potential synergistic actions of diarylpentanoids and further establish the use of diverse animal models.

Topics: Animals; Antineoplastic Agents; Curcumin; Extracellular Signal-Regulated MAP Kinases; Humans; Mitogen-Activated Protein Kinases; Neoplasms; NF-kappa B; Signal Transduction

Many chemotherapeutic drugs have been used for the treatment of cancer, for instance, doxorubicin, irinotecan, 5-fluorouracil, cisplatin, and paclitaxel. However, the effectiveness of chemotherapy is limited in cancer therapy due to drug resistance, therapeutic selectivity, and undesirable side effects. The combination of therapies with natural compounds is likely to increase the effectiveness of drug treatment as well as reduce the adverse outcomes. Curcumin, a polyphenolic isolated from

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Curcumin; Drug Compounding; Drug Evaluation, Preclinical; Drug Synergism; Humans; Neoplasms; Oxidative Stress; Theranostic Nanomedicine; Treatment Outcome

Immune system has critical roles in fighting against several diseases like cancer. Cancer cells evolve several ways to escape from the immune system to remain alive and trigger new phases of cancer progression. Regulatory T cells are one of the key components in tumor immune tolerance and contribute to the evasion of cancer cells from the immune system. Targeting regulatory T cells could provide new horizons in designing and development of effective therapeutic platforms for the treatment of various malignancies. Curcumin is the bioactive pigment of turmeric and a well-known phytochemical with a wide range of pharmacological activities. A growing body of evidence has demonstrated that curcumin affects manifold molecular pathways that are implicated in tumorigenesis and cancer metastasis. In this regard, some studies have indicated that this phytochemical could target regulatory T cells and convert them into T helper 1 cells, which possess anti-tumor effects. On the contrary, curcumin is able to increase the number of regulatory T cells in other conditions such as inflammatory bowel disease. Herein, we describe the anti-cancer roles of curcumin via targeting regulatory T cells. Moreover, we summarize the effects of curcumin on regulatory T cell population in other diseases.

Topics: Animals; Antineoplastic Agents, Phytogenic; Chemotherapy, Adjuvant; Curcumin; Humans; Immunotherapy; Neoplasms; T-Lymphocytes, Regulatory

Numerous studies have presented that curcumin could have a positive effect in the prevention of cancer and then in tumor therapy. Several hypotheses have highlighted that curcumin could decreases tumor growth and invasion by acting on both chronic inflammation and oxidative stress. This review focuses on the interest of use curcumin in cancer therapy by acting on the WNT/β-catenin pathway to repress chronic inflammation and oxidative stress. In the cancer process, one of the major signaling pathways involved is the WNT/β-catenin pathway, which appears to be upregulated. Curcumin administration participates to the downregulation of the WNT/β-catenin pathway and thus, through this action, in tumor growth control. Curcumin act as PPARγ agonists. The WNT/β-catenin pathway and PPARγ act in an opposed manner. Chronic inflammation, oxidative stress and circadian clock disruption are common and co-substantial pathological processes accompanying and promoting cancers. Circadian clock disruption related to the upregulation of the WNT/β-catenin pathway is involved in cancers. By stimulating PPARγ expression, curcumin can control circadian clocks through the regulation of many key circadian genes. The administration of curcumin in cancer treatment would thus appear to be an interesting therapeutic strategy, which acts through their role in regulating WNT/β-catenin pathway and PPARγ activity levels.

Topics: Cell Proliferation; Circadian Clocks; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Neoplasm Invasiveness; Neoplasms; Oxidative Stress; PPAR gamma; Wnt Signaling Pathway

Over the past decades curcuminoids have been extensively studied for their biological activities such as antiulcer, antifibrotic, antiviral, antibacterial, antiprotozoal, antimutagenic, antifertility, antidiabetic, anticoagulant, antivenom, antioxidant, antihypotensive, antihypocholesteremic, and anticancer activities. With the perception of limited toxicity and cost, these compounds forms an integral part of cancer research and is well established as a potential anticancer agent. However, only few studies have focused on the other bioactive molecules of turmeric, known as non-curcuminoids, which are also equally potent as curcuminoids. This review aims to explore the comprehensive potency including the identification, physicochemical properties, and anticancer mechanism inclusive of molecular docking studies of non-curcuminoids such as turmerones, elemene, furanodiene (FN), bisacurone, germacrone, calebin A (CA), curdione, and cyclocurcumin. An insight into the clinical studies of these curcumin-free compounds are also discussed which provides ample evidence that favors the therapeutic potential of these compounds. Like curcuminoids, limited solubility and bioavailability are the most fragile domain, which circumscribe further applications of these compounds. Thus, this review credits the encapsulation of non-curcuminoid components in diverse drug delivery systems such as co-crystals, solid lipid nanoparticles, liposomes, microspheres, polar-non-polar sandwich (PNS) technology, which help abolish their shortcomings and flaunt their ostentatious benefits as anticancer activities.

Topics: Antineoplastic Agents; Curcuma; Drug Carriers; Furans; Heterocyclic Compounds, 2-Ring; Microspheres; Nanoparticles; Neoplasms; Sesquiterpenes

Curcuminoids (CURs), a series of derivatives in turmeric (

Topics: Animals; Antineoplastic Agents; Coordination Complexes; Curcuma; Diarylheptanoids; Drug Development; Drug Discovery; Humans; Neoplasms

Ligustrazine is a main active fraction of the traditional medicine known as Ligusticum chuanxiong hort, which has been used as clinical medication for cerebral thrombosis, coronary heart disease and stenocardia recently. The rapid metabolism and short half-life of ligustrazine seriously limits its application in clinical practice. Therefore, derivatives of ligustrazine are designed and synthesized in our and other labs, including piperazine, cinnamic acid, styrene, acylguanidine, amides, curcumin and triterpenes derivatives of ligustrazine. Most of these compounds present better pharmacodynamics activities and more favorable pharmacokinetic properties compared to the parent compound. Besides, some new biological activities of these compounds are discovered. Hence, this review continues the previous review of our group as well as aims to highlight recent prominent advances in this field in the past ten years.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Bacteria; Cardiovascular Diseases; Humans; Inflammation; Molecular Structure; Neoplasms; Neuroprotective Agents; Pyrazines

Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which is involved in many physiological processes including visual transduction, cell proliferation and differentiation, cell-cycle regulation, gene expression, inflammation, apoptosis, and metabolic function. PDEs are composed of 11 different families and each family contains different subtypes. The distribution, expression, regulation mode and sensitivity to inhibitors of each subtype are different, and they are involved in cancer, inflammation, asthma, depression, erectile dysfunction and other pathological processes of development. A large number of studies have shown that PDEs play an important role in the development of tumors by affecting the intracellular level of cAMP and/or cGMP and PDEs could become diagnostic markers or therapeutic targets. This review will give a brief overview of the expression and regulation of PDE families in the process of tumorigenesis and their anti-tumor inhibitors, which may guide the design of novel therapeutic drugs targeting PDEs for anticancer agent.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neoplasms; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Structure-Activity Relationship

Curcumin is known as a natural dietary polyphenol which is extracted from Curcuma longa L. It has been shown that curcumin has a variety of pharmacological effects such as antioxidant, anti-cancer, anti-inflammatory, and anti-microbial activities. Anti-cancer effects of curcumin are due to targeting of a wide range of cellular and molecular pathways involved in cancer pathogenesis including NF-kB, MAPK, PTEN, P53, and microRNAs (miRNA) network. Multiple lines of evidence have indicated that curcumin exerts its therapeutic effects via regulating miRNA expression (e.g., miR-1, miR-7, miR-9, miR-34a, miR-181, miR-21, and miR-19) which could lead to the regulation of underlying cellular and molecular pathways involved in cancer pathogenesis. Exosomes are one of the important classes of biological vehicles which could be released from various types of cells such as cancer cells and stem cells and could change the behavior of recipient cells. It has been shown that treatment of cancer cells with different dose of curcumin leads to the release of exosomes containing curcumin. These exosomes could induce anti-cancer properties in recipient cells and reduce tumor growth. Hence, exosomes containing curcumin could be applied as powerful tools for cancer treatment. Here, we highlighted various miRNAs which could be affected by curcumin in various types of cancer. Moreover, we highlight exosomes containing curcumin as suitable therapeutic tools in cancer therapy.

Topics: Clinical Trials as Topic; Curcumin; Humans; MicroRNAs; Molecular Targeted Therapy; Neoplasms; Signal Transduction

Histone deacetylases (HDACs) are a group of histone modification enzymes with pivotal role in disease pathogenesis especially in cancer development. Increased activity of certain types of HDACs and positive effects of HDAC inhibition has been shown in several types of cancers. Furthermore, few HDAC inhibitors have been approved by the FDA for cancer treatment, and this has generated interest in finding new HDAC inhibitors as potential anti-cancer agents. Curcumin, a natural polyphenol extracted from turmeric, is a safe and bioactive phytochemical with a wide range of molecular targets and pharmacological activities including promising anti-cancer properties.. A systematic literature search using appropriate keywords was made to identify articles reporting the modulatory effect of curcumin on HDACs in different types of cancer in vitro and in vivo.. HDACs have emerged as novel targets of curcumin that their modulation may contribute to the putative anti-cancer effects of curcumin. Curcumin inhibits HDAC activity, and down-regulates the expression of HDAC types 1, 2, 3, 4, 5, 6, 8 and 11 in different cancer cell lines and mice, while the activity and expression of HDAC2 have been reported to be up-regulated by curcumin in COPD and heart failure models.. Available in vitro and in vivo data are encouraging and in favor of the HDAC inhibitory activity of curcumin but clinical evidence on the efficacy of curcumin as an adjunct treatment in cancer patients is lacking.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Neoplasms

5-Fluorouracil (5-FU) alone or in combination with other therapeutic drugs has been widely used for clinical treatment of various cancers. However, 5-FU-based chemotherapy has limited anticancer efficacy in clinic due to multidrug resistance and dose-limiting cytotoxicity. Some molecules and genes in cancer cells, such as nuclear factor kappa B, insulin-like growth factor-1 receptor, epidermal growth factor receptor, cyclooxygenase-2, signal transducer and activator of transcription 3, phosphatase and tensin homolog deleted on chromosome ten and Bcl-2 etc. are related to the chemoresistance and sensitivity of cancer cells to 5-FU. The activation of these molecules and genes expressions in cancer cells will be increased or decreased with long-term exposure of 5-FU. Curcumin has been found to be able to negatively regulate these processes. In order to overcome the problems of 5-FU, curcumin has been used to combine with 5-FU in cancer therapy.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Curcumin; Fluorouracil; Humans; Neoplasms

Curcumin, a bioactive and pharmacologically efficient component isolated from Curcuma longa has attracted considerable attention because of its ability to modulate diverse cellular and physiological pathways. WNT, TGF/SMAD, NOTCH, and SHH are fundamentally different signaling cascades, but their choreographed activation is strongly associated with cancer development and progression. In this review we have attempted to set spotlight on regulation of different cell signaling pathways by curcumin in different cancers. We partition this multi-component review into in-depth biological understanding of various signal transduction cascades and how curcumin targets intracellular signal transducers of deregulated pathways to inhibit cancer development and progression. Rapidly broadening landscape of both established and candidate oncogenic driver mutations identified in different cancers is a major stumbling block in the standardization of drugs having significant clinical outcome. Intra and inter-tumor heterogeneity had leveraged the complexity of therapeutic challenges to another level. Multi-pronged approach and molecularly guided treatments will be helpful in improving the clinical outcome.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Humans; Mutation; Neoplasm Proteins; Neoplasms; Signal Transduction; Translational Research, Biomedical

Apoptosis, the cell's natural mechanism for death, is a promising target for anticancer therapy. Both the intrinsic and extrinsic pathways use caspases to carry out apoptosis through the cleavage of hundreds of proteins. In cancer, the apoptotic pathway is typically inhibited through a wide variety of means including overexpression of antiapoptotic proteins and under-expression of proapoptotic proteins. Many of these changes cause intrinsic resistance to the most common anticancer therapy, chemotherapy. Promising new anticancer therapies are plant-derived compounds that exhibit anticancer activity through activating the apoptotic pathway.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Carcinogenesis; Caspases; Cell Line, Tumor; Curcumin; Fas Ligand Protein; fas Receptor; Gene Expression Regulation, Neoplastic; Humans; Mice; Molecular Targeted Therapy; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Signal Transduction

Doxorubicin (DOX)-induced toxicity and resistance are major obstacles in chemotherapeutic approaches. Despite effective in the treatment of numerous malignancies, some clinicians have voiced concern that DOX has the potential to cause debilitating consequences in organ tissues, especially the heart. The mechanisms of toxicity and resistance are respectively related to induction of reactive oxygen species (ROS) and up-regulation of ATP-binding cassette (ABC) transporter. Curcumin (CUR) with several biological and pharmacological properties is expected to restore DOX-mediated impairments to tissues. This review is intended to address the current knowledge on DOX adverse effects and CUR protective actions in the heart, kidneys, liver, brain, and reproductive organs. Coadministration of CUR and DOX is capable of ameliorating DOX toxicity pertained to antioxidant, apoptosis, autophagy, and mitochondrial permeability.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Autophagy; Curcumin; Doxorubicin; Drug Interactions; Drug Resistance, Neoplasm; Humans; Neoplasms

Curcumin, a low molecular weight, lipophilic, major yellow natural polyphenolic, and the most well-known plant-derived compound, is extracted from the rhizomes of the turmeric (

Topics: Aging; Arthritis, Rheumatoid; Atherosclerosis; Cardiovascular Diseases; Clinical Trials as Topic; Curcumin; Diabetes Mellitus; Humans; Inflammation; Molecular Structure; Neoplasms; Neurodegenerative Diseases; Osteoporosis

Despite significant advances in treatment modalities, millions of cancer-related deaths continue to occur annually, often as a consequence of developing resistance against the range of available chemotherapeutic drugs. Furthermore, available anti-cancer chemotherapeutic agents show limited efficacy, often have severe side effects, and are expensive. Thus, the discovery of pharmacological agents that do not have these disadvantages is necessary. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa L.), is one such agent that has been widely studied for its anti-inflammatory and/or anti-cancer effects. Curcumin exerts its anti-cancer effect by suppressing the initiation, progression, and metastasis of a variety of cancers and appears to inhibit carcinogenesis by affecting two main processes: angiogenesis and tumor growth. These anti-cancer effects are largely mediated via negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. The PI3K/AKT pathway is commonly activated in cancer initiation and progression. Considered to be the key signaling pathway, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway therefore represents a key target for cancer therapeutics. In the current review, we focus upon curcumin's targeting of PI3K/AKT in different malignancies to effect inhibition of cancer development and progression.

Topics: Apoptosis; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Signal Transduction

The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM) and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS) and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane), a well-known polyphenol derived from the rhizomes of turmeric

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Curcuma; Curcumin; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Immunomodulation; Neoplasms

Curcumin quite possibly represents one of the most diverse therapeutic agents yet isolated from natural sources. Therapeutic benefits of this extraordinary natural compound have been demonstrated during treatment of a variety of diseases, including cancer, inflammatory processes, immunological disorders, Diabetes, and oxidative stress often associated with hyperlipidemia. Due to its unique molecular chemical structure and functional groups, curcumin may bind with and subsequently either inhibit or activate a variety of endogenous biomolecules, including enzymes, receptors, signaling molecules, metals, transcription factors, and even certain proteins located in cell membranes. In fact, curcumin exerts pharmacologically useful effects through non-covalent interactions with biomolecules. With so many varied biological targets, curcumin (a polyphenol) elicits numerous pleiotropic effects, which is therapeutically advantageous owing to the fact that many pathological disease states involve more than one signaling pathway, receptor, protein/enzyme, or gene. In this paper, we will discuss the underlying mechanisms responsible for the chemical interaction of curcumin with selected classes of biomolecules, rather than attempt to provide an exhaustive list of each and every biomolecule with which curcumin may chemically interact.

Topics: Animals; Curcumin; Humans; Hyperlipidemias; Immune System Diseases; Inflammation; Molecular Structure; Neoplasms; Oxidative Stress

Immune dysfunction is caused by various factors, including changes in relevant immune regulators and environmental stress. Immune system imbalance leads to a variety of diseases in humans. Nutrition may play an essential role in immunity by interfering with proinflammatory cytokine synthesis, immune cell regulation, and gene expression. Polyphenols, one of many categories of natural substances, exhibit a range of biological activities. Polyphenols promote immunity to foreign pathogens via various pathways. Different immune cells express multiple types of polyphenol receptors that recognise and allow cellular uptake of polyphenols, which subsequently activate signalling pathways to initiate immune responses. Furthermore, the polyphenols curcumin and epigallocatechin gallate can induce epigenetic changes in cells. In summary, polyphenols can be used to regulate intestinal mucosal immune responses, allergic diseases, and antitumour immunity.

Topics: Animals; Catechin; Curcumin; Epigenesis, Genetic; Humans; Hypersensitivity; Immunity; Immunomodulation; Inflammation; Neoplasms; Nutritional Physiological Phenomena; Oxidative Stress; Polyphenols; Signal Transduction

Atherosclerosis (AS), a chronic arterial disease, is one of the major causes of morbidity and mortality worldwide. Several treatment modalities have been demonstrated to be effective in treating AS; however, the mortality rate due to AS remains high. Sonodynamic therapy (SDT) is a promising new treatment using low-intensity ultrasound in combination with sonosensitizers. Although SDT was developed from photodynamic therapy (PDT), it has a stronger tissue-penetrating capability and exhibits a more focused effect on the target lesional site requiring treatment. Furthermore, SDT has been demonstrated to suppress the formation of atheromatous plaques, and it can increase plaque stability both in vitro and in vivo. In this article, we critically summarize the recent literature on SDT, focusing on its possible mechanism of action as well as the existing and newly discovered sonosensitizers and chemotherapeutic agents for the treatment of AS.

Topics: Animals; Anthracenes; Antineoplastic Agents; Apoptosis; Atherosclerosis; Berberine; Cell Death; Chalcone; Curcumin; Emodin; Humans; Inflammation; Macrophages; Matrix Metalloproteinases; Mice; Neoplasms; Perylene; Photochemotherapy; Plaque, Atherosclerotic; Quinones; Reactive Oxygen Species; THP-1 Cells; Ultrasonic Therapy

The eradication of cancer in a patient remains an elusive challenge despite advances in early detection and diagnosis, chemo- and immunotherapy, pinpoint radiation treatments, and expert surgical intervention. Although significant gains have been made in our understanding of cancer cell biology, a definite cure for most cancers does not exist at present. Thus, it is not surprising that the research and medical communities continue to explore the importance and therapeutic potential of natural products in their multimodality cancer treatment approach. Curcuminoids found in turmeric are one such class of natural products that have been extensively investigated for their potential to halt the progression of cancer cell proliferation and, more important, to stop metastasis from occurring. In this review, we examine one curcuminoid (demethoxycurcumin [DMC]) largely because of its increased stability and better aqueous solubility at physiological pH, unlike the more well-known curcuminoid (curcumin), which is largely unabsorbed after oral ingestion. The present review will focus on the signaling pathways that DMC utilizes to modulate the growth, invasion, and metastasis of cancer cells in an effort to provide enhanced mechanistic insight into DMC's action as it pertains to brain, ovarian, breast, lung, skin, and prostate cancer. Additionally, this review will attempt to provide an overview of DMC's mechanism of action by modulating apoptosis, cell cycle, angiogenesis, metastasis, and chemosensitivity. Lastly, it is hoped that increased understanding will be gained concerning DMC's interactive role with microRNA-551a, 5' adenosine monophosphate-activated protein kinase, nuclear factor-κB, Wnt inhibitory factor-1, and heat shock protein 70 to affect the progression of cancer.

Topics: AMP-Activated Protein Kinases; Apoptosis; Cell Proliferation; Curcumin; Diarylheptanoids; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; NF-kappa B; Signal Transduction

Cancer Stem Cells (CSCs) or Tumor-Initiating Cells (TICs) are a small sub-population of cells within the tumor, able to give chemio- and radio-resistance and cause the onset of metastasis and the presence of relapses; for these reasons, they are recently becoming a potential target for anticancer therapy. One of the main characteristics of these cells is the self-renewal through the capability of modulating different molecular signalling pathways, including Wnt/β-Catenin, Sonic Hedgehog and Notch pathways. Natural bioactive compounds such as resveratrol, epigallocatechin, curcumin, quercetin, ellagic acid, anthocyanins and other compounds and extracts can have a direct or indirect effect on these molecular pathways, decreasing the pathological activities of CSCs. This review aims to report and summarize the in vitro and in vivo studies about the preventive, therapeutic and chemosensitizing effects of these natural bioactive compounds on CSCs deriving from different types of tumors.

Topics: Animals; Carbazoles; Curcumin; Ellagic Acid; Flavonoids; Humans; Neoplasms; Neoplastic Stem Cells

Radiotherapy is a mainstay of cancer treatment since decades. Ionizing radiation (IR) is used for destruction of cancer cells and shrinkage of tumors. However, the increase of radioresistance in cancer cells and radiation toxicity to normal tissues are severe concerns. The exposure to radiation generates intracellular reactive oxygen species (ROS), which leads to DNA damage by lipid peroxidation, removal of thiol groups from cellular and membrane proteins, strand breaks and base alterations.. Plants have to deal with radiation-induced damage (UV-light of sun, other natural radiation sources). Therefore, it is worth speculating that radioprotective mechanisms have evolved during evolution of life. We hypothesize that natural products from plants may also protect from radiation damage caused as adverse side effects of cancer radiotherapy.. The basis of this systematic review, we searched the relevant literature in the PubMed database.. Flavonoids, such as genistein, epigallocatechin-3-gallate, epicatechin, apigenin and silibinin mainly act as antioxidant, free radical scavenging and anti-inflammatory compounds, thus, providing cytoprotection in addition to downregulation of several pro-inflammatory cytokines. Comparable effects have been found in phenylpropanoids, especially caffeic acid phenylethylester, curcumin, thymol and zingerone. Besides, resveratrol and quercetin are the most important cytoprotective polyphenols. Their radioprotective effects are mediated by a wide range of mechanisms mainly leading to direct or indirect reduction of cellular stress. Ascorbic acid is broadly used as antioxidant, but it has also shown activity in reducing cellular damage after irradiation mainly due to its antioxidant capabilities. The metal ion chelator, gallic acid, represents another natural product attenuating cellular damage caused by radiation.. Some secondary metabolites from plants reveal radioprotective features against cellular damage caused by irradiation. These results warrant further analysis to develop phytochemicals as radioprotectors for clinical use.

Topics: Antioxidants; Ascorbic Acid; Curcumin; DNA Damage; Flavonoids; Humans; Lipid Peroxidation; Neoplasms; Phytochemicals; Plants; Polyphenols; Radiation Injuries; Radiation-Protective Agents; Radiotherapy; Reactive Oxygen Species; Resveratrol; Stilbenes

Curcumin is a polyphenol extracted from turmeric rhizome and has multiple pharmacological roles. Recently,its anticancer properties have been recognized. Also,curcumin regulates autophagy in tumor cells via signaling pathways including AMP-activated protein kinase,mammalian target of rapamycin,transcription factor EB,Beclin-1,B-cell lymphoma 2,and endoplasmic reticulum stress. Considering the complicated crosstalk between autophagy and apoptosis,in this article we summaize the mechanism of curcumin-induced autophagy and its effect on apoptosis,with an attempt to provide insights on tumor therapy.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Beclin-1; Curcumin; Endoplasmic Reticulum Stress; Humans; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; TOR Serine-Threonine Kinases

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that consists of two subunits, the HIF-1α and HIF-1β (ARNT). Under hypoxic conditions, HIF-1 is an adaptive system that regulates the transcription of multiple genes associated with growth, angiogenesis, proliferation, glucose transport, metabolism, pH regulation and cell death. However, aberrant HIF-1 activation contributes to the pathophysiology of several human diseases such as cancer, ischemic cardiovascular disorders, and pulmonary and kidney diseases. A growing body of evidence indicates that curcumin, a natural bioactive compound of turmeric root, significantly targets both HIF-1 subunits, but is more potent against HIF-1α. In this review, we have summarized the knowledge about the pharmacological effects of curcumin on HIF-1 and the related molecular mechanisms that may be effective candidates for the development of multi-targeted therapy for several human diseases.

Topics: Animals; Curcumin; Humans; Hypoxia-Inducible Factor 1; Liver Cirrhosis; Metabolic Diseases; Neoplasms; Vascular Remodeling

Cucurmin, a naturally yellow component isolated from turmeric, ability to prevent various life-style related disorders. The current review article mainly emphasizes on different anticancer perspectives of cucurmin, i.e., colon, cervical, uterine, ovarian, prostate head and neck, breast, pulmonary, stomach and gastric, pancreatic, bladder oral, oesophageal, and bone cancer. It holds a mixture of strong bioactive molecule known as cucurminoids that has ability to reduce cancer/tumor at initial, promotion and progression stages of tumor development. In particular, these compounds block several enzymes required for the growth of tumors and may therefore involve in tumor treatments. Moreover, it modulates an array of cellular progressions, i.e., nitric oxide synthetase activity, protein kinase C activity, epidermal growth factor (EGF) receptor intrinsic kinase activity, nuclear factor kappa (NF-kB) activity, inhibiting lipid peroxidation and production of reactive oxygen species. However, current manuscript summarizes most of the recent investigations of cucurmin but still further research should be conducted to explore the role of curcumin to mitigate various cancers.

Topics: Anticarcinogenic Agents; Curcumin; Humans; Neoplasms

Curcuminoids are turmeric-extracted phytochemicals with documented chemopreventive and anti-tumor activities against several types of malignancies. Curcuminoids can modulate several molecular pathways and cellular targets involved in different stages of tumor initiation, growth, and metastasis. Bisdemethoxycurcumin (BDMC) is a minor constituent (approximately 3%) of curcuminoids that has been shown to be more stable than the other two main curcuminoids, that is, curcumin and demthoxycurcumin. Recent studies have revealed that BDMC has anti-tumor effects exerted through a multimechanistic mode of action involving inhibition of cell proliferation, invasion and migration, metastasis and tumour growth, and induction of apoptotic death in cancer cells. The present review discusses the findings on the anti-tumor effects of BDMC, underlying mechanisms, and the relevance of finding for translational studies in human.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Diarylheptanoids; Humans; Neoplasms; Phytotherapy; Plants, Medicinal

Herbs have served as medicine throughout human history. Since the passage of the Dietary Supplement Health and Education Act (DSHEA), inconsistent regulatory practices have resulted in widespread, indiscriminate use of herbal supplements. Available data indicate that cancer patients use these products (along with standard treatments) more often than the general population. The reasons cited for such use include improving health, reducing the risk of recurrence, and reducing the side effects of cancer treatments. Herbs, however, contain biologically active compounds and can potentially interact with prescription medications, including chemotherapy drugs. We describe the mechanisms via which these interactions may occur, as divided into pharmacokinetics and pharmacodynamics. We highlight four popular herbs and a medicinal mushroom commonly used by cancer patients-turmeric, green tea, ginger, ashwagandha, and reishi mushroom-along with reports of their interactions with standard drugs. We conclude by emphasizing the need to inform patients and physicians about herb-drug interactions and how to advise patients on appropriate use of herbal supplements to minimize the risk for interactions.

Topics: Antineoplastic Agents; Curcuma; Herb-Drug Interactions; Humans; Neoplasms; Patient Education as Topic; Plant Extracts; Reishi; Tea; Zingiber officinale

Progress in chronobiology thus far has been built on botanical field investigation records, experiments on the development of biological clocks, open questions, established rules, and molecular mechanisms. In this review, three clock-related diseases, namely cancer, Alzheimer's disease (AD), and depression, are discussed. Evidence-based mechanisms of action of active compounds, namely epigallocatechin-3-gallate (EGCG), curcumin, and melatonin, from three medicinal plants, Camellia sinensis K., Curcuma longa L., and Hypericum perforatum L., respectively, as potential therapies against cancer, AD, and depression, respectively, have been explained. Feedback loops of basic inputs and application outputs of various studies will lead to the development of chronobiology for applications in time-keeping, disease prevention, and control, and future agricultural practices.

Topics: Agriculture; Alzheimer Disease; Biological Clocks; Camellia sinensis; Curcuma; Depression; Humans; Hypericum; Neoplasms; Plants, Medicinal

PAK family kinases are RAC/CDC42-activated kinases that were first found in a soil amoeba 4 decades ago, and 2 decades later, were discovered in mammals as well. Since then at least 6 members of this family have been identified in mammals. One of them called PAK1 has been best studied so far, mainly because it is essential not only for malignant cell growth and metastasis, but also for many other diseases/disorders such as diabetes (type 2), AD (Alzheimer's disease), hypertension, and a variety of inflammatory or infectious diseases, which definitely shorten our lifespan. Moreover, PAK1-deficient mutant of C. elegans lives longer than the wild-type by 60%, clearly indicating that PAK1 is not only an oncogenic but also ageing kinase. Thus, in theory, both anti-oncogenic and longevity-promoting activities are among the "intrinsic" properties or criteria of "clinically useful" PAK1-blockers. There are a variety of PAK1-blocking natural products such as propolis and curcumin which indeed extend the healthy lifespan of small animals such as C. elegans by inducing the autophagy. Recently, we managed to synthesize a series of potent water-soluble and highly cell-permeable triazolyl esters of COOH-bearing PAK1-blockers such as Ketorolac, ARC (artepillin C) and CA (caffeic acid) via "Click Chemistry" that boosts their anti-cancer activity over 500-fold, mainly by increasing their cell-permeability, and one of them called 15K indeed extends the lifespan of C. elegans. In this mini-review we shall discuss both synthetic and natural PAK1-blockers, some of which would be potentially useful for cancer therapy with least side effect (rather promoting the longevity as well).

Topics: Animals; Antineoplastic Agents; Click Chemistry; Drug Discovery; Humans; Longevity; Neoplasms; p21-Activated Kinases; Protein Kinase Inhibitors

Curcumin is a natural plant-derived compound that has attracted a lot of attention for its anti-cancer activities. Curcumin can slow proliferation of and induce apoptosis in cancer cell lines, but the precise mechanisms of these effects are not fully understood. However, many lines of evidence suggested that curcumin has a potent impact on gene expression profiles; thus, functional genomics should be the key to understanding how curcumin exerts its anti-cancer activities. Here, we review the published functional genomic studies of curcumin focusing on cancer. Typically, a cancer cell line or a grafted tumor were exposed to curcumin and profiled with microarrays, methylation assays, or RNA-seq. Crucially, these studies are in agreement that curcumin has a powerful effect on gene expression. In the majority of the studies, among differentially expressed genes we found genes involved in cell signaling, apoptosis, and the control of cell cycle. Curcumin can also induce specific methylation changes, and is a powerful regulator of the expression of microRNAs which control oncogenesis. We also reflect on how the broader technological progress in transcriptomics has been reflected on the field of curcumin. We conclude by discussing the areas where more functional genomic studies are highly desirable. Integrated OMICS approaches will clearly be the key to understanding curcumin's anticancer and chemopreventive effects. Such strategies may become a template for elucidating the mode of action of other natural products; many natural products have pleiotropic effects that are well suited for a systems-level analysis.

Topics: Apoptosis; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Genome, Human; Genomics; Humans; Neoplasms

Cancer is defined as the abnormal cell growth that can cause life-threatening malignancies with high financial costs for patients as well as the health care system. Natural polyphenols have long been used for the prevention and treatment of several disorders due to their antioxidant, anti-inflammatory, cytotoxic, antineoplastic, and immunomodulatory effects discussed in the literature; thus, these phytochemicals are potentially able to act as chemopreventive and chemotherapeutic agents in different types of cancer. One of the problems regarding the use of polyphenolic compounds is their low bioavailability. Different types of formulations have been designed for the improvement of bioavailability of these compounds, nanonization being one of the most notable approaches among them. This study aimed to review current data on the nanoformulations of natural polyphenols as chemopreventive and chemotherapeutic agents and to discuss their molecular anticancer mechanisms of action. Nanoformulations of natural polyphenols as bioactive agents, including resveratrol, curcumin, quercetin, epigallocatechin-3-gallate, chrysin, baicalein, luteolin, honokiol, silibinin, and coumarin derivatives, in a dose-dependent manner, result in better efficacy for the prevention and treatment of cancer. The impact of nanoformulation methods for these natural agents on tumor cells has gained wider attention due to improvement in targeted therapy and bioavailability, as well as enhancement of stability. Today, several nanoformulations are designed for delivery of polyphenolic compounds, including nanosuspensions, solid lipid nanoparticles, liposomes, gold nanoparticles, and polymeric nanoparticles, which have resulted in better antineoplastic activity, higher intracellular concentration of polyphenols, slow and sustained release of the drugs, and improvement of proapoptotic activity against tumor cells. To conclude, natural polyphenols demonstrate remarkable anticancer potential in pharmacotherapy; however, the obstacles in terms of their bioavailability in and toxicity to normal cells, as well as targeted drug delivery to malignant cells, can be overcome using nanoformulation-based technologies, which optimize the bioefficacy of these natural drugs.

Topics: Antineoplastic Agents; Antioxidants; Biological Availability; Catechin; Curcumin; Drug Delivery Systems; Humans; Nanocomposites; Nanoparticles; Neoplasms; Polyphenols; Quercetin; Resveratrol; Stilbenes

Cancer is one of the most common causes of death and remains the first in China and the second in the US. The common treatments for cancer include surgery, radiation, chemotherapy, targeted therapy and immunotherapy, while chemotherapy remains one of the most important treatments. However, the efficacy of chemotherapy is limited due to drug induced-toxicities and resistance, particularly multiple drug resistance (MDR). Therefore, discovery and development of novel therapeutic drugs and/or combination therapy are urgently needed to reduce toxicity and improve efficacy. Paclitaxel has been widely used to treat various cancers including cervical, breast, ovarian, brain, bladder, prostate, liver and lung cancers. However, its therapeutic efficacy is limited and MDR is a major obstacle. Recently, numerous preclinical studies have shown that the combination of paclitaxel and curcumin may be an ideal strategy to reverse MDR and synergistically improve their therapeutic efficacy in cancer therapy. This review mainly focuses on the current development and progress of the combination of paclitaxel and curcumin in cancer therapy preclinically.

Topics: Antineoplastic Combined Chemotherapy Protocols; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Paclitaxel

Natural products or nutraceuticals promote anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway. This review will focus on the effects of curcumin (CUR), berberine (BBR) and resveratrol (RES), on the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway, with a special focus on GSK-3. These natural products may regulate the pathway by multiple mechanisms including: reactive oxygen species (ROS), cytokine receptors, mirco-RNAs (miRs) and many others. CUR is present the root of turmeric (Curcuma longa). CUR is used in the treatment of many disorders, especially in those involving inflammatory processes which may contribute to abnormal proliferation and promote cancer growth. BBR is also isolated from various plants (Berberis coptis and others) and is used in traditional medicine to treat multiple diseases/conditions including: diabetes, hyperlipidemia, cancer and bacterial infections. RES is present in red grapes, other fruits and berries such as blueberries and raspberries. RES may have some anti-diabetic and anti-cancer effects. Understanding the effects of these natural products on the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway may enhance their usage as anti-proliferative agent which may be beneficial for many health problems.

Topics: Berberine; Cardiovascular Diseases; Curcumin; Gene Expression Regulation; Glycogen Synthase Kinase 3; Humans; Inflammation; Mechanistic Target of Rapamycin Complex 1; Neoplasms; Neurodegenerative Diseases; Osteoarthritis; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Resveratrol; Signal Transduction; Stilbenes

MicroRNAs (miRs) are short (~20 nucleotides) non-coding ribonuecleic acids (ncRNAs) known to be involved in cellular processes such as proliferation, differentiation, immune response, pathogenicity and tumourigenesis, among many others. The regulatory mechanisms exerted by miRs have been implicated in many cancers, including Human Papillomavirus (HPV)-associated cancers. Areas covered: In this review, the authors discuss the involvement of miRs (-143, -375, -21, -200, -296 etc.) that have been shown to be dysregulated in HPV-associated cancers. This review also encompasses both intracellular and exosomal miRs, and their potential as diagnostic biomarkers in saliva and blood. The authors have also attempted to dissect the functional impact of miRs on cellular processes such as changes in cellular polarity, loss of apoptosis and tumour suppression, and unchecked and uncontrolled cell cycle regulation, all of which ultimately lead to aberrant cellular proliferation. Expert commentary: Identification of dysregulated miRs in HPV-associated cancers opens up new opportunities to develop diagnostic, therapeutic and prognostic biomarkers. Studies on global expression patterns of miRs dysregulated in HPV-associated cancers can be instrumental in developing broader therapeutic strategies. Therapies like anti-miR, miR-replacement and those based on alternative natural products targeting miRs, need to be improved and better synchronized to be cost-effective and have better treatment outcomes.

Topics: Antineoplastic Agents; Body Fluids; Cell Transformation, Neoplastic; Curcumin; Humans; Interferons; MicroRNAs; Neoplasms; Papillomaviridae; Tumor Virus Infections; Virus Integration

Curcumin, the main bioactive compound found in the rhizome of Curcuma longa L., is considered a 'privileged structure', due to its ability to modulate different signaling pathways involved in the pathogenesis of several diseases. Unfortunately, its poor pharmacodynamic and pharmacokinetic properties, mainly related to chemical instability, low solubility and rapid metabolism, greatly reduce its therapeutic potential. In the last years a number of derivatives were developed and patented, aimed both at improving its multifaceted biological profile and overcoming its undesired effects. Areas covered: This review summarizes the patent literature of the last five years dealing with synthetic curcumin-related compounds in cancer and neurodegeneration, properly designed in order to avoid the so-called 'dark side of curcumin', and to take advantage of the beneficial properties of this molecule, worth to be further exploited to obtain effective therapeutics. Expert opinion: Due to the synergistic binding to several networked targets, curcumin turned out to be suitable for polypharmacological approaches, and its 'privileged structure' could also provide the key scaffold to develop novel multipotent drugs useful for treating multifactiorial pathologic conditions such as cancer and neurodegeneration.

Topics: Animals; Antineoplastic Agents; Curcuma; Curcumin; Drug Design; Drug Synergism; Humans; Neoplasms; Neurodegenerative Diseases; Patents as Topic; Solubility

Polyphenols have been extensively studied for their relevant anticancer activity. Quite often however their instability, extensive metabolization, low bioavailability and poor solubility limit their application in cancer prevention and therapy. Formulation in nanoparticles has been widely proposed as a means to overcome these limits, maximize localization and specific activity at tumor site. The present review is intended as an update of literature regarding nanoparticulate carriers aimed to deliver polyphenols to the cancer site. Three molecules were chosen, all of which were hydrophobic and poorly soluble, representative of different polyphenol classes: quercetin (QT) among the flavonoid group, curcumin (CUR) as representative of curcuminoids, and resveratrol (RSV) among the stilbenes. In particular, nanoparticulate systems suitable for poorly soluble drugs will be described and attention will be paid to characteristics designed to improve tumor targeting, specific delivery and interaction with tumor cells.

Topics: Biological Availability; Curcumin; Drug Compounding; Humans; Nanoparticles; Neoplasms; Polyphenols; Quercetin; Resveratrol; Stilbenes

Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of

Topics: Antineoplastic Agents; Clinical Trials as Topic; Curcumin; ErbB Receptors; Humans; Neoplasms; NF-kappa B; Signal Transduction; STAT3 Transcription Factor

Inflammation can promote the development of arthritis, obesity, cardiovascular, type II diabetes, pancreatitis, metabolic and neurodegenerative diseases, and certain types of cancer. Compounds isolated from plants have been practiced since ancient times for curing various ailments including inflammatory disorders and to support normal physiological functions. Curcumin (diferuloylmethane) is a yellow coloring agent, extracted from turmeric that has been used for the prevention and treatment of various inflammatory diseases. Numerous studies have shown that curcumin modulate multiple molecular targets and can be translated to the clinics for multiple therapeutic processes. There is compelling evidence that curcumin can block cell proliferation, invasion, and angiogenesis as well as reduced the prolonged survival of cancer cells. Curcumin mediates anti-inflammatory effect through downregulation of inflammatory cytokines, transcription factors, protein kinases, and enzymes that promote inflammation and development of chronic diseases. In addition, curcumin induces apoptosis through mitochondrial and receptor-mediated pathways by activating caspase cascades. Curcumin is a safe and nontoxic drug that has been reported to be well tolerated. Available clinical trials support the potential role of curcumin for treatment of various inflammatory disorders. However, curcumin's efficacy is hindered by poor absorption and low bioavailability, which limit its translation into clinics. This review outlines the potential pharmacological and clinical role of curcumin, which provide a gateway for the beneficial role of plant isolated compounds in treatment of various inflammatory diseases and cancer.

Topics: Animals; Curcuma; Curcumin; Diabetes Mellitus, Type 2; Humans; Inflammation; Neoplasms; Neurodegenerative Diseases; Obesity

Curcumin has been extensively studied for its anti-cancer properties. While a diverse array of in vitro and preclinical research support the prospect of curcumin use as an anti-cancer therapeutic, most human studies have failed to meet the intended clinical expectation. Poor systemic availability of orally-administered curcumin may account for this disparity. Areas covered: This descriptive review aims to concisely summarise available clinical studies investigating curcumin pharmacokinetics when administered in different formulations. A critical analysis of pharmacokinetic- and pharmacodynamic-based interactions of curcumin with concomitantly administered drugs is also provided. Expert opinion: The encouraging clinical results of curcumin administration are currently limited to people with colorectal cancer, given that sufficient curcumin concentrations persist in colonic mucosa. Higher parent curcumin systemic exposure, which can be achieved by several newer formulations, has important implications for optimal treatment of cancers other than those in gastrointestinal tract. Curcumin-drug pharmacokinetic interactions are also almost exclusively in the enterocytes, owing to extensive first pass metabolism and poor curcumin bioavailability. Greater scope of these interactions, i.e. modulation of the systemic elimination of co-administered drugs, may be expected from more-bioavailable curcumin formulations. Further studies are still warranted, especially with newer formulations to support the inclusion of curcumin in cancer therapy regimens.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biological Availability; Curcumin; Drug Interactions; Enterocytes; Humans; Neoplasms

Curcumin (CUR) is a yellow polyphenolic compound derived from the plant turmeric. It is widely used to treat many types of diseases, including cancers such as those of lung, cervices, prostate, breast, bone and liver. However, its effectiveness has been limited due to poor aqueous solubility, low bioavailability and rapid metabolism and systemic elimination. To solve these problems, researchers have tried to explore novel drug delivery systems such as liposomes, solid dispersion, microemulsion, micelles, nanogels and dendrimers. Among these, liposomes have been the most extensively studied. Liposomal CUR formulation has greater growth inhibitory and pro-apoptotic effects on cancer cells. This review mainly focuses on the preparation of liposomes containing CUR and its use in cancer therapy.

Topics: Antineoplastic Agents, Phytogenic; Biological Availability; Curcuma; Curcumin; Drug Delivery Systems; Humans; Liposomes; Nanoparticles; Neoplasms; Solubility

Cancer is a multi-factorial disease and is a major cause of morbidity and mortality worldwide. Dietary phytochemicals have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Several studies have been performed to elucidate the effects of dietary phytochemicals on cancer metabolism, and many molecular targets of phytochemicals have been discovered. In spite of remarkable progress, their effects on cancer metabolism have not yet been fully clarified. Recent developments in metabolomics allowed to probe much further the metabolism of cancer, highlighting altered metabolic pathways and offering a new powerful tool to investigate cancer disease. In this review, we discuss the main metabolic alterations of cancer cells and the potentiality of phytochemicals as promising modulators of cancer metabolism. We will focus on the application of nuclear magnetic resonance-based metabolomics on breast and hepatocellular cancer cell lines to evaluate the impact of curcumin and resveratrol on cancer metabolome with the aim to demonstrate the premise of this approach to provide useful information for a better understanding of impact of diet components on cancer disease.

Topics: Cell Line, Tumor; Curcumin; Humans; Magnetic Resonance Spectroscopy; Metabolome; Metabolomics; Neoplasms; Phytochemicals; Resveratrol; Stilbenes

Curcumin is widely available, inexpensive spice that has been used in ancient folk medicine for millennia, especially in India. Curcumin has the pharmacological properties that slow or reverse cellular proliferation and enhance apoptosis and differentiation associated with a diverse array of molecular effects. Despite its effective anticarcinogenesis properties, curcumin's poor solubility, instability, and extensive metabolism result in poor oral bioavailability. Strategies to enhance curcumin delivery include encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that resist metabolism while retaining curcumin's pharmacological properties, and adding another natural product that has bioenhancing properties to curcumin or combination of two of these strategies. This review comprehensively explores curcumin's chemistry and pharmacology followed by comparing and contrasting a vast number of strategies designed to enhance curcumin's bioavailability and its therapeutic effects. The review provides insights into which curcumin formulation strategies have the greatest promise to reach clinical application.

Topics: Animals; Anticarcinogenic Agents; Curcumin; Drug Carriers; Humans; Neoplasms; Tissue Distribution

Curcumin has been shown to have a wide variety of therapeutic effects, ranging from anti-inflammatory, chemopreventive, anti-proliferative, and anti-metastatic. This review provides an overview of the recent research conducted to overcome the problems with the bioavailability of curcumin, and of the preclinical and clinical studies that have reported success in combinatorial strategies coupling curcumin with other treatments. Research on the signaling pathways that curcumin treatment targets shows that it potently acts on major intracellular components involved in key processes such as genomic modulations, cell invasion and cell death pathways. Curcumin is a promising molecule for the prevention and treatment of cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Cell Proliferation; Cell Survival; Clinical Trials as Topic; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasms; Signal Transduction

curcumin is the main bioactive component contained in Curcuma Longa, largely employed in traditional medicine. Recently, beneficial properties, useful for prevention and treatment of several disorders, have been discovered for this compound. Peculiar structural feature is an α,β-unsaturated carbonyl system essential for establishing contacts with critical cysteine residues of several targets. This distinctive mechanism of action imparts to the molecule the ability to affect a large number of targets, accounting for its pleiotropic behaviour and definition of "privileged structure". Areas covered: The objective of the review is an examination of the recent developments in the field of the anti-cancer applications of curcumin, together with formulation issues, considering the patent literature in the years 2012-2016. Expert opinion: The wide therapeutic efficacy of curcumin is related to synergistic interactions with several biological targets, along with the modulation of several signaling pathways. This peculiar behaviour could be useful in the treatment of multifactorial diseases such as cancer. Combination of curcumin with a first line antineoplastic drug proved to be a valuable strategy to obtain an amplified response with minimized side effects. Innovative curcumin formulations based on the nanotechnology approach allowed improving both bioavailability and therapeutic efficacy.

Topics: Animals; Antineoplastic Agents; Biological Availability; Curcuma; Curcumin; Drug Design; Humans; Nanotechnology; Neoplasms; Patents as Topic

Curcumin is a naturally occurring polyphenol isolated from Curcuma longa that has gained considerable interest over the last decades due to its beneficial effects for human health. Moreover, the usage of cisplatin, a platinum-based chemotherapeutic, is associated with several adverse effects affecting the quality of life of the patients. Also, cisplatin therapy is jeopardized by a great challenge of resistance which reduces the efficacy of this drug. In order to conquer these dark sides of cisplatin therapy, curcumin has been widely used to fight against cisplatin-resistant cancer cells and decrease its unwanted side effects (e.g. ototoxicity, nephrotoxicity and neurotoxicity). In this review, we provide a summary of the studies done to show the protective effects of curcumin against cisplatin failure and toxicity.

Topics: Animals; Antineoplastic Agents; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Humans; Neoplasms

In the recent years, polyphenols have gained significant attention in scientific community owing to their potential anticancer effects against a wide range of human malignancies. Epidemiological, clinical and preclinical studies have supported that daily intake of polyphenol-rich dietary fruits have a strong co-relationship in the prevention of different types of cancer. In addition to direct antioxidant mechanisms, they also regulate several therapeutically important oncogenic signaling and transcription factors. However, after the discovery of microRNA (miRNA), numerous studies have identified that polyphenols, including epigallocatechin-3-gallate, genistein, resveratrol and curcumin exert their anticancer effects by regulating different miRNAs which are implicated in all the stages of cancer. MiRNAs are short, non-coding endogenous RNA, which silence the gene functions by targeting messenger RNA (mRNA) through degradation or translation repression. However, cancer associated miRNAs has emerged only in recent years to support its applications in cancer therapy. Preclinical experiments have suggested that deregulation of single miRNA is sufficient for neoplastic transformation of cells. Indeed, the widespread deregulation of several miRNA profiles of tumor and healthy tissue samples revealed the involvement of many types of miRNA in the development of numerous cancers. Hence, targeting the miRNAs using polyphenols will be a novel and promising strategy in anticancer chemotherapy. Herein, we have critically reviewed the potential applications of polyphenols on various human miRNAs, especially which are involved in oncogenic and tumor suppressor pathways.

Topics: Catechin; Curcumin; Gene Expression Regulation, Neoplastic; Genistein; Humans; MicroRNAs; Neoplasms; Polyphenols; Resveratrol; Signal Transduction; Stilbenes

Curcumin, a major yellow pigment and spice in turmeric and curry, is a powerful anti-cancer agent. The anti-tumor activities of curcumin include inhibition of tumor proliferation, angiogenesis, invasion and metastasis, induction of tumor apoptosis, increase of chemotherapy sensitivity, and regulation of cell cycle and cancer stem cell, indicating that curcumin maybe a strong therapeutic potential through modulating various cancer progression. It has been reported that microRNAs as small noncoding RNA molecules are related to cancer progression, which can be regulated by curcumin. Dysregulated microRNAs play vital roles in tumor biology via regulating expressions of target genes and then influencing multiple cancer-related signaling pathways. In this review, we focused on the inhibition effect of curcumin on various cancer progression by regulating expression of multiple microRNAs. Curcumin-induced dysregulation of microRNAs may activate or inactivate a set of signaling pathways, such as Akt, Bcl-2, PTEN, p53, Notch, and Erbb signaling pathways. A better understanding of the relation between curcumin and microRNAs may provide a potential therapeutic target for various cancers.

Topics: Antineoplastic Agents; Curcumin; Disease Progression; Humans; MicroRNAs; Neoplasms; Randomized Controlled Trials as Topic

This is a short review on the most recent studies on curcumin and its analogs, including the studies from the laboratories of authors. The diverse medicinal properties of curcumin itself reported in the recent years are reviewed. Although curcumin has shown great potential in treating various diseases, it has not been approved as a clinical drug candidate because of its poor pharmacokinetics.. The recent methods developed to solve this problem are briefly described.. The biological and other properties of synthetic curcumin analogs (diarylheptanoids and diarylpentanoid monocarbonyl derivatives) reported in the recent literature are also presented.

Topics: Animals; Antineoplastic Agents; Curcumin; Humans; Neoplasms

The effect of diet on cancer formation and prevention of carcinogenesis has attracted considerable attention for years and is the subject of several studies. Some components of the daily diet, such as resveratrol, curcumin, genistein, gingerol, can significantly reduce the risk of cancer or affect the rate of tumor progression. Cancer chemoprevention assumes the use of natural or synthetic biologically active substances in order to prevent, inhibit or reverse the progression of cancer. There are many biologically active compounds in several natural products, i.e. garlic, ginger, soy, curcuma, tomatoes, cruciferous plants or green tea. Their chemopreventive activity is based on the inhibition of processes underlying carcinogenesis (inflammation, transformation and proliferation), but also affects the final phase of carcinogenesis - angiogenesis and metastasis. Despite the relatively low toxicity of chemopreventive agents, their molecular targets often coincide with the objectives of the currently used cancer therapies. The widespread use of chemopreventive agents may contribute to reduction of the rate of cancer incidence, and increase the effectiveness of conventional cancer therapies. In the present study, selected molecular mechanisms of the chemopreventive activity have been discussed, especially their involvement in the regulation of signal transduction, cell cycle regulation, apoptosis, metastasis and angiogenesis. The role of chemopreventive agents in the inflammatory process, the metabolism of xenobiotics and multidrug resistance has been also characterized.

Topics: Anticarcinogenic Agents; Apoptosis; Catechols; Chemoprevention; Curcumin; Fatty Alcohols; Humans; Neoplasms; Neovascularization, Pathologic; Resveratrol; Signal Transduction; Stilbenes

Research over the past several years has developed many mono-targeted therapies for the prevention and treatment of cancer, but it still remains one of the fatal diseases in the world killing 8.2 million people annually. It has been well-established that development of chemoresistance in cancer cells against mono-targeted chemotherapeutic agents by modulation of multiple survival pathways is the major cause of failure of cancer chemotherapy. Therefore, inhibition of these pathways by non-toxic multi-targeted agents may have profoundly high potential in preventing drug resistance and sensitizing cancer cells to chemotherapeutic agents.. To study the potential of curcumin, a multi-targeted natural compound, obtained from the plant Turmeric (Curcuma longa) in combination with standard chemotherapeutic agents to inhibit drug resistance and sensitize cancer cells to these agents based on available literature and patents.. An extensive literature survey was performed in PubMed and Google for the chemosensitizing potential of curcumin in different cancers published so far and the patents published during 2014-2015.. Our search resulted in many in vitro, in vivo and clinical reports signifying the chemosensitizing potential of curcumin in diverse cancers. There were 160 in vitro studies, 62 in vivo studies and 5 clinical studies. Moreover, 11 studies reported on hybrid curcumin: the next generation of curcumin based therapeutics. Also, 34 patents on curcumin's biological activity have been retrieved.. Altogether, the present study reveals the enormous potential of curcumin, a natural, non-toxic, multi-targeted agent in overcoming drug resistance in cancer cells and sensitizing them to chemotherapeutic drugs.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Drug Delivery Systems; Drug Evaluation, Preclinical; Humans; Inflammation Mediators; Neoplasms; Patents as Topic; Transcription Factors

Invasive fungal infections (IFI) are important complications of cancer, and they have become a major cause of morbidity and mortality in cancer patients. Effective anti-infection therapy is necessary to inhibit significant deterioration from these infections. However, they are difficult to treat, and increasing antifungal drug resistance often leads to a relapse. Curcumin, a natural component that is isolated from the rhizome of Curcuma longa plants, has attracted great interest among many scientists studying solid cancers over the last half century. Interestingly, curcumin provides an ideal alternative to current therapies because of its relatively safe profile, even at high doses. To date, curcumin's potent antifungal activity against different strains of Candida, Cryptococcus, Aspergillus, Trichosporon and Paracoccidioides have been reported, indicating that curcumin anticancer drugs may also possess an antifungal role, helping cancer patients to resist IFI complications. The aim of this review is to discuss curcumin's dual pharmacological activities regarding its applications as a natural anticancer and antifungal agent. These dual pharmacological activities are expected to lead to clinical trials and to improve infection survival among cancer patients.

Topics: Animals; Antifungal Agents; Antineoplastic Agents; Curcumin; Drug Delivery Systems; Humans; Mycoses; Neoplasms

NF-κB pathway has long been considered as one of the potent prototypical pro-inflammatory signaling pathway and its role in several aspects of human health has been established. Recent studies have suggested that NF-κB activation is the master key in early development and pathobiology of several Cancers. Curcumin is a polyphenolic phytochemical compound with several stablished anti-inflammatory properties and is known to exert its anti-inflammatory effects mostly by interrupting NF-κB signaling pathway at multiple stages. Here we tried to provide a summary of recent finding, focusing on introducing NF-κB signaling pathways and its potential mechanism involved in development of several types of Cancers.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Carcinogenesis; Curcumin; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Physiologic; NF-kappa B; Signal Transduction

The landscape of cancer has changed considerably in past several years, due mainly to aggressive screening, accumulation of data from basic and epidemiological studies, and the advances in translational research. Natural anticancer agents have always been a part and parcel of cancer research. The initial focus on natural anticancer agents was in context of their cancer chemopreventive properties but their ability to selectively target oncogenic signaling pathways has also been recognized. In light of the rapid advancements in our understanding of the role of microRNAs, cancer stem cells, and epigenetic events in cancer initiation and progression, a number of natural anticancer agents are showing promise in vitro, in vivo as well as in preclinical studies. Moreover, parent structures of natural agents are being extensively modified with the hope of improving efficacy, specificity, and bioavailability. In this article, we focus on two natural agents, 3,3'-diindolylmethane and garcinol, along with 3,4-difluorobenzo curcumin, a synthetic analog of natural agent curcumin. We showcase how these anticancer agents are changing cancer landscape by modulating novel microRNAs, epigenetic factors, and cancer stem cell markers. These activities are relevant and being appreciated for overcoming drug resistance and inhibition of metastases, the two overarching clinical challenges in modern medicine.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Curcumin; Dietary Supplements; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Humans; Indoles; MicroRNAs; Neoplasms; Neoplastic Stem Cells; Signal Transduction; Terpenes

In recent years, natural compounds have received considerable attention in preventing and curing most dreadful diseases including cancer. The reason behind the use of natural compounds in chemoprevention is associated with fewer numbers of side effects than conventional chemotherapeutics. Curcumin (diferuloylmethane, PubMed CID: 969516), a naturally occurring polyphenol, is derived from turmeric, which is used as a common Indian spice. It governs numerous intracellular targets, including proteins involved in antioxidant response, immune response, apoptosis, cell cycle regulation and tumor progression. A huge mass of available studies strongly supports the use of Curcumin as a chemopreventive drug. However, the main challenge encountered is the low bioavailability of Curcumin. This extensive review covers various therapeutic interactions of Curcumin with its recognized cellular targets involved in cancer treatment, strategies to overcome the bioavailability issue and adverse effects associated with Curcumin consumption.

Topics: Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Curcumin; Forecasting; Humans; Mitochondrial Membranes; Neoplasms

Nowadays, there are some molecules that have shown over the years a high capacity to act against relevant pathologies such as cardiovascular disease, neurodegenerative disorders or cancer. This article provides a brief review about the origin, bioavailability and new research on curcumin and synthetized derivatives. It examines the beneficial effects on health, delving into aspects such as cancer, cardiovascular effects, metabolic syndrome, antioxidant capacity, anti-inflammatory properties, and neurological, liver and respiratory disorders. Thanks to all these activities, curcumin is positioned as an interesting nutraceutical. This is the reason why it has been subjected to several modifications in its structure and administration form that have permitted an increase in bioavailability and effectiveness against different diseases, decreasing the mortality and morbidity associated to these pathologies.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Biological Availability; Cardiotonic Agents; Cardiovascular Diseases; Curcuma; Curcumin; Humans; Inflammation; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents; Plants, Medicinal

Chemoprevention of human cancer by dietary products is a practical approach of cancer control, especially when chemoprevention is involved during the early stages of the carcinogenesis process. Research over the last few decades has clearly demonstrated the efficacy of dietary products for chemoprevention in cell culture and preclinical animal model systems. However, these in vitro and in vivo effects have not been able to be translated to bedside for clinical use. Among many reasons, inefficient systemic delivery and bioavailability of promising chemopreventive agents are considered to significantly contribute to such a disconnection. Since its advent in the field of cancer, nanotechnology has provided researchers with expertise to explore new avenues for diagnosis, prevention, and therapy of the disease. In a similar trait, we introduced a novel concept in which nanotechnology was utilized for enhancing the outcome of chemoprevention (Cancer Res. 2009; 69:1712-1716). This idea, which we termed as 'nanochemoprevention', was exploited by several laboratories and has now become an advancing field in chemoprevention research. This review summarizes some of these applications of nanotechnology in medicine, particularly focused on controlled and sustained release of bioactive compounds with emphasis on current and future utilization of nanochemoprevention for prevention and therapy of cancer.

Topics: Animals; Anticarcinogenic Agents; Biological Products; Catechin; Cell Line, Tumor; Chemoprevention; Curcumin; Disease Models, Animal; Humans; Nanoparticles; Nanotechnology; Neoplasms; Resveratrol; Stilbenes

Diet has been linked to an overwhelming proportion of cancers. Current chemotherapy and targeted therapies are limited by toxicity and the development of resistance against these treatments results in cancer recurrence or progression. In vitro evidence indicates that a number of dietary-derived agents have activity against a highly tumorigenic, chemoradiotherapy resistant population of cells within a tumour. This population is associated with cancer recurrence and is therefore clinically significant. Targeting this subpopulation, termed cancer stem-like cells with dietary-derived agents provides a potentially low toxicity strategy to enhance current treatment regimens. In addition, dietary-derived compounds also provide a novel approach to cancer prevention strategies. This review focusses on selected diet-derived agents that have been shown to specifically target cancer stem-like cells using in vivo models, or in clinical trials. Furthermore, the potential limitations of these studies are discussed, and areas of research that need to be addressed to allow successful translation of dietary-derived agents to the clinical arena are highlighted.

Topics: Animals; Anticarcinogenic Agents; Catechin; Cell Line, Tumor; Curcumin; Diet; Disease Models, Animal; Flavonoids; Humans; Isothiocyanates; Neoplasms; Neoplastic Stem Cells; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes; Sulfoxides; Vitamin A

Telomerase is a ribonucleoprotein enzyme, which has a significant role in synthesizing DNA telomeric in eukaryotes. Telomere maintenance can cause to immortalization and malignant transformation of human cells and thereby telomerase activity must be scrutinized as an important factor in most tumor cells. The proliferation of cancer cells or apoptosis induction can be suppressed by telomerase inhibition using different therapeutic agents without any side effects upon normal cells. Natural substances, with anti-tumor effects, such as those derived from plants can be suitable candidates due to their capabilities in preventing some side effects and resistance of tumors with respect to most chemotherapeutic drugs. In this regards, many studies have shown that natural phytochemicals have inhibitory effects on telomerase activity through affecting its subunits and components. Therefore, the aim of this paper is to review the recent studies on these kinds of phytochemicals in terms of property and mechanism. Moreover, strategies for improving the therapeutic efficacy of plant-derived substances such as combination therapy and nanoformulation based approaches are included.

Topics: Anticarcinogenic Agents; Catechin; Curcumin; Drug Compounding; Humans; Neoplasms; Phytochemicals; Polyphenols; Telomerase

Curcumin, is a polyphenol from Curcuma longa (turmeric plant), is a polyphenol that belongs to the ginger family which has long been used in Ayurveda medicines to treat various diseases such as asthma, anorexia, coughing, hepatic diseases, diabetes, heart diseases, wound healing and Alzheimer's. Various studies have shown that curcumin has anti-infectious, anti-inflammatory, anti-oxidant, hepatoprotective, thrombosuppressive, cardio protective, anti-arthritic, chemo preventive and anti-carcinogenic activities. It may suppress both initiation and progression stages of cancer. Anticancer activity of curcumin is due to negative regulation of inflammatory cytokines, transcription factors, protein kinases, reactive oxygen species (ROS) and oncogenes. This review focuses on the different targets of curcumin to treat cancer.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Curcumin; Humans; Neoplasms; Polyphenols

Naturally occurring polyphenols found in food sources provide huge health benefits. Several polyphenolic compounds are implicated in the prevention of disease states, such as cancer. One of the mechanisms by which polyphenols exert their biological actions is by interfering in the protein kinase C (PKC) signaling pathways. PKC belongs to a superfamily of serine-threonine kinase and are primarily involved in phosphorylation of target proteins controlling activation and inhibition of many cellular processes directly or indirectly.. Despite the availability of substantial literature data on polyphenols' regulation of PKC, no comprehensive review article is currently available on this subject. This article reviews PKC-polyphenol interactions and its relevance to various disease states. In particular, salient features of polyphenols, PKC, interactions of naturally occurring polyphenols with PKC, and future perspective of research on this subject are discussed.. Some polyphenols exert their antioxidant properties by regulating the transcription of the antioxidant enzyme genes through PKC signaling. Regulation of PKC by polyphenols is isoform dependent. The activation or inhibition of PKC by polyphenols has been found to be dependent on the presence of membrane, Ca(2+) ion, cofactors, cell and tissue types etc. Two polyphenols, curcumin and resveratrol are in clinical trials for the treatment of colon cancer.. The fact that 74% of the cancer drugs are derived from natural sources, naturally occurring polyphenols or its simple analogs with improved bioavailability may have the potential to be cancer drugs in the future.

Topics: Curcumin; Humans; Neoplasms; Polyphenols; Protein Kinase C; Resveratrol; Signal Transduction; Stilbenes

In recent years, natural edible products have been found to be important therapeutic agents for the treatment of chronic human diseases including cancer, cardiovascular disease, and neurodegeneration. Curcumin is a well-known diarylheptanoid constituent of turmeric which possesses anticancer effects under both pre-clinical and clinical conditions. Moreover, it is well known that the anticancer effects of curcumin are primarily due to the activation of apoptotic pathways in the cancer cells as well as inhibition of tumor microenvironments like inflammation, angiogenesis, and tumor metastasis. In particular, extensive studies have demonstrated that curcumin targets numerous therapeutically important cancer signaling pathways such as p53, Ras, PI3K, AKT, Wnt-β catenin, mTOR and so on. Clinical studies also suggested that either curcumin alone or as combination with other drugs possess promising anticancer effect in cancer patients without causing any adverse effects. In this article, we critically review the available scientific evidence on the molecular targets of curcumin for the treatment of different types of cancer. In addition, we also discuss its chemistry, sources, bioavailability, and future research directions.

Topics: Animals; Antineoplastic Agents; Curcumin; Humans; Molecular Targeted Therapy; Neoplasms; Signal Transduction

Spices have been widely used as food flavorings and folk medicines for thousands of years. Numerous studies have documented the antioxidant, anti-inflammatory and immunomodulatory effects of spices, which might be related to prevention and treatment of several cancers, including lung, liver, breast, stomach, colorectum, cervix, and prostate cancers. Several spices are potential sources for prevention and treatment of cancers, such as Curcuma longa (tumeric), Nigella sativa (black cumin), Zingiber officinale (ginger), Allium sativum (garlic), Crocus sativus (saffron), Piper nigrum (black pepper) and Capsicum annum (chili pepper), which contained several important bioactive compounds, such as curcumin, thymoquinone, piperine and capsaicin. The main mechanisms of action include inducing apoptosis, inhibiting proliferation, migration and invasion of tumors, and sensitizing tumors to radiotherapy and chemotherapy. This review summarized recent studies on some spices for prevention and treatment of cancers, and special attention was paid to bioactive components and mechanisms of action.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Benzodioxoles; Benzoquinones; Capsaicin; Capsicum; Cell Proliferation; Crocus; Curcuma; Curcumin; Garlic; Humans; Neoplasms; Nigella sativa; Phytotherapy; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Spices; Zingiber officinale

The formation of blood capillaries to sustain development and growth of new tissues is referred to as angiogenesis. Angiogenesis is pivotal in both carcinogenesis and metastasis since capillaries are the sole source of supplying nutrients and oxygen to the proliferating tumor cells; therefore, this dependency of tumor growth on angiogenesis challenges researchers to halt tumor growth by targeting angiogenesis with the help of either synthetic or natural inhibitors. Many synthetic inhibitors of angiogenesis have not only come into force but also resulted in some severe adverse effects. Natural compounds may effectively fit into this condition and possibly decrease the time of treatment. In the recent past, literature is replete with evidences advocating the usefulness of natural compounds that target multiple biochemical pathways. The additional advantage of natural compounds is that their active principles interact with one another and work synergistically to give more meaningful and reliable effects than individual principle. Hence, if we are somehow able to combine more than two natural compounds, then it may be possible to enhance their potential by many folds, which shall prove to be very effective in combating tumor angiogenesis. This review shall discuss the concept of angiogenesis, molecular pathways, and angiogenic inhibitors and their specific targets and potential of natural compounds to greatly enhance the current knowledge of angiogenesis-inhibiting factors.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Artemisinins; Catechin; Cell Proliferation; Curcumin; Humans; Neoplasms; Neovascularization, Pathologic; Plant Extracts; Resveratrol; Stilbenes; Triterpenes

Polyphenols, found abundantly in plants, display many anticarcinogenic properties including their inhibitory effects on cancer cell proliferation, tumor growth, angiogenesis, metastasis, and inflammation as well as inducing apoptosis. In addition, they can modulate immune system response and protect normal cells against free radicals damage. Most investigations on anticancer mechanisms of polyphenols were conducted with individual compounds. However, several studies, including ours, have indicated that anti-cancer efficacy and scope of action can be further enhanced by combining them synergistically with chemically similar or different compounds. While most studies investigated the anti-cancer effects of combinations of two or three compounds, we used more comprehensive mixtures of specific polyphenols and mixtures of polyphenols with vitamins, amino acids and other micronutrients. The mixture containing quercetin, curcumin, green tea, cruciferex, and resveratrol (PB) demonstrated significant inhibition of the growth of Fanconi anemia head and neck squamous cell carcinoma and dose-dependent inhibition of cell proliferation, matrix metalloproteinase (MMP)-2 and -9 secretion, cell migration and invasion through Matrigel. PB was found effective in inhibition of fibrosarcoma HT-1080 and melanoma A2058 cell proliferation, MMP-2 and -9 expression, invasion through Matrigel and inducing apoptosis, important parameters for cancer prevention. A combination of polyphenols (quercetin and green tea extract) with vitamin C, amino acids and other micronutrients (EPQ) demonstrated significant suppression of ovarian cancer ES-2 xenograft tumor growth and suppression of ovarian tumor growth and lung metastasis from IP injection of ovarian cancer A-2780 cells. The EPQ mixture without quercetin (NM) also has shown potent anticancer activity in vivo and in vitro in a few dozen cancer cell lines by inhibiting tumor growth and metastasis, MMP-2 and -9 secretion, invasion, angiogenesis, and cell growth as well as induction of apoptosis. The presence of vitamin C, amino acids and other micronutrients could enhance inhibitory effect of epigallocatechin gallate (EGCG) on secretion of MMPs. In addition, enrichment of NM with quercetin (EPQ mix) enhanced anticancer activity of NM in vivo. In conclusion, polyphenols, especially in combination with other polyphenols or micronutrients, have been shown to be effective against multiple targets in cancer development and progression, and s

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Biological Availability; Catechin; Cell Line, Tumor; Cell Proliferation; Curcumin; Disease Models, Animal; Humans; Micronutrients; Neoplasms; Plant Extracts; Polyphenols; Quercetin; Resveratrol; Stilbenes; Tea

Resveratrol and curcumin are natural products with important therapeutic properties useful to treat several human diseases, including cancer. In the last years, the number of studies describing the effect of both polyphenols against cancer has increased; however, the mechanism of action in all of those cases is not completely comprehended. The unspecific effect and the ability to interfere in assays by both polyphenols make this challenge even more difficult. Herein, we analyzed the anticancer activity of resveratrol and curcumin reported in the literature in the last 11 years, in order to unravel the molecular mechanism of action of both compounds. Molecular targets and cellular pathways will be described. Furthermore, we also discussed the ability of these natural products act as chemopreventive and its use in association with other anticancer drugs.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Humans; Neoplasms; Resveratrol; Stilbenes

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Cells reprogram their metabolism very early during carcinogenesis; this event is critical for the establishment of other cancer hallmarks. Many oncogenes and tumor suppressor genes control metabolism by interplaying with the existing nutrient-sensing intracellular pathways. Mammalian target of rapamycin, mTOR, is emerging as a collector and sorter of a metabolic network controlling upstream and downstream modulation of these same genes. Natural compounds represent a source of anti-cancer molecules with chemopreventive and therapeutic properties. This review describes selected pathways and genes orchestrating the metabolic reprogramming and discusses the potential of natural compounds to target oncogenic metabolic aberrations.

Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Cell Transformation, Neoplastic; Cellular Reprogramming; Curcumin; Humans; Neoplasms; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Quercetin; Resveratrol; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

Many nutrients are known for a wide range of activities in prevention and alleviation of various diseases. Recently, their potential role in regulating human health through effects on epigenetics has become evident, although specific mechanisms are still unclear. Thus, nutriepigenetics/nutriepigenomics has emerged as a new and promising field in current epigenetics research in the past few years. In particular, polyphenols, as part of the central dynamic interaction between the genome and the environment with specificity at physiological concentrations, are well known to affect mechanisms underlying human health. This review summarizes the effects of dietary compounds on epigenetic mechanisms in the regulation of gene expression including expression of enzymes and other molecules responsible for drug absorption, distribution, metabolism and excretion in cancer, metabolic syndrome, neurodegenerative disorders and hormonal dysfunction.

Topics: Antineoplastic Agents; Coffee; Curcumin; Diet; Epigenesis, Genetic; Folic Acid; Food; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Metabolic Syndrome; Neoplasms; Neurodegenerative Diseases; Phytoestrogens; Polyphenols; S-Adenosylmethionine; Selenium; Trace Elements; Vitamin B 12; Vitamin B Complex; Vitamins

Despite significant advances in treatment modalities over the last decade, neither the incidence of the disease nor the mortality due to cancer has altered in the last thirty years. Available anti-cancer drugs exhibit limited efficacy, associated with severe side effects, and are also expensive. Thus identification of pharmacological agents that do not have these disadvantages is required. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa), is one such agent that has been extensively studied over the last three to four decades for its potential anti-inflammatory and/or anti-cancer effects. Curcumin has been found to suppress initiation, progression, and metastasis of a variety of tumors. These anti-cancer effects are predominantly mediated through its negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. It also abrogates proliferation of cancer cells by arresting them at different phases of the cell cycle and/or by inducing their apoptosis. The current review focuses on the diverse molecular targets modulated by curcumin that contribute to its efficacy against various human cancers.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Cell Proliferation; Curcumin; Humans; Neoplasm Metastasis; Neoplasms

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is commonly used as a spice, food additive or dietary pigment. Accumulating evidence suggests that curcumin has several pharmacologic effects, including anti-inflammatory, anti-oxidant and anti-cancer activities. The molecular mechanisms underlying the targets of curcumin are diverse and involve combinations of multiple signaling pathways, including NF-κB and STAT3 signaling. Thus, curcumin is one of the most promising phytochemicals that target various cancers and inflammation-mediated diseases. Clinical trials have been ongoing or completed for various cancers, including breast, pancreatic and colorectal cancers, and multiple myeloma. In this review, the molecular mechanisms and the issue of bioavailability are mainly discussed.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Biological Availability; Curcumin; Humans; Inflammation; Inflammation Mediators; Molecular Targeted Therapy; Neoplasms; Signal Transduction

Cancer remains a major health problem worldwide. Among many other factors, two regulatory defects that are present in most cancer cells are constitutive activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway and the induction of indoleamine 2, 3-dioxygenase (IDO), an enzyme that catalyzes tryptophan degradation, through JAK/STAT signaling. Cytokine signaling activates STAT proteins in regulating cell proliferation, differentiation, and survival through modulation of target genes. Many phytochemicals can inhibit both JAK/STAT signaling and IDO expression in antigen-presenting cells by targeting different pathways. Some of the promising phytochemicals that are discussed in this review include resveratrol, cucurbitacin, curcumin, (-)-epigallocatechin gallate, and others. It is now evident that phytochemicals play key roles in inhibition of tumor proliferation and development and provide novel means for therapeutic targeting of cancer.

Topics: Animals; Catechin; Cell Proliferation; Cucurbitacins; Curcumin; Disease Models, Animal; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Janus Kinases; Neoplasms; Phytochemicals; Resveratrol; Signal Transduction; STAT Transcription Factors; Stilbenes

Curcumin is a highly pleiotropic molecule found in the rhizomes of Curcuma longa (turmeric). It is responsible for the yellow color of turmeric and has been shown to inhibit the proliferation of cancer cells and to be of use in preventing or treating a number of diseases. Curcumin has been shown to modulate multiple cell-signaling pathways simultaneously, thereby mitigating or preventing many different types of cancers, including multiple myeloma and colorectal, pancreatic, breast, prostate, lung, head, and neck cancers, in both animal models and humans. Current therapeutic approaches using a single cancer drug for a single target can be expensive, have serious side effects, or both. Consequently, new approaches to the treatment and prevention of cancer, including the integration of curcumin as a viable treatment strategy where dysregulation of many pathways is involved, are warranted. A methodical review of the evidence was performed to evaluate the effects of curcumin in support of a health claim, as established through the regulatory framework of Health Canada, for a relationship between the consumption of curcumin and the prevention and treatment of cancer.

Topics: Animals; Antineoplastic Agents; Curcuma; Curcumin; Humans; Mice; Neoplasms

The concept of using phytochemicals has ushered in a new revolution in pharmaceuticals. Naturally occurring polyphenols (like curcumin, morin, resveratrol, etc.) have gained importance because of their minimal side effects, low cost and abundance. Curcumin (diferuloylmethane) is a component of turmeric isolated from the rhizome of Curcuma longa. Research for more than two decades has revealed the pleiotropic nature of the biological effects of this molecule. More than 7000 published articles have shed light on the various aspects of curcumin including its antioxidant, hypoglycemic, anti-inflammatory and anti-cancer activities. Apart from these well-known activities, this natural polyphenolic compound also exerts its beneficial effects by modulating different signalling molecules including transcription factors, chemokines, cytokines, tumour suppressor genes, adhesion molecules, microRNAs, etc. Oxidative stress and inflammation play a pivotal role in various diseases like diabetes, cancer, arthritis, Alzheimer's disease and cardiovascular diseases. Curcumin, therefore, could be a therapeutic option for the treatment of these diseases, provided limitations in its oral bioavailability can be overcome. The current review provides an updated overview of the metabolism and mechanism of action of curcumin in various organ pathophysiologies. The review also discusses the potential for multifunctional therapeutic application of curcumin and its recent progress in clinical biology.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Antioxidants; Arthritis; Cardiovascular Diseases; Curcumin; Diabetes Complications; Dietary Supplements; Humans; Hypoglycemic Agents; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents

Curcumin (diferuloylmethane) is a bioactive and major phenolic component of turmeric derived from the rhizomes of curcuma longa linn. For centuries, curcumin has exhibited excellent therapeutic benefits in various diseases. Owing to its anti-oxidant and anti-inflammatory properties, curcumin plays a significant beneficial and pleiotropic regulatory role in various pathological conditions including cancer, cardiovascular disease, Alzheimer's disease, inflammatory disorders, neurological disorders, and so on. Despite such phenomenal advances in medicinal applications, the clinical implication of native curcumin is hindered due to low solubility, physico-chemical instability, poor bioavailability, rapid metabolism, and poor pharmacokinetics. However, these issues can be overcome by utilizing an efficient delivery system. Active scientific research was initiated in 2005 to improve curcumin's pharmacokinetics, systemic bioavailability, and biological activity by encapsulating or by loading curcumin into nanoform(s) (nanoformulations). A significant number of nanoformulations exist that can be translated toward medicinal use upon successful completion of pre-clinical and human clinical trials. Considering this perspective, current review provides an overview of an efficient curcumin nanoformulation for a targeted therapeutic option for various human diseases. In this review article, we discuss the clinical evidence, current status, and future opportunities of curcumin nanoformulation(s) in the field of medicine. In addition, this review presents a concise summary of the actions required to develop curcumin nanoformulations as pharmaceutical or nutraceutical candidates.

Topics: Animals; Anti-Inflammatory Agents; Chemistry, Pharmaceutical; Curcumin; Drug Delivery Systems; Humans; Nanotechnology; Neoplasms; Nervous System Diseases

Curcumin, commonly known as turmeric, is a spice that comes from the root Curcuma longa. The present article presents an update of new studies of curcumin activities as tested in anticancer models from 2011 to 2015.. Evidence from in-vitro and in-vivo research, together with clinical trials conducted over the past few decades, substantiates the potential of curcumin as an anticancer and anti-inflammatory agent. The development of formulations of curcumin in the form of nanoparticles, liposomes, micelles, or phospholipid complexes to enhance its bioavailability and efficacy are still in the early stages. Clinical trials with curcumin indicate safety, tolerability, and nontoxicity. However, the efficacy is questionable, based on the small numbers of patients in each study.. The laboratory and the clinical studies until 2011 were summarized in a review published in this journal. An update of the new studies and knowledge from 2011 to March 2015 focuses on new ways to overcome its low bioavailability and data from clinical trials.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Curcuma; Curcumin; Functional Food; Humans; Inflammation; Neoplasms; Plant Extracts

Ginger is a commonly used spice and herbal medicine worldwide. Besides its extensive use as a condiment, ginger has been used in traditional Chinese medicine for the management of various medical conditions. In recent years, ginger has received wide attention due to its observed antiemetic and anticancer activities. This paper reviews the potential role of ginger and its active constituents in cancer chemoprevention. The phytochemistry, bioactivity, and molecular targets of ginger constituents, especially 6-shogaol, are discussed. The content of 6-shogaol is very low in fresh ginger, but significantly higher after steaming. With reported anti-cancer activities, 6-shogaol can be served as a lead compound for new drug discovery. The lead compound derivative synthesis, bioactivity evaluation, and computational docking provide a promising opportunity to identify novel anticancer compounds originating from ginger.

Topics: Antiemetics; Antineoplastic Agents, Phytogenic; Catechols; Chemoprevention; Curcuma; Curcumin; Drug Discovery; Humans; Neoplasms; Steam; Structure-Activity Relationship; Zingiber officinale

Curcumin (1) is a secondary metabolite of turmeric, derived from Curcuma longa L. and was shown to have many biological activities. One of the most interesting properties of curcumin (1) is the antitumour activity allied with the ability to act as a multidrug resistance (MDR) modulator. Several curcumin derivatives have been synthesized with the purpose of discovering more information about the mechanisms of action, to establish structure-activity relationships (SAR), and to overcome pharmacokinetic problems. Over the past few decades, more potent and more stable curcumin derivatives have emerged with potential as drug candidates. Some important SAR studies pointed out that the unstable α,β-unsaturated diketone linker present in curcumin (1) may not be necessary for the antitumour activity; generally, shorter linkers result in more potent compounds than curcumin (1); the type of substituents and their substitution pattern are crucial regarding the biological activities of interest. Overall, the structure of curcumin (1) may represent an important basis for the development of more effective therapeutic agents, particularly in chemotherapy, as reflected by ongoing clinical trials. This article aims to review the synthesis and biological activities of curcumin (1) and derivatives, highlighting the MDR modulation properties of curcumin (1), since these effects makes this natural product a promising lead compound for the development of new anticancer drugs.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Curcumin; Drug Resistance, Multiple; Humans; Liposomes; Neoplasms; Structure-Activity Relationship

Multidrug resistance is a principal mechanism by which tumors become resistant to structurally and functionally unrelated anticancer drugs. Resistance to chemotherapy has been correlated with overexpression of p-glycoprotein (p-gp), a member of the ATP-binding cassette (ABC) superfamily of membrane transporters. P-gp mediates resistance to a broad-spectrum of anticancer drugs including doxorubicin, taxol, and vinca alkaloids by actively expelling the drugs from cells. Use of specific inhibitors/blocker of p-gp in combination with clinically important anticancer drugs has emerged as a new paradigm for overcoming multidrug resistance. The aim of this paper is to review p-gp regulation by dietary nutraceuticals and to correlate this dietary nutraceutical induced-modulation of p-gp with activity of anticancer drugs.

Topics: Abietanes; Alkaloids; Allyl Compounds; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Benzodioxoles; beta Carotene; Biflavonoids; Capsaicin; Catechin; Catechols; Curcumin; Dietary Supplements; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Fatty Alcohols; Furocoumarins; Humans; Indoles; Limonins; Neoplasms; Phytotherapy; Piperidines; Polyunsaturated Alkamides; Proanthocyanidins; Quercetin; Resveratrol; Stilbenes; Sulfides; Tea; Triterpenes; Xanthophylls

Curcumin, a natural phenolic compound mainly extracted from turmeric curcuma longa, has been employed to prevent or treat plenty of diseases particularly cancer. It has been proven to modulate various signal transduction pathways and exhibits antiinflammatory, anti-oxidative, anti-metastasis anti-proliferative, anti-angiogenic in addition anti-cancer activities. However, its poor solubility and rapid degradation severely hampers the introduction into clinical setting. In this review, we focus on the design of polymeric micelles (PMMCs) which are nano-scaled drug delivery vehicles and fabricated from biocompatible polymers for efficient curcumin delivery. In particular, recent progress of curcumin loaded internal stimuli responsive PMMCs for further intracellular uptake via internal triggers is also discussed.

Topics: Animals; Biocompatible Materials; Curcumin; Drug Delivery Systems; Drug Design; Humans; Micelles; Neoplasms; Polymers; Surface-Active Agents

Curcumin is the major yellow pigment extracted from turmeric, a commonly used spice in Asian cuisine and extensively employed in ayurvedic herbal remedies. A number of studies have shown that curcumin can be a prevention and a chemotherapeutic agent for colon, skin, oral and intestinal cancers. Curcumin is also well known for its antiinflammatory and antioxidant properties, showing high reactivity towards peroxyl radicals, and thus acting as a free radical scavenger. Recently, experimental studies have demonstrated that curcumin might be used in the prevention and the cure of Alzheimer's disease. Indeed, curcumin injected peripherally in vivo into aged Tg mice crossed the blood-brain barrier and bound to amyloid plaques, reducing amyloid levels and plaque formation decisively. The present review will resume the most recent developments in the medicinal chemistry of curcumin and curcumin-like molecules.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; Chemistry, Pharmaceutical; Curcumin; Humans; Molecular Structure; Neoplasms

Cancer is the second leading cause of death in the United States. Considering the quality of life and treatment cost, the best way to fight against cancer is to prevent or suppress cancer development. Cancer is preventable as indicated by human papilloma virus (HPV) vaccination and tamoxifen/raloxifen treatment in breast cancer prevention. The activities of superoxide dismutases (SODs) are often lowered during early cancer development, making it a rational candidate for cancer prevention.. SOD liposome and mimetics have been shown to be effective in cancer prevention animal models. They've also passed safety tests during early phase clinical trials. Dietary supplement-based SOD cancer prevention provides another opportunity for antioxidant-based cancer prevention. New mechanistic studies have revealed that SOD inhibits not only oncogenic activity, but also subsequent metabolic shifts during early tumorigenesis.. Lack of sufficient animal model studies targeting specific cancers; and lack of clinical trials and support from pharmaceutical industries also hamper efforts in further advancing SOD-based cancer prevention.. To educate and obtain support from our society that cancer is preventable. To combine SOD-based therapeutics with other cancer preventive agents to obtain synergistic effects. To formulate a dietary supplementation-based antioxidant approach for cancer prevention. Lastly, targeting specific populations who are prone to carcinogens, which can trigger oxidative stress as the mechanism of carcinogenesis.

Topics: Animals; Anticarcinogenic Agents; Clinical Trials as Topic; Curcumin; Humans; Mitochondria; Molecular Targeted Therapy; Neoplasms; Oxidative Stress; Superoxide Dismutase

Curcumin, a major component of the golden spice turmeric (Curcuma longa), has been linked with the prevention and treatment of a wide variety of cancers through modulation of multiple cell signaling pathways. Since the first report from our laboratory in 1995 that curcumin can inhibit activation of the proinflammatory transcription factor NF-κB by inhibiting the 26S proteasomal degradation of IκBα, an inhibitor of NF-κB, this yellow pigment has been shown to inhibit the protease activities of the proteasome. The carbonyl carbons of the curcumin molecule directly interact with the hydroxyl group of the amino-terminal threonine residue of the proteasomal CT-L subunit of 20S proteasome and cellular 26S proteasome. Curcumin is also a potent inhibitor of COP9 signalosome and associated kinases, casein kinase 2 and protein kinase D, all linked to the ubiquitin-proteasomal system (UPS). Curcumin can also directly inhibit ubiquitin isopeptidases, a family of deubiquitinases (DUBs) that salvage ubiquitin for reuse by the 26S proteasome system. The inhibition of this enzyme by curcumin is mediated through α,β-unsaturated ketone and two sterically accessible β-carbons. Regulation of the UPS pathway by curcumin has been linked to regulation of cancer-linked inflammatory proteins (such as COX-2 and iNOS), transcription factors (NF-κB, STAT3, Sp, AP-1, GADD153/CHOP, HIF-1α), growth factors (VEGF, HER2), apoptotic proteins (p53, Bcl-2, survivin, DNA topoisomerase II, HDAC2, p300, hTERT) and cell cycle proteins (cyclin D1, cyclin E, cyclin B, p21, p27) associated with the prevention and therapy of cancer. Interestingly, the effect of curcumin on 26S proteasome appears to be dose-dependent, as low doses (≥1 µM) increase proteasome activity whereas high doses (≤10 µM) inhibit the proteasome activity. In this review, we discuss in detail how modulation of these targets by curcumin is linked to prevention and treatment of cancer.

Topics: Animals; Curcumin; Humans; Neoplasms; Protease Inhibitors; Proteasome Endopeptidase Complex; Signal Transduction; Transcription Factors

Over 35 years research on PAKs, RAC/CDC42(p21)-activated kinases, comes of age, and in particular PAK1 has been well known to be responsible for a variety of diseases such as cancer (mainly solid tumors), Alzheimer's disease, acquired immune deficiency syndrome and other viral/bacterial infections, inflammatory diseases (asthma and arthritis), diabetes (type 2), neurofibromatosis, tuberous sclerosis, epilepsy, depression, schizophrenia, learning disability, autism, etc. Although several distinct synthetic PAK1-blockers have been recently developed, no FDA-approved PAK1 blockers are available on the market as yet. Thus, patients suffering from these PAK1-dependent diseases have to rely on solely a variety of herbal therapeutics such as propolis and curcumin that block PAK1 without affecting normal cell growth. Furthermore, several recent studies revealed that some of these herbal therapeutics significantly extend the lifespan of nematodes (C. elegans) and fruit flies (Drosophila), and PAK1-deficient worm lives longer than the wild type. Here, I outline mainly pathological phenotypes of hyper-activated PAK1 and a list of herbal therapeutics that block PAK1, but cause no side (harmful) effect on healthy people or animals.

Topics: Animals; Antineoplastic Agents, Phytogenic; Communicable Diseases; Curcumin; Humans; Inflammation; Longevity; Neoplasms; p21-Activated Kinases; Phytotherapy; Plants, Medicinal; Propolis

Excessive free radical generation overbalancing the rate of their removal leads to oxidative stress. Oxidative stress has been implicated in the etiology of cardiovascular disease, inflammatory diseases, cancer, and other chronic diseases. Antioxidants are compounds that hinder the oxidative processes and thereby delay or suppress oxidative stress. There is a growing interest in natural antioxidants found in plants. Herbs and spices are most important targets to search for natural antioxidants from the point of view of safety. A wide variety of phenolic compounds present in spices that are extensively used as food adjuncts possess potent antioxidant, anti-inflammatory, antimutagenic, and cancer preventive activities. This paper reviews a host of spice compounds as exogenous antioxidants that are experimentally evidenced to control cellular oxidative stress, both in vitro and in vivo, and their beneficial role in preventing or ameliorating oxidative-stress-mediated diseases, from atherosclerosis to diabetes to cataract to cancer. The antioxidative effects of turmeric/curcumin, clove/eugenol, red pepper/capsaicin, black pepper/piperine, ginger/gingerol, garlic, onion, and fenugreek, which have been extensively studied and evidenced as potential antioxidants, are specifically reviewed in this treatise.

Topics: Alkaloids; Anti-Inflammatory Agents; Antimutagenic Agents; Antioxidants; Benzodioxoles; Capsaicin; Cardiotonic Agents; Catechols; Curcumin; Eugenol; Fatty Alcohols; Garlic; Humans; Neoplasms; Onions; Oxidative Stress; Phenols; Piperidines; Polyunsaturated Alkamides; Spices; Trigonella

Chemoprevention is a relatively new and promising strategy to prevent human degenerative diseases, including cancer, and is defined as the use of natural dietary compounds and/or synthetic substances to block, inhibit, reverse, or retard the progress of human diseases. Tetrahydrocurcumin (THC) is a major metabolite of curcumin (extracted from the roots of the Curcuma longa Linn). THC has been demonstrated to prevent oxidative stress and inflammation, to act against neurodegeneration, and to possess anti-cancer activity. In this review, we summarize the current knowledge and underlying molecular mechanisms of the chemopreventative activities of THC and its potential effects on the development of various human diseases.

Topics: Animals; Curcuma; Curcumin; Diet Therapy; Humans; Neoplasms; Plant Extracts

This review addresses the oncopharmacological properties of curcumin at the molecular level. First, the interactions between curcumin and its molecular targets are addressed on the basis of curcumin's distinct chemical properties, which include H-bond donating and accepting capacity of the β-dicarbonyl moiety and the phenylic hydroxyl groups, H-bond accepting capacity of the methoxy ethers, multivalent metal and nonmetal cation binding properties, high partition coefficient, rotamerization around multiple C-C bonds, and the ability to act as a Michael acceptor. Next, the in vitro chemical stability of curcumin is elaborated in the context of its susceptibility to photochemical and chemical modification and degradation (e.g., alkaline hydrolysis). Specific modification and degradatory pathways are provided, which mainly entail radical-based intermediates, and the in vitro catabolites are identified. The implications of curcumin's (photo)chemical instability are addressed in light of pharmaceutical curcumin preparations, the use of curcumin analogues, and implementation of nanoparticulate drug delivery systems. Furthermore, the pharmacokinetics of curcumin and its most important degradation products are detailed in light of curcumin's poor bioavailability. Particular emphasis is placed on xenobiotic phase I and II metabolism as well as excretion of curcumin in the intestines (first pass), the liver (second pass), and other organs in addition to the pharmacokinetics of curcumin metabolites and their systemic clearance. Lastly, a summary is provided of the clinical pharmacodynamics of curcumin followed by a detailed account of curcumin's direct molecular targets, whereby the phenotypical/biological changes induced in cancer cells upon completion of the curcumin-triggered signaling cascade(s) are addressed in the framework of the hallmarks of cancer. The direct molecular targets include the ErbB family of receptors, protein kinase C, enzymes involved in prostaglandin synthesis, vitamin D receptor, and DNA.

Topics: Animals; Antineoplastic Agents; Curcumin; Humans; Neoplasms

Curcumin is a well-known dietary polyphenol derived from the rhizomes of turmeric, an Indian spice. The anticancer effect of curcumin has been demonstrated in many cell and animal studies, and recent research has shown that curcumin can target cancer stem cells (CSCs). CSCs are proposed to be responsible for initiating and maintaining cancer, and contribute to recurrence and drug resistance. A number of studies have suggested that curcumin has the potential to target CSCs through regulation of CSC self-renewal pathways (Wnt/β-catenin, Notch, sonic hedgehog) and specific microRNAs involved in acquisition of epithelial-mesenchymal transition (EMT). The potential impact of curcumin, alone or in combination with other anticancer agents, on CSCs was evaluated as well. Furthermore, the safety and tolerability of curcumin have been well-established by numerous clinical studies. Importantly, the low bioavailability of curcumin has been dramatically improved through the use of structural analogues or special formulations. More clinical trials are underway to investigate the efficacy of this promising agent in cancer chemoprevention and therapy. In this article, we review the effects of curcumin on CSC self-renewal pathways and specific microRNAs, as well as its safety and efficacy in recent human studies. In conclusion, curcumin could be a very promising adjunct to traditional cancer treatments.

Topics: Animals; Antineoplastic Agents; Curcumin; Humans; Neoplasms; Neoplastic Stem Cells

Nanotechnology-based drug delivery systems have the potential to enhance the efficacy of poorly soluble systemic drugs. Curcumin, a yellow pigment isolated from turmeric, possesses a wide range of pharmacological activities, including anticancer effects. The anticancer potential of curcumin is mediated through the inhibition and modulation of several intracellular signaling pathways, as confirmed in various in vitro and in vivo cancer studies. However, clinical application of dietary curcumin for the treatment of cancer and other chronic diseases have been hindered by poor bioavailability, due to low systemic solubility as well as rapid metabolism and elimination from the body. Different techniques for sustained and efficient curcumin delivery, including nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles are the focus of this study. Previous studies have shown that nanocurcumin has improved anticancer effects as compared to normal curcumin formulations. Among nanoformulations, few composite nanosystems have the simultaneous properties of therapeutic activity and multifunctional nanoparticles as enhanced image contrast agents. We also address the challenges to the development of nanocurcumin delivery platforms by enhancing a steady aqueous dispersion state. Further studies are needed using preclinical and clinical cancer models to recommend nanocurcumin as a drug of choice for cancer therapy.

Topics: Absorption; Animals; Antineoplastic Agents; Crystallization; Curcumin; Diffusion; Drug Compounding; Drug Design; Humans; Nanocapsules; Neoplasms

Cancer stem cells are a subset of cells that are responsible for cancer initiation and relapse. They are generally resistant to the current anticancer agents. Successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells, but also cancer stem cells. Emerging evidence suggested that the dietary agent curcumin exerted its anti-cancer activities via targeting cancer stem cells of various origins such as those of colorectal cancer, pancreatic cancer, breast cancer, brain cancer, and head and neck cancer. In order to enhance the therapeutic potential of curcumin, this agent has been modified or used in combination with other agents in the experimental therapy for many cancers. In this mini-review, we discussed the effect of curcumin and its derivatives in eliminating cancer stem cells and the possible underlying mechanisms.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcuma; Curcumin; Humans; Molecular Structure; Neoplasms; Neoplastic Stem Cells

Natural compounds are emerging as effective agents for the treatment of malignant diseases. Curcumin (diferuloylmethane), the active constituent of turmeric extract, has gained significant interest as a plant-based compound with anti-cancer properties. Curcumin is physiologically very well tolerated, with negligible systemic toxicity observed even after high oral doses administration. Despite curcumin's superior properties as an anti-cancer agent its applications are limited due to its low solubility and physico-chemical stability, rapid systemic clearance and low cellular uptake.. This review focuses on the development of curcumin nano-particle formulation to improve its therapeutic index through enhanced cellular uptake, localization to targeted areas and improved bioavailability. The feasibility of nano-formulation in delivering curcumin and the limitations and challenges in designing and administrating the nano-sized curcumin particles are also covered in this review.. Nanotechnology is a promising tool to enhance efficacy and delivery of drugs. In this context, formulation of curcumin as nano-sized particles could reduce the required therapeutic dosages and subsequently reduced its cell toxicity. These nanoparticles are capable to provide local delivery of curcumin targeted to specific areas and thereby preventing systemic clearance. In addition, using specific coating, better pharmacokinetic and internalization of nano-curcumin could be achieved. However, the potential toxicity of nano-carriers for curcumin delivery is an important issue, which should be taken into account in curcumin nano-formulation.

Topics: Antineoplastic Agents; Biological Availability; Chemistry, Pharmaceutical; Curcumin; Drug Delivery Systems; Humans; Nanoparticles; Nanotechnology; Neoplasms

Curcumin (CUR) is a yellow-coloured polyphenolic compound obtained from the rhizomes of Curcuma longa. In-depth pharmacological screening of curcumin has given the evidence that CUR persuades shielding and curative effects against various cancers, cardiovascular, wound healing effect and neuro disorders etc owning to anti-oxidant, antiproliferative, anti-inflammatory, anti-angiogenic and antimicrobial activities. However, miserable bioavailability due to poor aqueous solubility limits the application of CUR in various ailments. Different methodologies including the nanoparticle technology have been reported for the bioavailability enhancement of CUR. Nanoparticles exhibit not only the improvement in the solubility of CUR and alike lipophilic molecules (resulted in improved bioavailability) but also giving the opportunity for the disease specific cellular and organ targeting. Improved bioavailability and disease based site specific delivery of CUR is more likely to bring it as a safe multifunctional medicine.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Curcumin; Drug Delivery Systems; Food Additives; Humans; Nanoparticles; Nanotechnology; Neoplasms

It is becoming progressively more understandable that different phytochemicals isolated from edible plants interfere with specific stages of carcinogenesis. Cancer cells have evolved hallmark mechanisms to escape from death. Concordant with this approach, there is a disruption of spatiotemproal behaviour of signaling cascades in cancer cells, which can escape from apoptosis because of downregulation of tumor suppressor genes and over- expression of oncogenes. Genomic instability, intra-tumor heterogeneity, cellular plasticity and metastasizing potential of cancer cells all are related to molecular alterations. Data obtained through in vitro studies has convincingly revealed that curcumin, EGCG, resveratrol and quercetin are promising anticancer agents. Their efficacy has been tested in tumor xenografted mice and considerable experimental findings have stimulated researchers to further improve the bioavailability of these nutraceuticals. We partition this review into different sections with emphasis on how bioavailability of curcumin, EGCG, resveratrol and quercetin has improved using different nanotechnology approaches.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Catechin; Cell Proliferation; Cell Transformation, Neoplastic; Curcumin; Drug Carriers; Humans; Lactic Acid; Mice; Nanoparticles; Neoplasms; Phytochemicals; Polyglycolic Acid; Polyhydroxyethyl Methacrylate; Polylactic Acid-Polyglycolic Acid Copolymer; Quercetin; Resveratrol; Silicon Dioxide; Stilbenes; Xenograft Model Antitumor Assays

Curcumin is a lipophilic molecule with an active ingredient in the herbal remedy and dietary spice turmeric. It is used by different folks for treatment of many diseases. Recent studies have discussed poor bioavailability of curcumin because of poor absorption, rapid metabolism, and rapid systemic elimination. Nanotechnology is an emerging field that is potentially changing the way we can treat diseases through drug delivery with curcumin. The recent investigations established several approaches to improve the bioavailability, to increase the plasma concentration, and to enhance the cellular permeability processes of curcumin. Several types of nanoparticles have been found to be suitable for the encapsulation or loading of curcumin to improve its therapeutic effects in different diseases. Nanoparticles such as liposomes, polymeric nanoparticles, micelles, nanogels, niosomes, cyclodextrins, dendrimers, silvers, and solid lipids are emerging as one of the useful alternatives that have been shown to deliver therapeutic concentrations of curcumin. This review shows that curcumin's therapeutic effects may increase to some extent in the presence of nanotechnology. The presented board of evidence focuses on the valuable special effects of curcumin on different diseases and candidates it for future clinical studies in the realm of these diseases.

Topics: Antineoplastic Agents; Biological Availability; Curcumin; Drug Delivery Systems; Humans; Nanoparticles; Nanotechnology; Neoplasms

Curcumin, a phenolic compound extracted from Curcuma longa, is commonly used in Asia as a spice and pigment and has several biological functions, particularly antioxidant properties. It has been reported that curcumin exhibits bifunctional antioxidant properties related to its capability to react directly with reactive oxygen species (ROS) and also to its ability to induce the expression of cytoprotective and antioxidant proteins through the transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2). Recently, it has been postulated that the mitochondrial function and metabolism are associated with Nrf2 and that curcumin has shown activities against mitochondrial dysfunction. The damage in mitochondria has been implicated in the pathogenesis of diseases like diabetes, cancer, aging, and neurodegenerative disorders. This review focuses on some of the most recent findings of curcumin properties that suggest a close relationship of this antioxidant with the mitochondrial function.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Curcuma; Curcumin; Humans; Mitochondria; Neoplasms; NF-E2-Related Factor 2; Oxidative Stress; Phytotherapy; Plant Extracts; Plants, Medicinal; Reactive Oxygen Species; Signal Transduction

Intake of dietary phytochemicals has frequently been associated with health benefits. Noninfectious diseases including cardiovascular disease (CVD), cancer and diabetes are major causes of death, whereas dementia cases are also increasing to 'epidemic' proportion. This review will focus on recent progress on mechanisms underlying the potential role of dietary phytochemicals in CVD, diabetes, cancer and dementia, with consideration of the latest clinical data.. The association of tea (Camellia sinensis), particularly catechins, with reported mechanistic effects for CVD, diabetes, cancer and cognition contributes to our understanding of the suggested benefits of tea consumption on health from limited and inconclusive clinical trial and epidemiological data. Resveratrol, which occurs in grapes (Vitis vinifera) and wine, and curcumin, a component of turmeric (Curcuma longa), are also emerging as potentially relevant to health, particularly for CVD and dementia, with some promising data also concluded for curcumin in cancer. Other phytochemicals mechanistically relevant for health include anthocyanins, isoflavones and glucosinolates, which are also discussed.. Evidence for the role of phytochemicals in health and disease is growing, but associations between phytochemicals and disease need to be more firmly understood and established from more robust clinical data using preparations that have been phytochemically characterized.

Topics: Cardiovascular Diseases; Catechin; Clinical Trials as Topic; Curcuma; Curcumin; Dementia; Diabetes Mellitus; Humans; Micronutrients; Neoplasms; Phytochemicals; Plant Extracts; Resveratrol; Stilbenes; Tea; Vitis; Wine

MicroRNAs (miRNAs) are short noncoding RNA which regulate gene expression by messenger RNA (mRNA) degradation or translation repression. The plethora of published reports in recent years demonstrated that they play fundamental roles in many biological processes, such as carcinogenesis, angiogenesis, programmed cell death, cell proliferation, invasion, migration, and differentiation by acting as tumour suppressor or oncogene, and aberrations in their expressions have been linked to onset and progression of various cancers. Furthermore, each miRNA is capable of regulating the expression of many genes, allowing them to simultaneously regulate multiple cellular signalling pathways. Hence, miRNAs have the potential to be used as biomarkers for cancer diagnosis and prognosis as well as therapeutic targets. Recent studies have shown that natural agents such as curcumin, resveratrol, genistein, epigallocatechin-3-gallate, indole-3-carbinol, and 3,3'-diindolylmethane exert their antiproliferative and/or proapoptotic effects through the regulation of one or more miRNAs. Therefore, this review will look at the regulation of miRNAs by natural agents as a means to potentially enhance the efficacy of conventional chemotherapy through combinatorial therapies. It is hoped that this would provide new strategies in cancer therapies to improve overall response and survival outcome in cancer patients.

Topics: Antineoplastic Agents; Biological Products; Biomarkers, Tumor; Catechin; Curcumin; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Resveratrol; RNA Stability; Stilbenes

Cancer is the most dreadful disease worldwide in terms of morbidity and mortality. The exact cause of cancer development and progression is not fully known. But it is thought that cancer occurs due to the structural and functional changes in the genes. The current approach to cancer treatment based on allopathic is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a safe and effective mode of treatment is needed to control the cancer development and progression. Some medicinal plants provide a safe, effective and affordable remedy to control the progression of malignant cells. The importance of medicinal plants and their constituents has been documented in Ayurveda, Unani medicine, and various religious books. Curcumin, a vital constituent of the spice turmeric, is an alternative approach in the prevention of cancer. Earlier studies have shown the effect of curcumin as an antioxidant, antibacterial, antitumor and it also has a noteworthy role in the control of different diseases. In this review, we summarize the understanding of chemopreventive effects of curcumin in the prevention of cancer via the regulation of various cell signaling and genetic pathways.

Topics: Antioxidants; Curcuma; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Medicine, Ayurvedic; Neoplasms; Plants, Medicinal; Signal Transduction

Defects in initiating or executing cell death programs are responsible for cancer chemoresistance. The growing understanding of apoptotic programs suggests that compounds simultaneously inhibiting multiple signaling pathways might provide a better therapeutic outcome than that of individual inhibitors.. Natural compounds can modulate different survival pathways, thus enhancing the therapeutic effects of anticancer treatments. This review provides an overview of the preclinical and clinical relevance of chemosensitization, giving special reference to curcumin (CUR) and sulforaphane (SFN) as agents to overcome apoptosis resistance against chemotherapy.. Even if CUR and SFN are common dietary constituents, they are characterized by several problems still unresolved and hampering their development as anticancer drugs. For a drug to be safe, it must be devoid of toxicity, and some studies conducted to date raises concern about CUR and SFN safety. Moreover, the efficacy of a drug, alone or in association, is usually determined by randomized, placebo-controlled, double-blind clinical trials. No such trials have shown CUR and SFN to be effective so far. Thus, caution should be exercised when suggesting the use of CUR or SFN for cancer-related therapeutic purpose, especially for very early stage of malignancy, or in patients who are undergoing chemotherapy.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Curcumin; Drug Resistance, Neoplasm; Fluorouracil; Humans; Isothiocyanates; Neoplasms; Platinum Compounds; Signal Transduction; Sulfoxides

The mechanisms of beneficial preventive and therapeutic effects achieved by traditional and complementary medicine are currently being deciphered in molecular medicine. Curcumin, a yellow-colored polyphenol derived from the rhizome of turmeric (Curcuma longa), influences a wide variety of cellular processes through the reshaping of many molecular targets. One of them, nuclear factor kappa B (NF-κB), represents a strong mediator of inflammation and, in a majority of systems, supports the pro-proliferative features of cancer cells. The application of various anticancer drugs, cytostatics, triggers signals which lead to an increase in cellular NF-κB activity. As a consequence, cancer cells often reshape their survival signaling pathways and, over time, become resistant to applied therapy. Curcumin was shown to be a strong inhibitor of NF-κB activity and its inhibitory effect on NF-κB related pathways often leads to cellular apoptotic response. All these facts, tested and confirmed in many different biological systems, have paved the way for research aimed to elucidate the potential beneficial effects of combining curcumin and various anti-cancer drugs in order to establish more efficient and less toxic cancer treatment modalities. This review addresses certain aspects of NF-κB-related inflammatory response, its role in carcinogenesis and therapy benefits that may be gained through silencing NF-κB by selectively combining curcumin and various anticancer drugs.

Topics: Antineoplastic Agents, Phytogenic; Cell Proliferation; Curcuma; Curcumin; Humans; Neoplasms; NF-kappa B

Autophagy, a lysosomal degradation pathway for cellular constituents and organelles, is an adaptive and essential process required for cellular homeostasis. Although autophagy functions as a survival mechanism in response to cellular stressors such as nutrient or growth factor deprivation, it can also lead to a non-apoptotic form of programmed cell death (PCD) called autophagy-induced cell death or autophagy-associated cell death (type II PCD). Current evidence suggests that cell death through autophagy can be induced as an alternative to apoptosis (type I PCD), with therapeutic purpose in cancer cells that are resistant to apoptosis. Thus, modulating autophagy is of great interest in cancer research and therapy. Natural polyphenolic compounds that are present in our diet, such as rottlerin, genistein, quercetin, curcumin, and resveratrol, can trigger type II PCD via various mechanisms through the canonical (Beclin-1 dependent) and non-canonical (Beclin-1 independent) routes of autophagy. The capacity of these compounds to provide a means of cancer cell death that enhances the effects of standard therapies should be taken into consideration for designing novel therapeutic strategies. This review focuses on the autophagy- and cell death-inducing effects of these polyphenolic compounds in cancer.

Topics: Acetophenones; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Benzopyrans; Cell Line, Tumor; Curcumin; Gene Expression Regulation, Neoplastic; Genistein; Humans; Membrane Proteins; Neoplasms; Polyphenols; Quercetin; Resveratrol; Signal Transduction; Stilbenes

Cancer is a multifactorial disease that requires treatments able to target multiple intracellular components and signaling pathways. The natural compound, curcumin, was already described as a promising anticancer agent due to its multipotent properties and huge amount of molecular targets in vitro. Its translation to the clinic is, however, limited by its reduced solubility and bioavailability in patients. In order to overcome these pharmacokinetic deficits of curcumin, several strategies, such as the design of synthetic analogs, the combination with specific adjuvants or nano-formulations, have been developed. By taking into account the risk-benefit profile of drug combinations, as well as the knowledge about curcumin's structure-activity relationship, a new concept for the combination of curcumin with scaffolds from different natural products or components has emerged. The concept of a hybrid curcumin molecule is based on the incorporation or combination of curcumin with specific antibodies, adjuvants or other natural products already used or not in conventional chemotherapy, in one single molecule. The high diversity of such conjugations enhances the selectivity and inherent biological activities and properties, as well as the efficacy of the parental compound, with particular emphasis on improving the efficacy of curcumin for future clinical treatments.

Topics: Antineoplastic Agents; Biological Availability; Chemistry, Pharmaceutical; Curcumin; Drug Synergism; Humans; Neoplasms

Curcumin is a natural product with several thousand years of heritage. Its traditional Asian application to human ailments has been subjected in recent decades to worldwide pharmacological, biochemical and clinical investigations. Curcumin's Achilles heel lies in its poor aqueous solubility and rapid degradation at pH ~ 7.4. Researchers have sought to unlock curcumin's assets by chemical manipulation. One class of molecules under scrutiny are the monocarbonyl analogs of curcumin (MACs). A thousand plus such agents have been created and tested primarily against cancer and inflammation. The outcome is clear. In vitro, MACs furnish a 10-20 fold potency gain vs. curcumin for numerous cancer cell lines and cellular proteins. Similarly, MACs have successfully demonstrated better pharmacokinetic (PK) profiles in mice and greater tumor regression in cancer xenografts in vivo than curcumin. The compounds reveal limited toxicity as measured by murine weight gain and histopathological assessment. To our knowledge, MAC members have not yet been monitored in larger animals or humans. However, Phase 1 clinical trials are certainly on the horizon. The present review focuses on the large and evolving body of work in cancer and inflammation, but also covers MAC structural diversity and early discovery for treatment of bacteria, tuberculosis, Alzheimer's disease and malaria.

Topics: Animals; Crystallography, X-Ray; Curcumin; Humans; Inflammation; Mice; Molecular Mimicry; Neoplasms

To examine the role of two nutritional factors implicated in the healthy aging of the Okinawans: caloric restriction; and traditional foods with potential caloric restriction-mimetic properties.. Caloric restriction is a research priority for the US National Institute on Aging. However, little is known regarding health effects in humans. Some caloric restriction-related outcomes, such as cause-specific mortality and lifespan, are not practical for human clinical trials. Therefore, epidemiological data on older Okinawans, who experienced a caloric restriction-like diet for close to half their lives, are of special interest. The nutritional data support mild caloric restriction (10-15%) and high consumption of foods that may mimic the biological effects of caloric restriction, including sweet potatoes, marine-based carotenoid-rich foods, and turmeric. Phenotypic evidence is consistent with caloric restriction (including short stature, low body weight, and lean BMI), less age-related chronic disease (including cardiovascular diseases, cancer, and dementia), and longer lifespan (mean and maximum).. Both caloric restriction and traditional Okinawan functional foods with caloric restriction-mimetic properties likely had roles in the extended healthspan and lifespan of the Okinawans. More research is needed on health consequences of caloric restriction and foods with caloric restriction-mimetic properties to identify possible nutritional interventions for healthy aging.

Topics: Aging; Caloric Restriction; Cardiovascular Diseases; Chronic Disease; Curcuma; Dementia; Diet; Functional Food; Humans; Ipomoea batatas; Japan; Longevity; Neoplasms; Seafood

Many studies confirm that a majority of patients undergoing cancer therapy use self-selected forms of complementary therapies, mainly dietary supplements. Unfortunately, patients often do not report their use of supplements to their providers. The failure of physicians to communicate effectively with patients on this use may result in a loss of trust within the therapeutic relationship and in the selection by patients of harmful, useless, or ineffective and costly nonconventional therapies when effective integrative interventions may exist. Poor communication may also lead to diminishment of patient autonomy and self-efficacy and thereby interfere with the healing response. To be open to the patient's perspective, and sensitive to his or her need for autonomy and empowerment, physicians may need a shift in their own perspectives. Perhaps the optimal approach is to discuss both the facts and the uncertainty with the patient, in order to reach a mutually informed decision. Today's informed patients truly value physicians who appreciate them as equal participants in making their own health care choices. To reach a mutually informed decision about the use of these supplements, the Clinical Practice Committee of The Society of Integrative Oncology undertook the challenge of providing basic information to physicians who wish to discuss these issues with their patients. A list of leading supplements that have the best suggestions of benefit was constructed by leading researchers and clinicians who have experience in using these supplements. This list includes curcumin, glutamine, vitamin D, Maitake mushrooms, fish oil, green tea, milk thistle, Astragalus, melatonin, and probiotics. The list includes basic information on each supplement, such as evidence on effectiveness and clinical trials, adverse effects, and interactions with medications. The information was constructed to provide an up-to-date base of knowledge, so that physicians and other health care providers would be aware of the supplements and be able to discuss realistic expectations and potential benefits and risks.

Topics: Camellia sinensis; Curcumin; Dietary Supplements; Fish Oils; Glutamine; Grifola; Humans; Integrative Medicine; Neoplasms; Probiotics; Vitamin D

Numerous natural compounds have been extensively investigated for their potential for cancer prevention over the decades. Curcumin, from Curcuma longa, is a highly promising natural compound that can be potentially used for chemoprevention of multiple cancers. Curcumin modulates multiple molecular pathways involved in the lengthy carcinogenesis process to exert its chemopreventive effects through several mechanisms: promoting apoptosis, inhibiting survival signals, scavenging reactive oxidative species (ROS), and reducing the inflammatory cancer microenvironment. Curcumin fulfills the characteristics for an ideal chemopreventive agent with its low toxicity, affordability, and easy accessibility. Nonetheless, the clinical application of curcumin is currently compromised by its poor bioavailability. Here, we review the potential of curcumin in cancer prevention, its molecular targets, and mechanisms of action. Finally, we suggest specific recommendations to improve its efficacy and bioavailability for clinical applications.

Topics: Animals; Anticarcinogenic Agents; Curcumin; Humans; Neoplasms

Curcumin, a natural bioactive polyphenol, has been widely investigated as a conventional medicine for centuries. Over the past two decades, major pre-clinical and clinical trials have demonstrated its safe therapeutic profile but clinical translation has been hampered due to rapid degradation, poor water solubility, bioavailability and pharmaco-kinetics. To overcome such translational issues, many laboratories have focused on developing curcumin nanoformulations for cancer therapeutics. In this review, we discuss the evolution of curcumin nanomedicine in cancer therapeutics, the possible interactions between the surface of curcumin nanoparticles and plasma proteins, the role of nanoparticle-protein complex architecture parameters, and the rational design of clinically useful curcumin nanoformulations. Considering all the biologically relevant phenomena, curcumin nanoformulations can be developed as a new neutraceutical or pharmaceutical agent.

Topics: Animals; Blood Proteins; Curcumin; Humans; Nanoparticles; Neoplasms; Protein Binding

Epigenetic alterations correspond to changes in DNA methylation, covalent modifications of histones, or altered miRNA expression patterns. These three mechanisms are interconnected and appear to be key players in tumor progression and failure of conventional chemotherapy. Dietary components emerged as a promising source of new epigenetically active compounds able to reverse these alterations and to actively regulate gene expression as well as molecular targets implicated in tumorigenesis. The polyphenolic compound curcumin (diferuloylmethane), a yellow spice that enters into the composition of curry, already described for its diverse and broad biological activities, is nowadays well described as an inhibitor of DNA methyltransferase so that it is considered as a DNA hypomethylating agent. It reestablishes the balance between histone acetyl transferase and histone deacetylase (HDAC 1, 3, 4, 5, 8) activity to selectively activate or inactivate the expression of genes implicated in cancer death and progression, respectively. Finally curcumin modulates miRNAs (miR-15a, miR-16, miR-21, miR-22, miR-26, miR-101, miR-146, miR-200, miR-203, and let-7) and their multiple target genes. In conclusion, this dietary compound is able to restore the epigenetic regulation balance and appears as an attractive preventive and/or therapeutic approach against human cancer.

Topics: Animals; Curcumin; Disease Models, Animal; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Acetyltransferases; Histone Deacetylases; Histones; Humans; MicroRNAs; Neoplasms; Promoter Regions, Genetic

Curcumin, a natural polyphenolic compound derived from turmeric (Curcuma longa L), has proven to be a modulator of multiple intercellular signalling pathways linked to inflammation, to proliferation, growth, invasion, drug sensitivity, angiogenesis and metastasis of cancer cells. Although curcumin has shown significant efficacy in cell culture studies, it has shown limited efficacy in clinical studies when administered in conventional oral formulations. This discrepancy is largely attributed to its poor oral bioavailability, which may result from its poor solubility, its poor pharmacokinetic profile, or a combination of both. To circumvent these barriers, alternative drug delivery strategies and systems should be explored. In this article, after a brief review of the physicochemical properties and pharmacokinetic profiles of curcumin, recent advances in curcumin oral delivery systems are discussed.

Topics: Administration, Oral; Animals; Curcumin; Drug Delivery Systems; Humans; Neoplasms

MicroRNAs (miRNAs) are small single-strand non-coding endogenous RNAs that regulate gene expression by multiple mechanisms. Recent evidence suggests that miRNAs are critically involved in the pathogenesis, evolution, and progression of cancer. The miRNAs are also crucial for the regulation of cancer stem cells (CSCs). In addition, miRNAs are known to control the processes of Epithelial-to-Mesenchymal Transition (EMT) of cancer cells. This evidence suggests that miRNAs could serve as targets in cancer treatment, and as such manipulating miRNAs could be useful for the killing CSCs or reversal of EMT phenotype of cancer cells. Hence, targeting miRNAs, which are deregulated in cancer, could be a promising strategy for cancer therapy. Recently, the regulation of miRNAs by natural, nontoxic chemopreventive agents including curcumin, resveratrol, isoflavones, (-)-epigallocatechin-3-gallate (EGCG), lycopene, 3,3'- diindolylmethane (DIM), and indole-3-carbinol (I3C) has been described. Therefore, natural agents could inhibit cancer progression, increase drug sensitivity, reverse EMT, and prevent metastasis though modulation of miRNAs, which will provide a newer therapeutic approach for cancer treatment especially when combined with conventional therapeutics.

Topics: Animals; Antineoplastic Agents; Carotenoids; Catechin; Curcumin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Lycopene; MicroRNAs; Molecular Targeted Therapy; Neoplasms; Neoplastic Stem Cells; Resveratrol; Stilbenes

Turmeric, a dried powder derived from the rhizome of Curcuma longa, has been used for centuries in certain parts of the world and has been linked to numerous biological activities including antioxidant, anti-inflammatory, anticancer, antigrowth, anti-arthritic, anti-atherosclerotic, antidepressant, anti-aging, antidiabetic, antimicrobial, wound healing, and memory-enhancing activities. One component of turmeric is curcumin, which has been extensively studied, as indicated by more than 5600 citations, most of which have appeared within the past decade. Recent research has identified numerous chemical entities from turmeric other than curcumin. It is unclear whether all of the activities ascribed to turmeric are due to curcumin or whether other compounds in turmeric can manifest these activities uniquely, additively, or synergistically with curcumin. However, studies have indicated that turmeric oil, present in turmeric, can enhance the bioavailability of curcumin. Studies over the past decade have indicated that curcumin-free turmeric (CFT) components possess numerous biological activities including anti-inflammatory, anticancer, and antidiabetic activities. Elemene derived from turmeric is approved in China for the treatment of cancer. The current review focuses on the anticancer and anti-inflammatory activities exhibited by CFT and by some individual components of turmeric, including turmerin, turmerone, elemene, furanodiene, curdione, bisacurone, cyclocurcumin, calebin A, and germacrone.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Clinical Trials as Topic; Curcuma; Curcumin; Cyclohexanols; Disease Models, Animal; Furans; Heterocyclic Compounds, 2-Ring; Humans; Hypoglycemic Agents; Inflammation; Neoplasms; Sesquiterpenes; Sesquiterpenes, Germacrane

Although much has been published about curcumin, which is obtained from turmeric, comparatively little is known about turmeric itself. Turmeric, a golden spice obtained from the rhizome of the plant Curcuma longa, has been used to give color and taste to food preparations since ancient times. Traditionally, this spice has been used in Ayurveda and folk medicine for the treatment of such ailments as gynecological problems, gastric problems, hepatic disorders, infectious diseases, and blood disorders. Modern science has provided the scientific basis for the use of turmeric against such disorders. Various chemical constituents have been isolated from this spice, including polyphenols, sesquiterpenes, diterpenes, triterpenoids, sterols, and alkaloids. Curcumin, which constitutes 2-5% of turmeric, is perhaps the most-studied component. Although some of the activities of turmeric can be mimicked by curcumin, other activities are curcumin-independent. Cell-based studies have demonstrated the potential of turmeric as an antimicrobial, insecticidal, larvicidal, antimutagenic, radioprotector, and anticancer agent. Numerous animal studies have shown the potential of this spice against proinflammatory diseases, cancer, neurodegenerative diseases, depression, diabetes, obesity, and atherosclerosis. At the molecular level, this spice has been shown to modulate numerous cell-signaling pathways. In clinical trials, turmeric has shown efficacy against numerous human ailments including lupus nephritis, cancer, diabetes, irritable bowel syndrome, acne, and fibrosis. Thus, a spice originally common in the kitchen is now exhibiting activities in the clinic. In this review, we discuss the chemical constituents of turmeric, its biological activities, its molecular targets, and its potential in the clinic.

Topics: Animals; Anti-Inflammatory Agents; Antidepressive Agents; Antineoplastic Agents; Curcuma; Curcumin; Diabetes Mellitus; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hypoglycemic Agents; Medicine, Traditional; Neoplasms; Neurodegenerative Diseases; Randomized Controlled Trials as Topic; Spices; Wound Healing

A hydrophobic polyphenol compound extracted from turmeric, curcumin has been widely utilized as traditional medicines for centuries in China and India. Over the last decades, because of its low toxicity, extensive studies have been focused on its physicochemical properties and pharmacological activities on various diseases, such as cancer, cardio-vascular disease, inflammatory bowel, wound healing, Alzheimer's disease, rheumatoid arthritis, and diabetes. In particular, bioactivities of curcumin as an effective chemopreventive agent, chemo-/radio-sensitizer for tumor cells, and chemo-/radio-protector for normal organs, are of extraordinary research interests in the literature. Despite these advantages, applications of curcumin are limited in clinical trials because of its poor water solubility and low oral bioavailability. Nano-preparations as an emerging platform for the efficient delivery of anti-cancer drugs should overcome these problems. In this review, we at first briefly revisit important properties of curcumin as well as its uses in cancer treatments, and then overview various nano-preparations of curcumin for cancer therapy, including nanoparticles, liposomes, micelles, nanoemulsions, cyclodextrin complexes, nanodisks, nanofibres, solid lipid nanoparticles, and curcumin conjugates.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biological Availability; Chemistry, Pharmaceutical; Curcumin; Drug Carriers; Humans; Liposomes; Micelles; Molecular Structure; Nanostructures; Nanotechnology; Neoplasms; Technology, Pharmaceutical

Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months. Curcumin's pleiotropic activities emanate from its ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E(2), prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.

Topics: Arthritis; Clinical Trials as Topic; Curcumin; Humans; Inflammatory Bowel Diseases; Irritable Bowel Syndrome; Neoplasms; Peptic Ulcer; Vitiligo

The polyphenol natural product curcumin possesses a plethora of biological and pharmacological properties. For years, much interest has been placed in the development and use of curcumin and its derivatives for the prevention and treatment of cardiovascular, diabetic, and neurodegenerative diseases, as well as cancer. Increasing evidence suggests that curcumin displays amazing molecular versatility, and the number of its proposed cellular targets grows as the research continues. The mammalian target of rapamycin (mTOR) is a master kinase, regulating cell growth/proliferation, survival, and motility. Dysregulated mTOR signaling occurs frequently in cancer, and targeting mTOR signaling is a promising strategy for cancer therapy. Recent studies have identified mTOR as a novel target of curcumin. Here we focus on reviewing current knowledge regarding the effects of curcumin on mTOR signaling for better understanding the anticancer mechanism of curcumin. The emerging studies of mTOR signaling and clinical studies on curcumin with cancer patients are also discussed here.

Topics: Animals; Antineoplastic Agents; Curcumin; Humans; Molecular Targeted Therapy; Neoplasms; Signal Transduction; TOR Serine-Threonine Kinases

Curcumin, a natural diphenolic compound derived from turmeric Curcuma longa, has proven to be a modulator of intracellular signaling pathways that control cancer cell growth, inflammation, invasion and apoptosis, revealing its anticancer potential. In this review, we focus on the design and development of nanoparticles, self-assemblies, nanogels, liposomes and complex fabrication for sustained and efficient curcumin delivery. We also discuss the anticancer applications and clinical benefits of nanocurcumin formulations. Only a few novel multifunctional and composite nanosystem strategies offer simultaneous therapy as well as imaging characteristics. We also summarize the challenges to developing curcumin delivery platforms and up-to-date solutions for improving curcumin bioavailability and anticancer potential for therapy.

Topics: Animals; Curcumin; Drug Delivery Systems; Drug Design; Humans; Nanomedicine; Nanoparticles; Neoplasms

Curcumin, one of the most studied chemopreventive agents, is a natural compound extracted from Curcuma longa L. Extensive research over the last half century has revealed that curcumin can inhibit the proliferation of various tumor cells in culture, prevent carcinogen induced cancers in rodents and inhibit the growth of human tumors in xenotransplant or orthotransplant animal models. Several phase I and phase II clinical trials indicated that curcumin is quite safe and may exhibit therapeutic efficacy. The utility of curcumin is limited by its lack of water solubility and relatively low in vivo bioavailability. Multiple approaches including nanoparticles, liposomes, micelles and phospholipid complexes are being sought to overcome these limitations. This review describes the general properties of curcumin and its potential effect against cancer including evidences of its antitumor action in vitro, in vivo, clinically and the strategies to overcome its low bioavailability.

Topics: Animals; Antineoplastic Agents, Phytogenic; Chemistry, Pharmaceutical; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Curcumin; Humans; Neoplasms; Randomized Controlled Trials as Topic

Tumors are multifaceted; in fact, numerous things happen in synchrony to enable tumor promotion and progression. Any type of cancer is associated with the modification of 300-500 normal genes and characterized by the deregulation of cell signaling pathways at multiple steps leading to cancer phenotype. Thus a proper management of tumorigenesis requires the development of multi-targeted therapies. Several adverse effects associated with present day cancer therapies and the thirsts for multi-targeted safe anticancer drug instigate the use of natural polyphenol, curcumin. It appears to involve a blend of anti-carcinogenic, pro-apoptotic, anti-angiogenic, anti-metastatic, immunomodulatory and antioxidant activities. Also the molecular mechanisms implicated for the pleotropic activities of curcumin are diverse and seem to involve a combination of cell signaling pathways at multiple levels of tumorigenesis. Being a potent scavenger of reactive oxygen species, curcumin also ameliorates systemic toxicity in tumor-bearer. Taken together, by placing particular emphasis on molecular basis of tumor promotion and progression this review summarizes the anti-cancer properties of curcumin that may be exploited for successful clinical cancer prevention.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Cell Transformation, Neoplastic; Curcumin; Humans; Neoplasms; Reactive Oxygen Species

Obesity is characterized as an increased BMI, which is associated with the increased risk of several common cancers, including colorectal, breast, endometrial, renal, esophageal, gallbladder, melanoma, multiple myeloma, leukemia, lymphoma and prostate cancer. The increased risk of obesity-related cancers could be mediated by insulin resistance, adipokines, obesity-related inflammatory cytokines, sex hormones, transcription factors and oxidative stress, which disrupt the balance between cell proliferation and apoptosis. The yellowish compound, curcumin (diferuloylmethane), is known to possess multifaceted pharmacological effects. The molecular mechanisms linking obesity to cancer risk, and how curcumin mediates anticancer and obesity activities, have not yet been publicized. Curcumin modulates multiple molecular targets and reverses insulin resistance as well as other symptoms that are associated with obesity-related cancers. In this study, we show that ample evidence exists to support recommendations that curcumin mediates multiple molecular pathways, and is considered to be of therapeutic value in the treatment and prevention of obesity-related cancers.

Topics: Adipokines; Animals; Antineoplastic Agents; Curcumin; Gonadal Steroid Hormones; Humans; Inflammation Mediators; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Lipid Metabolism; Neoplasms; Obesity; Oxidative Stress

Chemotherapy remains the core of anticancer treatment. However, despite the tremendous strides made in the development of targeted anticancer therapies, emergence of resistance to chemotherapeutic drugs is still a major obstacle in the successful management of resistant tumours. Therefore, profound investigation into the in-depth molecular mechanisms of drug resistance is essential and may hopefully translate into effective therapies that can flip the switch from drug resistance to susceptibility. Mechanistically, resistance phenomena may be explained by (i) overexpression of drug efflux pumps, (ii) enhanced drug detoxification, (iii) rapid DNA repair efficiency, (iv) defects in apoptosis regulation, and (v) active cell survival signals. Several adverse effects associated with multidrug resistance and the need for safe multi-targeted anticancer drugs instigated the use of the phytochemical, curcumin, the yellow pigment of the spice turmeric, which has pleotropic activities. We performed a structured literature review using PubMed and Medline searches with secondary review of cited publications, identifying studies on the role of curcumin in conquering drug resistance in cancer. This review describes how curcumin sensitizes cancer cells through regulation of multiple multidrug resistance pathways, thus employing one drug for multiple targets. Curcumin helps the cancer cells to regain their 'forgotten' apoptosis, modulates drug-target interaction at different levels, restrains survival pathways when their proteins are overexpressed, and finds an alternate way to carry forward the process of sensitization of different resistant tumours. Additionally, the review dissects the role of curcumin, if any, in targeting the major culprit of drug resistance, cancer stem cells (CSC), thereby circumventing resistance. Taken together, this review strongly suggests that curcumin is a promising chemosensitizing agent and that the unique properties of curcumin may be exploited for successful management of resistant tumours.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Curcumin; Drug Resistance, Neoplasm; Humans; Neoplasms

Curcumin (CUR), a bioactive component of turmeric, which is a commonly used spice and nutritional supplement, is isolated from the rhizomes of Curcuma longa Linn. (Zingiberaceae). In recent years, the potential pharmacological actions of CUR in inflammatory disorders, cardiovascular disease, cancer, Alzheimer's disease and neurological disorders have been shown. However, the clinical application of CUR is severely limited by its main drawbacks such as instability, low solubility, poor bioavailability and rapid metabolism. Multifarious nanotechnology-based delivery approaches have been used to enhance the oral bioavailability, biological activity or tissue-targeting ability of CUR. This article reviews potential novel drug delivery systems for CUR including liposomes, polymeric nanoparticles, solid lipid nanoparticles, micelles, nanogels, nanosuspensions, nanoemulsions, complexes and dendrimer/dimer, which provide promising results for CUR to improve its biological activities.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Curcuma; Curcumin; Drug Delivery Systems; Humans; Nanostructures; Nanotechnology; Neoplasms

Mesenchymal stem cells (MSCs) are one subgroup of adult stem cells and possess a proliferative potential and ability to differentiate into various ceells.. Emerging evidence suggests that MSCs can reprogram toward cancer stem cells (CSCs), due to alterations of intrinsic and extrinsic microenvironments, leading to tumorigenesis. The CSC concept has fundamental clinical implications because of its involvement in cell migration/invasion, metastasis, and treatment resistance. Therefore, targeting CSCs provides a novel therapeutic strategy for cancer treatment. However, the origin of CSCs and its molecular connections are not fully understood. Emerging evidence suggests the existence of an inter-relationship between CSCs and epithelial-to-mesenchymal transition (EMT) phenotypic cells, in the context of inflammation and hypoxia, as well as the potential role of miRNAs.. We suggest that targeting CSC signatures along with EMT, inflammation, and hypoxia will provide a more effective therapeutic approach for the elimination of CSCs. To that end, curcumin especially its synthetic novel analog CDF have been shown to attenuate CSC characteristics along with the deregulation of multiple pathways and miRNAs, leading to the inhibition of human tumor growth in vivo, suggesting the potential role of CDF as an anti-tumor agent for the prevention/treatment of tumor progression.

Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Curcumin; Epithelial-Mesenchymal Transition; Humans; Inflammation; Mesenchymal Stem Cells; MicroRNAs; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment

Curcumin, a natural yellow pigment of turmeric, has become focus of interest with regard to its role in regulation of matrix metalloproteinases (MMPs). MMPs are metal-dependent endopeptidases capable of degrading components of the extracellular matrix. MMPs are involved in chronic diseases such as arthritis, Alzheimer's disease, psoriasis, chronic obstructive pulmonary disease, asthma, cancer, neuropathic pain, and atherosclerosis.. Curcumin regulates the expression and secretion of various MMPs. This review documents the matrix metalloproteinase inhibitory activity of curcumin on various diseases viz., cancer, arthritis, and ulcer. Finally, the steps to be taken for getting potent curcuminoids have also been discussed in the structure-activity relationship (SAR) section. From this review, readers can get answer to the question: Is curcumin a potential MMPI candidate?. Numerous approaches have been taken to beget a molecule with specificity restricted to a particular MMP as well as good oral bioavailability; however, nearly all the molecules lack these criteria. Using quantitative structure-activity relationship (QSAR) modeling and virtual screening, new analogs of curcumin can be designed which will be selectively inhibiting different MMPs.

Topics: Animals; Curcumin; Humans; Inflammation; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms; Structure-Activity Relationship

Cancer is one of the leading causes of death in the United States and around the world. Most modern drug-targeted therapies, besides being enormously expensive, are associated with serious side effects and morbidity. Still, the search continues for an ideal treatment that has minimal side effects and is cost-effective. Indeed, the design and development of chemopreventive agents that act on specific and/or multiple molecular and cellular targets is gaining support as a rational approach to prevent and treat cancer. We present evidence on numerous dietary agents identified from fruits and vegetables that act on multiple signal transduction and apoptotic cascades in various tumor cells and animal models. Some of the most interesting and well documented are turmeric (curcumin), resveratrol, silymarin, EGCG, and genistein. This review will provide an insight on the cellular and molecular mechanism(s) by which dietary agents modulate multiple signaling and apoptotic pathways in tumor cells and elucidate the role of these agents in both prevention and treatment of cancer.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Catechin; Clinical Trials as Topic; Curcuma; Curcumin; Diet; Disease Models, Animal; Fruit; Genistein; Humans; Neoplasms; Resveratrol; Signal Transduction; Silymarin; Stilbenes; United States; Vegetables

The emergence of cancer stem cell theory has profound implications for cancer chemoprevention and therapy. Cancer stem cells give rise to the tumor bulk through continuous self-renewal and differentiation. Understanding the mechanisms that regulate self-renewal is of greatest importance for discovery of anticancer drugs targeting cancer stem cells. Naturally occurring dietary compounds have received increasing attention in cancer chemoprevention. The anticancer effects of many dietary components have been reported for both in vitro and in vivo studies. Recently, a number of studies have found that several dietary compounds can directly or indirectly affect cancer stem cell self-renewal pathways. Herein we review the current knowledge of most common natural dietary compounds for their impact on self-renewal pathways and potential effect against cancer stem cells. Three pathways (Wnt/β-catenin, Hedgehog and Notch) are summarized for their functions in self-renewal of cancer stem cells. The dietary compounds, including curcumin, sulforaphane, soy isoflavone, epigallocatechin-3-gallate, resveratrol, lycopene, piperine and vitamin D(3), are discussed for their direct or indirect effect on these self-renewal pathways. Curcumin and piperine have been demonstrated to target breast cancer stem cells. Sulforaphane has been reported to inhibit pancreatic tumor-initiating cells and breast cancer stem cells. These studies provide a basis for preclinical and clinical evaluation of dietary compounds for chemoprevention of cancer stem cells. This may enable us to discover more preventive strategies for cancer management by reducing cancer resistance and recurrence and improving patient survival.

Topics: Alkaloids; Animals; Anticarcinogenic Agents; Benzodioxoles; beta Catenin; Carotenoids; Catechin; Cell Differentiation; Cell Proliferation; Cholecalciferol; Curcumin; Diet; Humans; Isoflavones; Isothiocyanates; Lycopene; Neoplasms; Neoplastic Stem Cells; Piperidines; Polyunsaturated Alkamides; Resveratrol; Signal Transduction; Stilbenes; Sulfoxides; Thiocyanates; Wnt Proteins

Since ancient times, chemopreventive agents have been used to treat/prevent several diseases including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, antioxidant, antiproliferative, anticarcinogenic, and antiangiogenic activity in various cell cultures and some animal studies. Research over the past 4 decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been shown to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician's armamentarium.

Topics: Animals; Anticarcinogenic Agents; Chemoprevention; Curcumin; Drug Delivery Systems; Emulsions; Humans; Lactic Acid; Liposomes; Mice; Microscopy, Atomic Force; Models, Chemical; Nanoparticles; Neoplasms; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

Oxidative damage and inflammation have been pointed out in preclinical studies as the root cause of cancer and other chronic diseases such as diabetes, hypertension, Alzheimer's disease, etc. Epidemiological and clinical studies have suggested that cancer could be prevented or significantly reduced by treatment with anti-oxidant and anti-inflammatory drugs, therefore, curcumin, a principal component of turmeric (a curry spice) showing strong anti-oxidant and anti-inflammatory activities, might be a potential candidate for the prevention and/or treatment of cancer and other chronic diseases. However, curcumin, a highly pleiotropic molecule with an excellent safety profile targeting multiple diseases with strong evidence on the molecular level, could not achieve its optimum therapeutic outcome in past clinical trials, largely due to its low solubility and poor bioavailability. Curcumin can be developed as a therapeutic drug through improvement in formulation properties or delivery systems, enabling its enhanced absorption and cellular uptake. This review mainly focuses on the anti-inflammatory potential of curcumin and recent developments in dosage form and nanoparticulate delivery systems with the possibilities of therapeutic application of curcumin for the prevention and/or treatment of cancer.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Biological Availability; Chemistry, Pharmaceutical; Curcuma; Curcumin; Drug Delivery Systems; Humans; Inflammation; Molecular Targeted Therapy; Neoplasms; Phytotherapy; Plant Extracts; Signal Transduction

Several nutritional compounds are the focus of public attention because of their potential beneficial health effects. Turmeric is a spice that comes from the root Curcuma longa. Extensive research over the past half century and especially in recent years has revealed important functions of curcumin and a timely review of clinical state-of-the-art using curcumin.. In-vitro and in-vivo research has shown various activities, such as anti-inflammatory, antiviral, antifungal, cytokines release, antioxidant, immunomodulatory, enhancing of the apoptotic process, and antiangiogenic properties. Curcumin also have been shown to be a mediator of chemo-resistance and radio-resistance.. Various in-vitro and in-vivo and scarce number of clinical studies on curcumin were identified. The various effects and properties of curcumin are summarized in this review, including preclinical and especially clinical studies. This review concentrates on recent knowledge and research with curcumin clinical applications, and clinical studies, focusing on studies published between 2008 and 2011 demonstrating the gap between preclinical and clinical research.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Antifungal Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Clinical Trials as Topic; Curcuma; Curcumin; Drug Evaluation, Preclinical; Functional Food; Humans; Inflammation; Models, Animal; Neoplasms; Plant Extracts; Plant Roots; Spices

A number of bioactive dietary components are of particular interest in the field of epigenetics. Many of these compounds display anticancer properties and may play a role in cancer prevention. Numerous studies suggest that a number of nutritional compounds have epigenetic targets in cancer cells. Importantly, emerging evidence strongly suggests that consumption of dietary agents can alter normal epigenetic states as well as reverse abnormal gene activation or silencing. Epigenetic modifications induced by bioactive dietary compounds are thought to be beneficial. Substantial evidence is mounting proclaiming that commonly consumed bioactive dietary factors act to modify the epigenome and may be incorporated into an 'epigenetic diet'. Bioactive nutritional components of an epigenetic diet may be incorporated into one's regular dietary regimen and used therapeutically for medicinal or chemopreventive purposes. This article will primarily focus on dietary factors that have been demonstrated to influence the epigenome and that may be used in conjunction with other cancer prevention and chemotherapeutic therapies.

Topics: Anticarcinogenic Agents; Catechin; Curcumin; Diet; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; Epigenesis, Genetic; Epigenomics; Genistein; Histones; Humans; Isothiocyanates; MicroRNAs; Neoplasms; Polyphenols; Resveratrol; Stilbenes; Tea

Turmeric, a plant rhizome that is often dried, ground and used as a cooking spice, has also been used medicinally for several thousand years. Curcumin, the phytochemical that gives turmeric its golden color, is responsible for most of the therapeutic effects of turmeric. In recent years curcumin has been studied for its effects on chronic diseases such as diabetes, Alzheimer's, and cancer. Though many researchers are investigating turmeric/curcumin in cancer therapy, there is little epidemiologic information on the effects of turmeric consumption. With limited availability of pharmacologic interventions in many areas of the world, use of turmeric in the diet may help to alleviate some of the disease burden through prevention. Here we provide a brief overview of turmeric consumption in different parts of the world, cancer rates in those regions, possible biochemical mechanisms by which turmeric acts and practical recommendations based on the information available.

Topics: Curcuma; Curcumin; Diet; Humans; Neoplasms; Phytotherapy

Although safe in most cases, ancient treatments are ignored because neither their active components nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. Recently, extensive research has addressed the chemotherapeutic potential of this relatively nontoxic-plant-derived polyphenol. Because most cancers are caused by deregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. In this regard, curcumin has been reported to have immense potentiality for being used in cancer chemotherapy because of its control over the machineries of cell survival, proliferation, invasion, and angiogenesis. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. This review seeks to summarize the unique multifocal signal modulatory properties of the "ancient weapon," curcumin, which may be exploited for successful clinical cancer prevention.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Proliferation; Curcuma; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Medicine, Ayurvedic; Neoplasm Metastasis; Neoplasms; Rhizome; Signal Transduction

Chemoprevention of malignant tumor growth is a novel and potentially powerful approach for tumor therapy. Recent in vitro and in vivo investigations provide increasing evidence that naturally occurring substances may exhibit significant chemopreventive activities. To this regard, the spice Curcumin, widely used in Indian cuisine, has been identified to show considerable anti-tumor effects. Most interestingly, numerous studies have not shown toxic side effects of this substance. Curcumin induces tumor cell apoptosis along with a reduction of tumor cell invasion and metastasis. Recent molecular studies provide evidence that Curcumin acts via a control of the NFkappaB pathway exerting most of the various modulating and moderating effects on malignant cells. Along with these in vitro studies, ex vivo and first clinical investigations confirm the anti-tumor effects of Curcumin, either as an isolated chemoprevention substance or in combination with chemotherapeutic agents as supportive measure reducing pharmaceutical resistance of tumor cells to certain chemotherapeutics. Despite our increasing knowledge on this interesting substance there still remain many unknown effects that deserve intense investigation.

Topics: Anticarcinogenic Agents; Apoptosis; Cell Cycle; Cell Proliferation; Chemoprevention; Curcuma; Curcumin; Humans; MicroRNAs; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms

Curcumin is the active ingredient of turmeric. It is widely used as a kitchen spice and food colorant throughout India, Asia and the Western world. Curcumin is a major constituent of curry powder, to which it imparts its characteristic yellow colour. For over 4000 years, curcumin has been used in traditional Asian and African medicine to treat a wide variety of ailments. There is a strong current public interest in naturally occurring plant-based remedies and dietary factors related to health and disease. Curcumin is non-toxic to human subjects at high doses. It is a complex molecule with multiple biological targets and different cellular effects. Recently, its molecular mechanisms of action have been extensively investigated. It has anti-inflammatory, antioxidant and anti-cancer properties. Under some circumstances its effects can be contradictory, with uncertain implications for human treatment. While more studies are warranted to further understand these contradictions, curcumin holds promise as a disease-modifying and chemopreventive agent. We review the evidence for the therapeutic potential of curcumin from in vitro studies, animal models and human clinical trials.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antineoplastic Agents; Antioxidants; Cell Line; Cell Line, Tumor; Clinical Trials as Topic; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammatory Bowel Diseases; Neoplasms; Randomized Controlled Trials as Topic; Transcription Factors

Scientific progress in genetics, cell and molecular biology has greatly ameliorated our comprehensive understanding of the molecular mechanisms of neoplastic transformation and progression. The rapidly advancing identification of molecular targets in human cancers during the last decade has provided an excellent starting point for the development of novel therapeutics. A huge variety of potential molecular targets have been identified, many of which are already in the market for therapeutic purposes. It is now becoming possible to target pathways and/or molecules that are crucial in maintaining the malignant phenotype. Traditional Chinese medicine (TCM) is often considered as alternative or complementary medicine. TCM represents a holistic approach and lacks high-quality scientific evidence on its effectiveness. Therefore, it is frequently regarded with some scepticism by western academic medicine. In this review, we report that application of modern technologies allowed identification of novel molecular targets modulating the anti-tumour activity of natural products derived from TCM. Moreover, we tried to cross the bridge between TCM and Western modern medicine to be able to implement them for the sake of cancer patients.

Topics: Animals; Antineoplastic Agents, Phytogenic; Arsenic Trioxide; Arsenicals; Artemisinins; Artesunate; Berberine; Biological Products; Cantharidin; Complementary Therapies; Curcumin; Drug Delivery Systems; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Humans; Medicine, Chinese Traditional; Models, Biological; Neoplasms; Oxides

The proteasome is a multicatalytic protease complex whose activity is required for the growth of normal or tumor cells. It has been shown that human cancer cells are more sensitive to proteasome inhibition than normal cells, indicating that the proteasome could be a target of chemotherapy. Studies suggest that traditional Chinese medicine (TCM) is an effective approach for cancer treatment. Here we reviewed several TCMs for their potential in treatment of cancer. This short review focuses mainly on the TCMs that potentially target the tumor cellular proteasome and NF-kappaB pathway whose activation is dependent on the proteasome activity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Benzyl Compounds; Curcumin; Diterpenes; Drug Delivery Systems; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Epoxy Compounds; Humans; Medicine, Chinese Traditional; Molecular Structure; Naphthoquinones; Neoplasms; Pentacyclic Triterpenes; Phenanthrenes; Phenols; Proteasome Endopeptidase Complex; Signal Transduction; Triterpenes

Curcumin, commonly called diferuloyl methane, is a hydrophobic polyphenol derived from rhizome (turmeric) of the herb Curcuma longa. Extensive research over the last half century has revealed important functions of curcumin. In vitro and in vivo research has shown various activities, such as anti-inflammatory, cytokines release, antioxidant, immunomodulatory, enhancing of the apoptotic process, and anti-angiogenic properties. Curcumin has also been shown to be a mediator of chemo-resistance and radio-resistance. The anti-cancer effect has been seen in a few clinical trials, mainly as a native chemoprevention agent in colon and pancreatic cancer, cervical neoplasia and Barrets metaplasia. Some clinical studies with healthy volunteers revealed a low bioavailability of curcumin, casting doubt on the use of curcumin only as food additive. Our clinical experience with curcumin, along with the anti-metabolite gemcitabine in the treatment of patients with advanced pancreatic carcinoma, produced an objective response in less than 10% of patients, with a minor effect on survival. However, the safety of this combination was proved. Curcumin's potent anti-proliferative activity interacting with several intracellular signal transduction pathways may potentiate the anti-tumor effect of gemcitabine. The preclinical data lead to various, but still scarce, clinical studies (some on-going) that demonstrated the possible efficacy of this treatment as a chemopreventive or chemotherapeutic agent. This review will focus on the clinical evidence, including our experience with curcumin as a chemopreventive and therapeutic agent and the in vitro background results.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Curcumin; Humans; Neoplasms

Curcumin is a natural polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over past 50 years has indicated that this polyphenol is highly pleiotropic molecule capable of preventing and treating various cancers. The anticancer potential of Curcumin is severely affected by its limited systemic and target tissue bioavailability and rapid metabolism. In the present review article, we provide a summarized account of different drug delivery systems employed for tackling the problem of cucumin's bioavailability such as liposomes, phospholipid complexes and nanoparticles. Concomitantly we have reviewed the large volume of literature reports describing structural modifications of Curcumin and the anticancer potential of its analogs. Some of the difluorocurcumin analogs allowing longer circulation times and preferential accumulation in the pancreas seem to offer promising leads for conducting first in-depth animal studies and subsequently clinical trials for the use of these analogs for prevention of tumor progression and/or treatments of human malignancies.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Curcuma; Curcumin; Drug Delivery Systems; Humans; Models, Molecular; Neoplasms; Rats

The clinical benefits of curcumin as a single agent were demonstrated in patients with advanced pancreatic cancer in a phase 2 study despite pharmacokinetic analysis showing a much lower plasma concentration of curcumin in humans than in vitro. The diverse and broad biological activities of curcumin are mediated through direct interaction of curcumin with target proteins as well as epigenetic modulation of target genes, supported by evidence that curcumin modulates gene expression in a time- and concentration-dependent manner in human cancer cells. This review delineates the novel mechanisms of curcumin as an epigenetic agent through its interaction with histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and microRNAs. Accumulating data support curcumin's functionality in modulating multiple biological processes at low concentrations through its activity as an epigenetic agent. The development of curcumin as an epigenetic agent warrants further preclinical and clinical studies to explore its diversity and efficacy in cancer treatment and in combination with other anticancer agents.

Topics: Antineoplastic Agents; Curcumin; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Acetyltransferases; Histone Deacetylases; Humans; MicroRNAs; Neoplasms

Curcumin (diferuloylmethane), a derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Abundant sources provide interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancer. The pleiotropic role of this dietary compound includes the inhibition of several cell signaling pathways at multiple levels, such as transcription factors (NF-κB and AP-1), enzymes (COX-2, MMPs), cell cycle arrest (cyclin D1), proliferation (EGFR and Akt), survival pathways (β-catenin and adhesion molecules), and TNF. Curcumin up-regulates caspase family proteins and down-regulates anti-apoptotic genes (Bcl-2 and Bcl-X(L)). In addition, cDNA microarrays analysis adds a new dimension for molecular responses of cancer cells to curcumin at the genomic level. Although, curcumin's poor absorption and low systemic bioavailability limits the access of adequate concentrations for pharmacological effects in certain tissues, active levels in the gastrointestinal tract have been found in animal and human pharmacokinetic studies. Currently, sufficient data has been shown to advocate phase II and phase III clinical trials of curcumin for a variety of cancer conditions including multiple myeloma, pancreatic, and colon cancer.

Topics: Animals; Antineoplastic Agents; Biological Availability; Chemoprevention; Clinical Trials as Topic; Curcumin; Drug Delivery Systems; Humans; Neoplasms; Oligonucleotide Array Sequence Analysis

Curcumin (diferuloylmethane), the yellow pigment in Indian saffron (Curcuma longa; also called turmeric, haldi, or haridara in the East and curry powder in the West), has been consumed by people for centuries as a dietary component and for a variety of proinflammatory ailments. Extensive research within the last decade in cell culture and in rodents has revealed that curcumin can sensitize tumors to different chemotherapeutic agents including doxorubicin, 5-FU, paclitaxel, vincristine, melphalan, butyrate, cisplatin, celecoxib, vinorelbine, gemcitabine, oxaliplatin, etoposide, sulfinosine, thalidomide, and bortezomib. Chemosensitization has been observed in cancers of the breast, colon, pancreas, gastric, liver, blood, lung, prostate, bladder, cervix, ovary, head and neck, and brain and in multiple myeloma, leukemia, and lymphoma. Similar studies have also revealed that this agent can sensitize a variety of tumors to gamma radiation including glioma, neuroblastoma, cervical carcinoma, epidermal carcinoma, prostate cancer, and colon cancer. How curcumin acts as a chemosensitizer and radiosensitizer has also been studied extensively. For example, it downregulates various growth regulatory pathways and specific genetic targets including genes for NF-κB, STAT3, COX2, Akt, antiapoptotic proteins, growth factor receptors, and multidrug-resistance proteins. Although it acts as a chemosensitizer and radiosensitizer for tumors in some cases, curcumin has also been shown to protect normal organs such as liver, kidney, oral mucosa, and heart from chemotherapy and radiotherapy-induced toxicity. The protective effects of curcumin appear to be mediated through its ability to induce the activation of NRF2 and induce the expression of antioxidant enzymes (e.g., hemeoxygenase-1, glutathione peroxidase, modulatory subunit of gamma-glutamyl-cysteine ligase, and NAD(P)H:quinone oxidoreductase 1, increase glutathione (a product of the modulatory subunit of gamma-glutamyl-cysteine ligase), directly quench free radicals, and inhibit p300 HAT activity. These preclinical studies are expected to lead to clinical trials to prove the potential of this age-old golden spice for treating cancer patients.

Topics: Animals; Anticarcinogenic Agents; Clinical Trials as Topic; Curcumin; Drug Resistance, Neoplasm; Humans; Neoplasms; Radiation-Protective Agents; Radiation-Sensitizing Agents

Turmeric, the source of the polyphenolic active compound curcumin (diferuloylmethane), has been used extensively in traditional medicine since ancient times as a household remedy against various diseases, including hepatic disorders, cough, sinusitis, rheumatism, and biliary disorders. In the past few decades, a number of studies have been done on curcumin showing its potential role in treating inflammatory disorders, cardiovascular disease, cancer, AIDS, and neurological disorders. However, the main drawback associated with curcumin is its poor aqueous solubility and stability in gastrointestinal fluids, which leads to poor bioavailability. Multifarious novel drug-delivery approaches, including microemulsions, nanoemulsions, liposomes, solid lipid nanoparticles, microspheres, solid dispersion, polymeric nanoparticles, and self-microemulsifying drug-delivery systems have been used to enhance the bioavailability and tissue-targeting ability of curcumin. These attempts have revealed promising results for enhanced bioavailability and targeting to disease such as cancer, but more extensive research on tissue-targeting and stability-related issues is needed. Tissue targeting and enhanced bioavailability of curcumin using novel drug-delivery methods with minimum side effects will in the near future bring this promising natural product to the forefront of therapy for the treatment of human diseases such as cancer and cardiovascular ailments. We provide a detailed analysis of prominent research in the field of curcumin drug delivery with special emphasis on bioavailability-enhancement approaches and novel drug-delivery system approaches.

Topics: Animals; Antineoplastic Agents; Biological Availability; Cardiovascular Diseases; Curcuma; Curcumin; Dosage Forms; Drug Delivery Systems; Drug Stability; Humans; Molecular Targeted Therapy; Neoplasms; Rats; Rats, Sprague-Dawley; Solubility

Despite considerable improvements in the tolerance and efficacy of novel chemotherapeutic agents, the mortality of hematological malignancies is still high due to therapy relapse, which is associated with bad prognosis. Dietary polyphenolic compounds are of growing interest as an alternative approach, especially in cancer treatment, as they have been proven to be safe and display strong antioxidant properties. Here, we provide evidence that both resveratrol and curcumin possess huge potential for application as both chemopreventive agents and anticancer drugs and might represent promising candidates for future treatment of leukemia. Both polyphenols are currently being tested in clinical trials. We describe the underlying mechanisms, but also focus on possible limitations and how they might be overcome in future clinical use--either by chemically synthesized derivatives or special formulations that improve bioavailability and pharmacokinetics.

Topics: Antioxidants; Apoptosis; Cell Cycle; Cell Proliferation; Clinical Trials as Topic; Curcumin; Diet; Hematologic Neoplasms; Humans; Molecular Structure; Neoplasms; Oxidative Stress; Reactive Oxygen Species; Resveratrol; Stilbenes

A voluminous literature suggests that an increase in consumption of fruit and vegetables is a relatively easy and practical strategy to reduce significantly the incidence of cancer. The beneficial effect is mostly associated with the presence of phytochemicals in the diet. This review focuses on a group of them, namely isothiocyanate, curcumin, genistein, epigallocatechin gallate, lycopene and resveratrol, largely studied as chemopreventive agents and with potential clinical applications. Cellular and animal studies suggest that these molecules induce apoptosis and arrest cell growth by pleiotropic mechanisms. The anticancer efficacy of these compounds may result from their use in monotherapy or in association with chemotherapeutic drugs. This latter approach may represent a new pharmacological strategy against several types of cancers. However, despite the promising results from experimental studies, only a limited number of clinical trials are ongoing to assess the therapeutic efficacy of these molecules. Nevertheless, the preliminary results are promising and raise solid foundations for future investigations.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Carotenoids; Catechin; Curcumin; Genistein; Humans; Isothiocyanates; Lycopene; Neoplasms; Resveratrol; Stilbenes

Although safe in most cases, ancient treatments are ignored because neither their active component nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. For centuries it has been known that turmeric exhibits anti-inflammatory activity, but extensive research performed within the past two decades has shown that this activity of turmeric is due to curcumin (diferuloylmethane). This agent has been shown to regulate numerous transcription factors, cytokines, protein kinases, adhesion molecules, redox status and enzymes that have been linked to inflammation. The process of inflammation has been shown to play a major role in most chronic illnesses, including neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. In the current review, we provide evidence for the potential role of curcumin in the prevention and treatment of various proinflammatory chronic diseases. These features, combined with the pharmacological safety and negligible cost, render curcumin an attractive agent to explore further.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Autoimmune Diseases; Cardiovascular Diseases; Curcuma; Curcumin; Cytokines; Humans; Inflammation; Lung Diseases; Metabolic Diseases; Neoplasms; Neurodegenerative Diseases; Plant Extracts

Cancer cells are known to have alterations in multiple cellular signaling pathways and because of the complexities in the communication between multiple signaling networks, the treatment and the cure for most human malignancies is still an open question. Perhaps, this is the reason why specific inhibitors that target only one pathway have been typically failed in cancer treatment. However, the in vitro and in vivo studies have demonstrated that some natural products such as isoflavones, indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), curcumin, (-)-epigallocatechin-3-gallate (EGCG), resveratrol, lycopene, etc, have inhibitory effects on human and animal cancers through targeting multiple cellular signaling pathways and thus these "natural agents" could be classified as multi-targeted agents. This is also consistent with the epidemiological studies showing that the consumption of fruits, soybean and vegetables is associated with reduced risk of several types of cancers. By regulating multiple important cellular signaling pathways including NF-kappaB, Akt, MAPK, Wnt, Notch, p53, AR, ER, etc, these natural products are known to activate cell death signals and induce apoptosis in pre-cancerous or cancer cells without affecting normal cells. Therefore, non-toxic "natural agents" harvested from the bounties of nature could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies.

Topics: Antineoplastic Agents; Carotenoids; Catechin; Curcumin; Humans; Indoles; Isoflavones; Lycopene; Neoplasms; Resveratrol; Signal Transduction; Stilbenes

Cancer and cardiovascular disease (CVD) chemoprevention can be achieved by the use of natural, synthetic, or biologic compounds to reverse, suppress, or prevent the development of diseases. Chemoprevention is a potential anti-cancer approach, which has reduced secondary effects in comparison to classical prophylaxis. Natural compounds such as flavonoids reduce oxidative stress, which is the most likely mechanism in the protective effects of these compounds. Even though the exact mechanisms of action are not well understood another central action mechanism of polyphenolic flavonoids seems to be an induction of apoptosis as demonstrated in numerous cellular systems. Moreover, flavonoids may modulate protein and lipid kinase signaling pathways. Understanding the mechanism of these natural products will contribute to the development of more specific preventive strategies against cancer and CVD. Much of the research in the field is focused on epigallocatechin-3-O-gallate (EGCG), quercetin and curcumin, which were found to have beneficial effects against cancer and CVD. We review the chemoprotective mechanisms through which these natural compounds exert their beneficial effects against cancer and CVDs.

Topics: Anticarcinogenic Agents; Antioxidants; Cardiovascular Diseases; Catechin; Curcumin; Humans; Models, Biological; Molecular Structure; Neoplasms; Oxidative Stress; Quercetin

Drugs able to regulate the histone modifier enzymes are very promising tools for the treatment of several diseases, such as cancer. Histone acetyltransferase (HAT) inhibitors are compounds able to inhibit the catalytic activity of HATs reported to be active in cancer, or in several other diseases, such as Alzheimer (AD), diabetes and hyperlipidaemia.. Here we review the status and the rationale for the use of HAT inhibitors in the treatment of various diseases.. Patents have been found on the espacenet database; the clinical trials have been reported as in the clinicaltrial.gov website.. Despite the fact that other drugs able to regulate the histone modifier enzymes (such as histone deacetylase inhibitors) have been already approved for the treatment of cancer, HAT inhibitors seem promising for the treatment of human diseases such as AD and diabetes, although side effects and toxicity need to be investigated.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Curcumin; Drug Evaluation, Preclinical; Enzyme Inhibitors; Histone Acetyltransferases; Humans; Neoplasms; Patents as Topic

There is a large body of evidence that the consumption of fruit and vegetables can decrease the risk of cancer. However, the link between diet and health is extremely complex. Some dietary phytochemicals seem to offer protection in an exposure-related manner and many molecular targets and signaling pathways affected by phytochemicals have been discovered. Although in vitro studies have contributed significantly to our understanding, quite a number use concentrations orders of magnitude greater than those achievable in humans or toxic to normal tissues (exemplified by toxic concentrations of indole-3-carbinol, epigallocatechin-3-gallate, curcumin, and genistein for breast cells). Such studies may produce results that are physiologically irrelevant, thus hindering predictions of efficacy. Here, we argue for careful consideration to be given to the in vitro experimental conditions under which dietary phytochemicals are investigated. Design features, such as the use of appropriate nontoxic concentrations, extended treatment times, three-dimensional cultures, primary tumor cultures, and comparison of susceptibility of various cancer subtypes, should improve our understanding of their molecular targets. This in turn would facilitate predictions as to their potential usefulness in the clinic.

Topics: Animals; Catechin; Cell Transformation, Neoplastic; Curcumin; Diet; Food; Fruit; Genistein; Humans; Indoles; Mice; Models, Biological; Neoplasms; Phytotherapy; Vegetables

Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.

Topics: Antineoplastic Agents; Cell Death; Curcumin; Humans; Neoplasms

Cancer cells exhibit deregulation in multiple cellular signaling pathways. Therefore, treatments using specific agents that target only one pathway usually fail in cancer therapy. The combination treatments using chemotherapeutic agents with distinct molecular mechanisms are considered more promising for higher efficacy; however, using multiple agents contributes to added toxicity. Emerging evidence has shown that some "natural products" such as isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin among many others, have growth inhibitory and apoptosis inducing effects on human and animal cancer cells mediated by targeting multiple cellular signaling pathways in vitro without causing unwanted toxicity in normal cells. Therefore, these non-toxic "natural products" from natural resources could be useful in combination with conventional chemotherapeutic agents for the treatment of human malignancies with lower toxicity and higher efficacy. In fact, recently increasing evidence from pre-clinical in vivo studies and clinical trials have shown some success in support of the use of rational design of multi-targeted therapies for the treatment of cancers using conventional chemotherapeutic agents in combination with "natural products". These studies have provided promising results and further opened-up newer avenues for cancer therapy. In this review article, we have succinctly summarized the known effects of "natural products" especially by focusing on isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin, and provided a comprehensive view on the molecular mechanisms underlying the principle of cancer therapy using combination of "natural products" with conventional therapeutics.

Topics: Animals; Antineoplastic Agents; Biological Products; Curcumin; Humans; Indoles; Isoflavones; Neoplasms

Curcumin [1, 7-bis (4-hydroxy-3-methoxyphenyl)-1, 6 heptadiene-3, 5-dione] is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. It is known to have a variety of biologic and pharmacologic activities, including anti-inflammatory, anti-oxidant, and anticarcinogenic potential. It is a potent inhibitor of cytochrome P450 with capacity to simultaneously induce detoxifying enzymes such as glutathione S-transferase and as such may find application as a chemopreventive agent. Curcumin is a potent inhibitor of cyclooxygenase-2, lipooxygenase, ornithine decarboxylase (ODC), nuclear factor-kappaB, c-Jun N-terminal kinase and protein kinase C and has also been demonstrated to play a vital role against pathological conditions such as cancer, atherosclerosis, and neurodegenerative diseases.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Arachidonate 12-Lipoxygenase; Curcumin; Cyclooxygenase 2; Dietary Supplements; Glutathione Transferase; Humans; JNK Mitogen-Activated Protein Kinases; Lipoxygenase Inhibitors; Molecular Structure; Neoplasms; NF-kappa B; Ornithine Decarboxylase Inhibitors; Protein Kinase C

Curcuma longa (turmeric) has a long history of use in Ayurvedic medicine as a treatment for inflammatory conditions. Turmeric constituents include the three curcuminoids: curcumin (diferuloylmethane; the primary constituent and the one responsible for its vibrant yellow color), demethoxycurcumin, and bisdemethoxycurcumin, as well as volatile oils (tumerone, atlantone, and zingiberone), sugars, proteins, and resins. While numerous pharmacological activities, including antioxidant and antimicrobial properties, have been attributed to curcumin, this article focuses on curcumin's anti-inflammatory properties and its use for inflammatory conditions. Curcumin's effect on cancer (from an anti-inflammatory perspective) will also be discussed; however, an exhaustive review of its many anticancer mechanisms is outside the scope of this article. Research has shown curcumin to be a highly pleiotropic molecule capable of interacting with numerous molecular targets involved in inflammation. Based on early cell culture and animal research, clinical trials indicate curcumin may have potential as a therapeutic agent in diseases such as inflammatory bowel disease, pancreatitis, arthritis, and chronic anterior uveitis, as well as certain types of cancer. Because of curcumin's rapid plasma clearance and conjugation, its therapeutic usefulness has been somewhat limited, leading researchers to investigate the benefits of complexing curcumin with other substances to increase systemic bioavailability. Numerous in-progress clinical trials should provide an even deeper understanding of the mechanisms and therapeutic potential of curcumin.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Autoimmune Diseases; Cardiovascular Diseases; Clinical Trials as Topic; Curcuma; Humans; Inflammation; Metabolic Diseases; Neoplasms; Neurodegenerative Diseases; Plant Extracts

The proteasome is a multicatalytic protease complex that degrades most endogenous proteins including misfolded or damaged proteins to ensure normal cellular function. The ubiquitin-proteasome degradation pathway plays an essential role in multiple cellular processes, including cell cycle progression, proliferation, apoptosis and angiogenesis. It has been shown that human cancer cells are more sensitive to proteasome inhibition than normal cells, indicating that a proteasome inhibitor could be used as a novel anticancer drug. Indeed, this idea has been supported by the encouraging results of the clinical trials using the proteasome inhibitor Bortezomib (Velcade, PS-341), a drug approved by the US Food and Drug Administration (FDA). Several natural compounds, including the microbial metabolite lactacystin, green tea polyphenols, and traditional medicinal triterpenes, have been shown to be potent proteasome inhibitors. These findings suggest the potential use of natural proteasome inhibitors as not only chemopreventive and chemotherapeutic agents, but also tumor sensitizers to conventional radiotherapy and chemotherapy. In this review, we will summarize the structures and biological activities of the proteasome and several natural compounds with proteasome inhibitory activity, and will discuss the potential use of these compounds for the prevention and treatment of human cancers.

Topics: Acetylcysteine; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Boronic Acids; Bortezomib; Clinical Trials as Topic; Curcumin; Humans; Neoplasms; Pentacyclic Triterpenes; Protease Inhibitors; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Triterpenes; Ubiquitin

MicroRNAs (miRNAs) are an abundant class of short noncoding RNAs that are widely expressed in mammalian cells and are important in post-translational gene regulation, including regulation of cell proliferation, apoptosis, and differentiation processes. miRNAs are involved in cancer initiation and progression and their expression patterns serve as phenotypic signatures of different cancers. Recent evidence suggests that dietary components as diverse as folate, retinoids, and curcumin exert cancer-protective effects through modulation of miRNA expression. miRNAs may be useful as biomarkers of cancer prevention or nutritional status, as well as serve as potential molecular targets that are influenced by dietary interventions.

Topics: Curcumin; Diet; Folic Acid; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; Tretinoin

Apoptosis is a highly regulated mechanism by which cells undergo cell death in an active way. As one of the most challenging tasks concerning cancer is to induce apoptosis in malignant cells, researchers increasingly focus on natural products to modulate apoptotic signaling pathways. Curcumin, a natural compound isolated from the plant Curcuma longa, has chemopreventive properties, which are mainly due to its ability to arrest cell cycle and to induce apoptosis. This article reviews the main effects of curcumin on the different apoptotic signaling pathways involved in curcumin-induced apoptosis of cancer cells, including the intrinsic and extrinsic apoptosis pathways, the NF-kappaB-mediated pathway as well as the PI3K/Akt signaling pathway. This review also focuses on the sensitization of cells to TRAIL-induced apoptosis after curcumin treatment and shows that curcumin enhances the capacity to induce cell death of different chemotherapeutical drugs.

Topics: Antineoplastic Agents; Apoptosis; Cell Survival; Curcumin; Drug Synergism; Humans; Neoplasms; NF-kappa B; Proto-Oncogene Proteins c-akt; Signal Transduction

Free radicals play a main pathogenic role in several human diseases such as neurodegenerative disorders, diabetes, and cancer. Although there has been progress in treatment of these diseases, the development of important side effects may complicate the therapeutic course. Curcumin, a well known spice commonly used in India to make foods colored and flavored, is also used in traditional medicine to treat mild or moderate human diseases. In the recent years, a growing body of literature has unraveled the antioxidant, anticarcinogenic, and antinfectious activity of curcumin based on the ability of this compound to regulate a number of cellular signal transduction pathways. These promising data obtained in vitro are now being translated to the clinic and more than ten clinical trials are currently ongoing worldwide. This review outlines the biological activities of curcumin and discusses its potential use in the prevention and treatment of human diseases.

Topics: Animals; Antineoplastic Agents; Curcumin; Diabetes Mellitus; Disease Models, Animal; Food Coloring Agents; Free Radicals; Humans; Hypoglycemic Agents; India; Mice; Mice, Knockout; Neoplasms; Neurodegenerative Diseases; NF-E2-Related Factor 2; Stress, Physiological; Taste

The development of cancer is associated with disorders in the regulation of the cell cycle. The purpose of this review is to briefly summarize the known sequence of events that regulate cell cycle progression with an emphasis on the checkpoints and the mechanisms cell employ to insure DNA stability in the face of genotoxic stress. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinases (CDK) molecules. The cyclins are CDK binding partners which are required for kinase activity and their protein levels are intimately linked to the cell cycle stage. CDK activity can be regulated by other mechanisms, such as phosphorylation events, that may contribute to deregulation of cell cycle and the development of cancer. While fruits and vegetables are recommended for prevention of cancer, their active ingredients and mechanisms of action are less well understood. Here, we briefly present evidence that dietary agents identified from fruits and vegetables can act to modulate the effects of deregulated cell cycle checkpoints, and that this may contribute to the prevention of cancer. The agents include apigenin (celery, parsley), curcumin (turmeric), (-)-epigallocatechin-3-gallate (green tea), resveratrol (red grape, peanuts and berries), genistein (soybean), and silymarin (milk thistle). The teachings of Hippocrates are still true "let food be thy medicine and medicine be thy food".

Topics: Animals; Anticarcinogenic Agents; Apigenin; Catechin; Cell Cycle; Cell Proliferation; Curcumin; Cyclin-Dependent Kinases; Diet; Genistein; Humans; Neoplasms; Resveratrol; Silymarin; Stilbenes; Tea

Cyclin D1 is known as a proto-oncogene whose gene amplification and protein overexpression are frequently observed in tumor cells. It acts as a mitogenic signal sensor and is expressed as a delayed-early response to many mitogenic signals. Cyclin-dependent kinases (CDKs) 4 and 6 are cyclin D1 binding partners, and activated cyclin D1/CDK4 and cyclin D1/CDK6 complex phosphorylate the retinoblastoma protein to induce the expression of target genes essential for S phase entry, resulting in facilitation of the progression from G1 to S phase. As well as acting as a positive regulator of the cell cycle, cyclin D1 is known to bind and modulate the actions of several transcription factors. Since the protein level of cyclin D1 reflects cell cycle progression, the rates of protein production and degradation are strictly regulated. Glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been shown to play an important role in the determination of cyclin D1 expression level by regulating mRNA transcription and protein degradation. This review highlights the regulatory mechanisms of cyclin D1 expression level, with special attention to the involvement of GSK-3beta.

Topics: Animals; Antineoplastic Agents; beta Catenin; Celecoxib; Cell Cycle; Cell Differentiation; Curcumin; Cyclin D1; Dyrk Kinases; Enzyme Activation; Enzyme Activators; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Neoplasms; Phosphorylation; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Pyrazoles; Retinoids; Signal Transduction; Sulfonamides; Transcription, Genetic; Ubiquitins; Wnt Proteins

It is estimated that nearly one-third of all cancer deaths in the United States could be prevented through appropriate dietary modification. Various dietary antioxidants have shown considerable promise as effective agents for cancer prevention by reducing oxidative stress which has been implicated in the development of many diseases, including cancer. Therefore, for reducing the incidence of cancer, modifications in dietary habits, especially by increasing consumption of fruits and vegetables rich in antioxidants, are increasingly advocated. Accumulating research evidence suggests that many dietary factors may be used alone or in combination with traditional chemotherapeutic agents to prevent the occurrence of cancer, their metastatic spread, or even to treat cancer. The reduced cancer risk and lack of toxicity associated with high intake of fruits and vegetables suggest that specific concentrations of antioxidant agents from these dietary sources may produce cancer chemopreventive effects without causing significant levels of toxicity. This review presents an extensive analysis of the key findings from studies on the effects of dietary antioxidants such as tea polyphenols, curcumin, genistein, resveratrol, lycopene, pomegranate, and lupeol against cancers of the skin, prostate, breast, lung, and liver. This research is also leading to the identification of novel cancer drug targets.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Carotenoids; Curcumin; Dietary Supplements; Fruit; Genistein; Humans; Lycopene; Neoplasms; Oxidative Stress; Pentacyclic Triterpenes; Resveratrol; Stilbenes; Triterpenes

The ability of the curry constituent curcumin to delay the onset of cancer has been the topic of extensive research for many years. Abundant literature is devoted to mechanisms by which curcumin may mediate this activity. These insights have prompted investigations in which curcumin as lead molecule serves as a scaffold for synthetic chemical attempts to optimize pharmacological potency. Among the published analogues with notable efficacy are dimethylcurcumin, 1,5-bis(3-pyridyl)-1,4-pentadien-3-one and 3,5-bis-(2-fluorobenzylidene)-piperidinium-4-one acetate. Results of a small number of clinical pilot studies conducted with curcumin at doses of up to 12 g suggest tentatively that it is safe in humans. Prevention of adenoma recurrence constitutes a clinical paradigm worthy of further investigation for curcumin. Future clinical study should include measurement of mechanism-based pharmacodynamic parameters.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Crohn Disease; Curcumin; Drug Design; Humans; Models, Molecular; Neoplasms; Pilot Projects; Precancerous Conditions; Reference Values; Structure-Activity Relationship

Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's disease.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; Clinical Trials as Topic; Curcuma; Curcumin; Free Radical Scavengers; Humans; Iron; Neoplasms; NF-kappa B; Oxidation-Reduction; Signal Transduction

Cancer is primarily a disease of old age, and that life style plays a major role in the development of most cancers is now well recognized. While plant-based formulations have been used to treat cancer for centuries, current treatments usually involve poisonous mustard gas, chemotherapy, radiation, and targeted therapies. While traditional plant-derived medicines are safe, what are the active principles in them and how do they mediate their effects against cancer is perhaps best illustrated by curcumin, a derivative of turmeric used for centuries to treat a wide variety of inflammatory conditions. Curcumin is a diferuloylmethane derived from the Indian spice, turmeric (popularly called "curry powder") that has been shown to interfere with multiple cell signaling pathways, including cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF-kappaB, TNF, IL-6, IL-1, COX-2, and 5-LOX). The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets. Thus an "old-age" disease such as cancer requires an "age-old" treatment.

Topics: Antineoplastic Agents; Curcumin; Drug Delivery Systems; Humans; Neoplasms; Pain; Plant Extracts; Signal Transduction

Preclinical studies revealed that curcumin, the yellow curry pigment, emodin, a compound derived from grapes, and taurolidine, derived from a biogenic amino acid, and some of their structural homologs possess anti-angiogenic and cancer chemopreventive properties. Whereas curcumin and emodin can act via inhibition of COP9 signalosome-associated kinases, taurolidine blocks protein biosynthesis.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; COP9 Signalosome Complex; Curcumin; Drug Screening Assays, Antitumor; Emodin; Humans; Models, Molecular; Multiprotein Complexes; Neoplasms; Peptide Hydrolases; Protein Kinase Inhibitors; Structure-Activity Relationship; Taurine; Thiadiazines

Because most cancers are caused by dysregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. Curcumin, a yellow coloring agent in turmeric, has been shown to interact with a wide variety of proteins and modify their expression and activity. These include inflammatory cytokines and enzymes, transcription factors, and gene products linked with cell survival, proliferation, invasion, and angiogenesis. Curcumin has been found to inhibit the proliferation of various tumor cells in culture, prevents carcinogen-induced cancers in rodents, and inhibits the growth of human tumors in xenotransplant or orthotransplant animal models either alone or in combination with chemotherapeutic agents or radiation. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy. These aspects of curcumin are discussed further in detail in this review.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Clinical Trials as Topic; Curcumin; Gastrointestinal Neoplasms; Humans; Interleukins; MAP Kinase Signaling System; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; NF-kappa B; PPAR gamma; Signal Transduction; STAT Transcription Factors; Transcription Factor AP-1; Vascular Endothelial Growth Factor A

Curcumin (diferuloylmethane) is an orange-yellow component of turmeric (Curcuma longa), a spice often found in curry powder. In recent years, considerable interest has been focused on curcumin due to its use to treat a wide variety of disorders without any side effects. It is one of the major curcuminoids of turmeric, which impart its characteristic yellow colour. It was used in ancient times on the Indian subcontinent to treat various illnesses such as rheumatism, body ache, skin diseases, intestinal worms, diarrhoea, intermittent fevers, hepatic disorders, biliousness, urinary discharges, dyspepsia, inflammations, constipation, leukoderma, amenorrhea, and colic. Curcumin has the potential to treat a wide variety of inflammatory diseases including cancer, diabetes, cardiovascular diseases, arthritis, Alzheimer's disease, psoriasis, etc, through modulation of numerous molecular targets. This article reviews the use of curcumin for the chemoprevention and treatment of various diseases.

Topics: Antioxidants; Curcumin; Diabetes Mellitus; Humans; Inflammation; Liver Diseases; Neoplasms

A growing body of research suggests that curcumin, the major active constituent of the dietary spice turmeric, has potential for the prevention and therapy of cancer. Preclinical data have shown that curcumin can both inhibit the formation of tumors in animal models of carcinogenesis and act on a variety of molecular targets involved in cancer development. In vitro studies have demonstrated that curcumin is an efficient inducer of apoptosis and some degree of selectivity for cancer cells has been observed. Clinical trials have revealed that curcumin is well tolerated and may produce antitumor effects in people with precancerous lesions or who are at a high risk for developing cancer. This seems to indicate that curcumin is a pharmacologically safe agent that may be used in cancer chemoprevention and therapy. Both in vitro and in vivo studies have shown, however, that curcumin may produce toxic and carcinogenic effects under specific conditions. Curcumin may also alter the effectiveness of radiotherapy and chemotherapy. This review article analyzes the in vitro and in vivo cancer-related activities of curcumin and discusses that they are linked to its known antioxidant and pro-oxidant properties. Several considerations that may help develop curcumin as an anticancer agent are also discussed.

Topics: Anticarcinogenic Agents; Carcinogens; Curcuma; Curcumin; Female; Humans; Male; Neoplasms; Reactive Oxygen Species

Epidemiological and preclinical evidence suggests that polyphenolic phytochemicals exemplified by epigallocatechin gallate from tea, curcumin from curry and soya isoflavones possess cancer chemopreventive properties. Whilst such naturally occurring polyphenols have been the subject of numerous mechanistic studies in cells, information on their clinical properties, which might help assess their promise as human cancer chemopreventive agents, is scarce. Therefore, we present a review of pilot studies and trials with a cancer chemoprevention-related rationale, in which either healthy individuals or patients with premalignant conditions or cancer received polyphenolic phytochemicals. The review identifies trial design elements specifically applicable to polyphenolic phytochemicals. The available evidence for tea polyphenols tentatively supports their advancement into phase III clinical intervention trials aimed at the prevention of progression of prostate intraepithelial neoplasia, leukoplakia or premalignant cervical disease. In the case of curcumin and soya isoflavones more studies in premalignacies seem appropriate to optimise the nature and design of suitable phase III trials. The abundance of flavonoids and related polyphenols in the plant kingdom makes it possible that several hitherto uncharacterised agents with chemopreventive efficacy are still to be identified, which may constitute attractive alternatives to currently used chemopreventive drugs.

Topics: Antineoplastic Agents, Phytogenic; Catechin; Clinical Trials, Phase III as Topic; Curcumin; Dietary Supplements; Flavonoids; Humans; Molecular Structure; Neoplasms; Phenols; Polyphenols

Lysine acetyltransferases (LATs) are a structurally disparate group of enzymes involved in regulating transcription by participating as cofactors in transcriptional regulatory complexes, and by acetylation of lysine residues in histones and other proteins. Aberrant LAT function probably plays an important part in the pathogenesis of certain cancers, especially leukaemias and endocrine tumours. However, LAT activity might also be an important drug target in a range of other indications, including inflammatory lung diseases, viral infections and metabolic disorders. At present, comparatively few LAT inhibitors are known, but progress regarding the understanding of their structural and functional biology is now beginning to reveal LATs as promising new epigenetic drug targets.

Topics: Acetyltransferases; Curcumin; Drug Delivery Systems; Drug Design; Enzyme Inhibitors; Humans; Lysine; Models, Molecular; Molecular Structure; Neoplasms

Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal "Spice for Life".

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antifungal Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiviral Agents; Arthritis, Rheumatoid; Curcuma; Curcumin; Humans; India; Medicine, Ayurvedic; Models, Biological; Molecular Structure; Neoplasms; Phytotherapy; Plants, Medicinal; Spices; Structure-Activity Relationship

Chemoprevention, which is referred to as the use of nontoxic natural or synthetic chemicals to intervene in multistage carcinogenesis, has emerged as a promising and pragmatic medical approach to reduce the risk of cancer. Numerous components of edible plants, collectively termed "phytochemicals" have been reported to possess substantial chemopreventive properties. Curcumin, a yellow coloring ingredient derived from Curcuma longa L. (Zingiberaceae), is one of the most extensively investigated and well-defined chemopreventive phytochemicals. Curcumin has been shown to protect against skin, oral, intestinal, and colon carcinogenesis and also to suppress angiogenesis and metastasis in a variety animal tumor models. It also inhibits the proliferation of cancer cells by arresting them in the various phases of the cell cycle and by inducing apoptosis. Moreover, curcumin has a capability to inhibit carcinogen bioactivation via suppression of specific cytochrome P450 isozymes, as well as to induce the activity or expression of phase II carcinogen detoxifying enzymes. Well-designed intervention studies are necessary to assess the chemopreventive efficacy of curcumin in normal individuals as well as high-risk groups. Sufficient data from pharmacodynamic as well as mechanistic studies are necessary to advocate clinical evaluation of curcumin for its chemopreventive potential.

Topics: Animals; Antineoplastic Agents, Phytogenic; Chemoprevention; Curcumin; Humans; Models, Biological; Neoplasms

Curcumin was found to be cytotoxic in nature to a wide variety of tumor cell lines of different tissue origin. The action of curcumin is dependent on with the cell type, the concentration of curcumin (IC50: 2-40 microg/mL), and the time of the treatment. The major mechanism by which curcumin induces cytotoxicity is the induction of apoptosis. Curcumin decreased the expression of antiapoptotic members of the Bcl-2 family and elevated the expression of p53, Bax, procaspases 3, 8, and 9. Curcumin prevents the entry of nuclear factor KB (NF-KB) into the nucleus there by decreasing the expression of cell cycle regulatory proteins and survival factors such as Bcl-2 and survivin. Curcumin arrested the cell cycle by preventing the expression of cyclin D1, cdk-1 and cdc-25. Curcumin inhibited the growth of transplantable tumors in different animal models and increased the life span of tumor-harboring animals. Curcumin inhibits metastasis of tumor cells as shown in in vitro as well as in vivo models, and the possible mechanism is the inhibition of matrix metalloproteases. Curcumin was found to suppress the expression of cyclooxygenase-2, vascular endothelial growth factor, and intercellular adhesion molecule- and elevated the expression of antimetastatic proteins, the tissue inhibitor of metalloproteases-2, nonmetastatic gene 23, and Ecadherin. These results indicate that curcumin acts at various stages of tumor cell progression.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms

Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive-oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase, and inducible nitric oxide synthase (iNOS); it is an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF-receptor tyrosine kinase, and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF-KB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs, and iNOS. It is considered that PKC, mTOR, and EGFR tyrosine kinase are the major upstream molecular targest for curcumin intervention, whereas the nuclear oncogenes such as c-jun, c-fos, c-myc, CDKs, FAS, and iNOS might act as downstream molecular targets for curcumin actions. It is proposed that curcumin might suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, whereas the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes, including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome pathway.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Neoplasms, Experimental; Oncogenes; Protein Kinase C

This overview presents curcumin as a significant chemosensitizer in cancer chemotherapy. Although the review focuses on curcumin and its analogues on multidrug resistance (MDR) reversal, the relevance of curcumin as a nuclear factor (NF)-KB blocker and sensitizer of many chemoresistant cancer cell lines to chemotherapeutic agents will also be discussed. One of the major mechanisms of MDR is the enhanced ability of tumor cells to actively efflux drugs, leading to a decrease in cellular drug accumulation below toxic levels. Active drug efflux is mediated by several members of the ATP-binding cassette (ABC) superfamily of membrane transporters, which have now been subdivided into seven families designated A through G. Among these ABC families, the classical MDR is attributed to the elevated expression of ABCB1 (Pgp), ABCC1 (MRP1), and ABCG2 (MXR). The clinical importance of Pgp, MRP1, and MXR for MDR and cancer treatment has led to the investigation of the inhibiting properties of several compounds on these transporters. At present, due in part to the disappointing results associated with the many side effects of synthetic modulators that have been used in clinical trials, current research efforts are directed toward the identification of novel compounds, with attention to dietary natural products. The advantage is that they exhibit little or virtually no side effects and do not further increase the patient's medication burden.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Forecasting; Gene Expression Regulation, Neoplastic; Humans; Mitoxantrone; Neoplasms; Neoplasms, Experimental

Curcumin, the active ingredient of turmeric (Curcuma longa) used in culinary and medical practices in Asia, has immense potential for being used in cancer chemotherapy because of its control over the cell growth regulatory mechanisms. The present chapter throws light on the role of curcumin in modulating the various phases of the cell cycle and its apoptosis-inducing effects. This is followed by a discussion on the implications of these effects of curcumin for its use as a chemotherapeutic agent in cancer. Curcumin affects various cell cycle proteins and checkpoints involving downregulation of some of the cyclins and cyclin-dependent kinases, upregulation of cdk inhibitors, and inhibition of DNA synthesis. In addition, curcumin also exerts indirect control over cell division such as inhibition of telomerase activity. Remarkably, some studies point toward a selective growth-inhibitory effect of curcumin on transformed cell lines compared to nontransformed cell lines. Curcumin has also been demonstrated to have proapoptotic effects in several in vitro studies, mostly through the mitochondria-mediated pathway of apoptosis. Curcumin-mediated regulation of apoptosis involves caspases, Bcl2 family members, inhibitors of apoptosis proteins, and heat shock proteins. The accumulating data on the in vitro and in vivo actions of curcumin together with the ongoing human clinical trials will provide a better understanding of curcumin-mediated cell growth regulation, ultimately catering to the needs of human welfare.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Proliferation; Curcumin; Forecasting; Humans; Models, Biological; Neoplasms

There is growing interest in the ability of phytochemicals to prevent chronic diseases, such as cancer and heart disease. However, some of these agents have poor bioavailability and many of the in-depth studies into their mechanisms of action have been carried out in vitro using doses which are unachievable in humans. In order to optimize the design of chemopreventive treatment, it is important to determine which of the many reported mechanisms of action are clinically relevant. In this review we consider the physiologically achievable doses for a few of the best studied agents (indole-3-carbinol, diindolylmethane, curcumin, epigallocatechin-3-gallate and resveratrol) and summarize the data derived from studies using these low concentrations in cell culture. We then cite examples of in vitro effects which have been observed in vivo. Finally, the ability of agent combinations to act synergistically or antagonistically is considered. We conclude that each of the compounds shows an encouraging range of activities in vitro at concentrations which are likely to be physiologically relevant. There are also many examples of in vivo studies which validate in vitro observations. An important consideration is that combinations of agents can result in significant activity at concentrations where any single agent is inactive. Thus, for each of the compounds reviewed here, in vitro studies have provided useful insights into their mechanisms of action in humans. However, data are lacking on the full range of activities at low doses in vitro and the benefits or otherwise of combinations in vivo.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Catechin; Curcumin; Humans; Indoles; Neoplasms; Resveratrol; Stilbenes

As cancer chemopreventive agents are intended for use by healthy individuals as prophylactics to prevent or retard the development of cancer, they must be amenable to ingestion over prolonged periods without toxicity. Therefore, putative chemopreventive agents need to undergo stringent testing to ensure their safety with regard to chronic exposure in humans. The diet is thought to be a source of chemopreventive agents, and dietary compounds are generally considered to be of low hazard, albeit this notion has not often been put to the test. Here the safety information available for 5 dietary putative chemopreventive compounds, indole-3-carbinol (I3C), curcumin, quercetin, epigallocatechin gallate (EGCG), and capsaicin is reviewed. For these agents, normal dietary intake, doses used in clinical trials, efficacious doses in rodents, and where available, toxic doses are compared. For curcumin, quercetin and capsaicin, toxicological data is only available from studies in rodents. Information on long-term effects in animals beyond 28 or 90 days is lacking for EGCG. Capsaicin and quercetin are suspected carcinogens. I3C and quercetin can modulate the absorption of other drugs given concomitantly. Without further investigation of their toxicology, it is difficult to recommend any of these agents for long-term use in the healthy population.

Topics: Antineoplastic Agents, Phytogenic; Capsaicin; Catechin; Chemoprevention; Consumer Product Safety; Curcumin; Diet; Humans; Indoles; Male; Neoplasms; Quercetin; Toxicity Tests

Cancer is the second leading cause of death worldwide. There is thus increased interest in alternative treatment modalities that include chemotherapy, hormonal supplements, surgery, radiation therapy, complementary or alterative medicine, used alone or in combination. Therefore patients who are subjected to combination treatments such as hormonal supplements or alternative medicine face considerable risk of drug-drug interactions. The administration of herbal drugs by patients without a physician's prior counseling is increasing globally and there is a possibility of herb-drug interactions too. Herbal drugs or extracts themselves contain a combination of active constituents, which interact within themselves and also between other prescribed pharmaceutical drugs to either enhance (synergize) or decrease (antagonize) the therapeutic effect. This review focuses on a number of reports of herb-drug interactions, their mechanism of action with a special emphasis on dietetic phytochemicals such as quercetin, genistein, curcumin and catechins. All phytochemicals tend to increase the therapeutic effect by blocking one or more targets of the signal transduction pathway, by increasing the bioavailability of the other drug or, by stabilizing the other drug in the system.

Topics: Antineoplastic Agents, Phytogenic; Camellia sinensis; Curcumin; Drug Synergism; Genistein; Herb-Drug Interactions; Humans; Neoplasms; Plant Extracts; Quercetin; Signal Transduction

Curcumin, a natural component of the rhizome of curcuma longa has emerged as one of the most powerful chemopreventive and anticancer agents. Its biological effects range from antioxidant, anti-inflammatory to inhibition of angiogenesis and is also shown to possess specific antitumoral activity. The molecular mechanism of its varied cellular effects has been studied in some details and it has been shown to have multiple targets and interacting macromolecules within the cell. Curcumin has been shown to possess anti-angiogenic properties and the angioinhibitory effects of curcumin manifest due to down regulation of proangiogenic genes such as VEGF and angiopoitin and a decrease in migration and invasion of endothelial cells. One of the important factors implicated in chemoresistance and induced chemosensitivity is NFkB and curcumin has been shown to down regulate NFkB and inhibit IKB kinase thereby suppressing proliferation and inducing apoptosis. Cell lines that are resistant to certain apoptotic inducers and radiation become susceptible to apoptosis when treated in conjunction with curcumin. Besides this it can also act as a chemopreventive agent in cancers of colon, stomach and skin by suppressing colonic aberrant crypt foci formation and DNA adduct formation. This review focuses on the various aspects of curcumin as a potential drug for cancer treatment and its implications in a variety of biological and cellular processes vis-à-vis its mechanism of action.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Curcumin; Humans; Mast Cells; Neoplasms; Oxidation-Reduction; Oxidative Stress; Transcription Factors

This review focuses on the value of several groups of agents for the prevention and treatment of mucositis. The review refers to alimentary mucositis as a generalized term that includes oral mucositis and gastrointestinal mucositis. This paper is part of the systematic review made by the mucositis study group which operates in the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO). Several new guidelines are suggested in this review as an update to the primary systematic review that was published by the same group in 2004.

Topics: Administration, Topical; Adult; Analgesics; Anesthetics, Local; Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Child; Clinical Trials as Topic; Curcumin; Dietary Supplements; Disease Models, Animal; Drug Evaluation; Evidence-Based Medicine; Gastrointestinal Diseases; Graft vs Host Disease; Humans; Medical Oncology; Mucositis; Neoplasms; Practice Guidelines as Topic; Primary Prevention; Radiotherapy; Stomatitis

Carcinogenesis encompasses 3 closely associated stages: initiation, progression, and promotion. Phytochemicals are nonnutritive components of plants that are currently being studied in chemoprevention of various diseases for their pleiotropic effects and nontoxicity. Cancer chemoprevention involves the use of either natural or synthetic chemicals to prevent the initiation, promotion, or progression of cancer. Curcumin is the active constituent of turmeric, which is widely used as a spice in Indian cooking. It has been shown to possess anti-inflammatory, antioxidant, and antitumor properties. Curcumin has also been shown to be beneficial in all 3 stages of carcinogenesis. Much of its beneficial effect is found to be due to its inhibition of the transcription factor nuclear factor kappa B (NF-kappaB) and subsequent inhibition of proinflammatory pathways. This review summarizes the inhibition of NF-kappaB by curcumin and describes the recently identified molecular targets of curcumin. It is hoped that continued research will lead to development of curcumin as an anticancer agent.

Topics: Anticarcinogenic Agents; beta Catenin; Cell Transformation, Neoplastic; Chemoprevention; Curcumin; Neoplasms; NF-E2-Related Factor 2; NF-kappa B

A major challenge in cancer therapy is tumor drug resistance. To overcome it, it is essential to understand the mechanisms and identify the molecules involved, so that they can be specifically targeted in combination therapies. The proteasome is such a validated target: it plays a key role in cancer cell proliferation, inhibition of chemotherapy-induced apoptosis and drug resistance development. Bortezomib (Velcade, PS-341) was the first proteasome inhibitor to receive regulatory approval from the US Food and Drug Administration for the treatment of multiple myeloma. Clinical combination trials have demonstrated a chemo-sensitizing effect of bortezomib on conventional agents in hematological malignancies and some solid tumors such as androgen-independent prostate and ovarian cancer. Although generally well-tolerated, bortezomib still generates toxicity which underscores the need for less toxic proteasome inhibitors. Several naturally occurring products, such as green tea polyphenols and the antibiotic lactacystin, have been shown to be potent proteasome inhibitors. Significantly, green tea polyphenols, as well as several flavonoids such as genistein, curcumin and resveratrol, have also been shown to have chemo-sensitizing properties in prostate, breast, hepatic, and lung tumors. Further studies on natural proteasome inhibitors as chemo-sensitizers could lead to identification of more potent and less toxic compounds that could be used in combination therapies for drug-resistant tumors.

Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Catechin; Clinical Trials as Topic; Curcumin; Drug Resistance, Neoplasm; Drug Therapy, Combination; Genistein; Humans; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; Radiation-Sensitizing Agents; Resveratrol; Stilbenes; Structure-Activity Relationship; Ubiquitin

The use of complementary and alternative medicine (CAM) is increasing rapidly in developed countries, which is already in use as traditional medicines in various Asian countries. The Indian system of medicine, named as Ayurveda has an edge in this field. Many plant products are in use as herbal medicine, as food supplement or as spices, in every day cooking. Some of them have been well studied in various experimental models of cancer, both in vivo and in vitro models. They have shown significant inhibition of cell proliferation. Some of them are in the phase of clinical trial or already available as food supplement. Cancer patients are specially exploring the use of CAM, because of the high risk of mortality and long-term morbidity associated with surgical procedures of cancer management and high side effects of chemotherapy. This paper reviews different class of phytomedicines, used in Indian system of medicine, and also in Europe, which have shown positive results in preventing cancer progression. It also covers the role of vitamins, minerals, dietary fat in relation to cancer control. The mechanisms of action of these phytomolecules have also been discussed.

Topics: Antioxidants; Capsaicin; Carotenoids; Catechin; Catechols; Complementary Therapies; Curcumin; Fatty Alcohols; Flavones; Genistein; Herbal Medicine; Humans; Isoflavones; Lycopene; Minerals; Neoplasms; Phytoestrogens; Phytotherapy; Plant Preparations; Vitamins

Angiogenesis, the formation of new blood vessels from preexisting vascular network is a driving force of organ development in ontogeny, is necessary for ovulation and hair growth, and is prerequisite for proper wound healing. It is also a critical mechanism of numerous diseases, the most important of which are cancer and atherosclerosis. Therefore, modulation of angiogenesis is considered as therapeutic strategies of great importance for human health. Numerous bioactive plant compounds, often referred to as nutraceuticals are recently tested for the potential clinical applications. Among the most frequently studied are resveratrol, a polyphenol present in red-wine and grape-seed, epigallocatechin-3-gallate (EGCG) from green tea and curcumin from Curcuma longa. It is also possible that components of other plants, including the constituents of local food diet may find application for modulation of angiogenesis, provided that their effectiveness will be confirmed in controlled, scientifically validated trials.

Topics: Angiogenesis Inhibitors; Animals; Atherosclerosis; Catechin; Curcumin; Dietary Supplements; Flavonoids; Humans; Neoplasms; Neovascularization, Pathologic; Phenols; Polyphenols; Resveratrol; Stilbenes; Vascular Endothelial Growth Factor A

Curcumin (diferuloyl methane), the yellow pigment in turmeric (Curcuma longa), is a potent chemopreventive agent that inhibits proliferation of cancer cells by arresting them at various phases of the cell cycle depending upon the cell type. Curcumin-induced apoptosis mainly involves the mitochondria-mediated pathway in various cancer cells of different tissues of origin. In some cell types like thymocytes, curcumin induces apoptosis-like changes whereas in many other normal and primary cells curcumin is either inactive or inhibits proliferation, but does not appear to induce apoptosis. These together with reports that curcumin protects cells against apoptosis induced by other agents, underscore the need for further understanding of the multiple mechanisms of cell death unleashed by curcumin. Tumor cells often evade apoptosis by expressing several antiapoptotic proteins, down-regulation and mutation of proapoptotic genes and alterations in signaling pathways that give them survival advantage and thereby allow them to resist therapy-induced apoptosis. Many researchers including ourselves, have demonstrated the involvement of several pro and antiapoptotic molecules in curcumin-induced apoptosis, and ways to sensitize chemoresistant cancer cells to curcumin treatment. This review describes the mechanisms of curcumin-induced apoptosis currently known, and suggests several potential strategies that include down-regulation of antiapoptotic proteins by antisense oligonucleotides, use of proapoptotic peptides and combination therapy, and other novel approaches against chemoresistant tumors. Several factors including pharmacological safety, scope for improvement of structure and function of curcumin and its ability to attack multiple targets are in favor of curcumin being developed as a drug for prevention and therapy of various cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Curcumin; Humans; Neoplasms

Chemoprevention is a promising anti-cancer approach with reduced secondary effects in comparison to classical chemotherapy. Curcumin, one of the most studied chemopreventive agents, is a natural compound extracted from Curcuma longa L. that allows suppression, retardation or inversion of carcinogenesis. Curcumin is also described as an anti-tumoral, anti-oxidant and anti-inflammatory agent capable of inducing apoptosis in numerous cellular systems. In this review, we describe both properties and mode of action of curcumin on carcinogenesis, gene expression mechanisms and drug metabolism.

Topics: Antineoplastic Agents; Apoptosis; Cell Transformation, Neoplastic; Chemoprevention; Curcumin; Cytochrome P-450 Enzyme System; Enzyme Activation; Humans; Neoplasms; NF-kappa B; Transcription Factors

Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric. It possesses diverse anti-inflammatory and anti-cancer properties following oral or topical administration. Apart from curcumin's potent antioxidant capacity at neutral and acidic pH, its mechanisms of action include inhibition of several cell signalling pathways at multiple levels, effects on cellular enzymes such as cyclooxygenase and glutathione S-transferases, immuno-modulation and effects on angiogenesis and cell-cell adhesion. Curcumin's ability to affect gene transcription and to induce apoptosis in preclinical models is likely to be of particular relevance to cancer chemoprevention and chemotherapy in patients. Although curcumin's low systemic bioavailability following oral dosing may limit access of sufficient concentrations for pharmacological effect in certain tissues, the attainment of biologically active levels in the gastrointestinal tract has been demonstrated in animals and humans. Sufficient data currently exist to advocate phase II clinical evaluation of oral curcumin in patients with invasive malignancy or pre-invasive lesions of the gastrointestinal tract, particularly the colon and rectum.

Topics: Angiogenesis Inhibitors; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Biological Availability; Cell Adhesion; Curcumin; Cyclooxygenase Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Humans; Neoplasms

Topics: Angiogenesis Inhibitors; Animals; Binding Sites; Calmodulin; CD13 Antigens; Cell Proliferation; Chemical Phenomena; Chemistry; Curcumin; Depression, Chemical; Drug Design; Genomics; Humans; Neoplasms; Neovascularization, Pathologic; Peptide Library; Proteomics

Curcumin (diferuloylmethane) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animal models. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase; and an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF(Epidermal growth factor)-receptor tyrosine kinase and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF(nucleor factor)kappaB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, while the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the major metabolites of curcumin in mice, rats and humans.

Topics: Animals; Anticarcinogenic Agents; Biotransformation; Cell Nucleus; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Oncogenes; Protein Kinase C

It is currently estimated that > 50% of all patients diagnosed with cancer explore complementary and alternative medicine - especially herbal medicine. We conducted a comprehensive review to assess the safety and efficacy of herbal medicines commonly used by patients in an attempt to: prevent cancer; treat cancer; and treat adverse effects associated with conventional cancer treatments. Current evidence suggests that Asian ginseng, garlic, green tea, tomatoes and soy intake as part of the diet may be useful in preventing various cancers; additional research is needed in order to determine the efficacy of essiac, evening primrose oil, mistletoe, reishi, shiitake and turmeric as cancer treatments; and ginger may be effective in treating chemotherapy-induced nausea and vomiting.

Topics: Beverages; Complementary Therapies; Curcuma; Echinacea; Garlic; Herbal Medicine; Humans; Mistletoe; Neoplasms; Panax; Phytotherapy; Plant Extracts; Zingiber officinale

Chemoprotection has established itself as a "major arm" in the "war against cancer" and induction of phase 2 detoxification enzymes as an effective strategy. Prominent among inducers are Michael reaction acceptors. Such functionalities are intrinsic to many phenylpropanoids present in edible plants, where they play roles in plant defense. This minireview focuses on the ability of such plant metabolites to elevate phase 2 enzymes in various cell culture and animal models and ultimately to protect against carcinogenesis.

Topics: Animals; Anticarcinogenic Agents; Cinnamates; Coumarins; Curcumin; Enzyme Induction; Enzymes; Flavonoids; Humans; Molecular Structure; Neoplasms; Plant Preparations

Curcumin, an active yellow pigment of turmeric and curry, possesses anti-inflammatory, antioxidative and anticarcinogenic properties. Analysis of its structure revealed the presence of beta-diketone moiety and phenolic hydroxy groups that were believed to contribute to antioxidation. And vanillin, ferulic acid and a dimer of curcumin were identified as the curcumin-derived radical reaction products. In addition to antioxidation, curcumin could also induce apoptosis by targeting mitochondria, affecting p53-related signaling and blocking NF-kappaB activation. To further dissect its anticarcinogenic mechanisms, a number of curcumin targets were identified. These included the aryl hydrocarbon receptor, cytochrome P450, glutathione S-transferase, serine/threonine kinases, transcription factors, cyclooxygenase, ornithine decarboxylase, nitric oxide synthase, matrix metalloproteinases and tyrosine kinases. This review will summarize our current knowledge on how these important proteins are affected by curcumin, and hopefully, may provide a whole picture illustrating how the chemopreventive and antitumorigenic effect of curcumin is achieved.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Apoptosis; Biotransformation; Curcumin; Humans; Neoplasms; Protein Serine-Threonine Kinases; Receptors, Aryl Hydrocarbon; Transcription Factors

Curcumin is a major component of the Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animals as indicated by its ability to block colon tumor initiation by azoxymethane and skin tumor promotion induced by phorbol ester TPA. Recently, curcumin has been considered by oncologists as a potential third generation cancer chemopreventive agent, and clinical trials using it have been carried out in several laboratories. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes, such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase. Curcumin is also a potent inhibitor of protein kinase C, EGF-receptor tyrosine kinase and IkappaB kinase. In addition, curcumin inhibits the activation of NFkappaB and the expression of c-jun, c-fos, c-myc and iNOS. It is proposed that curcumin may suppress tumor promotion by blocking signal transduction pathways in the target cells. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin, and these compounds were subsequently convened into monoglucuronide conjugates. The experimental results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are major metabolites of curcumin in mice.

Topics: Animals; Antineoplastic Agents; Curcumin; Humans; Mice; Neoplasms; Neoplasms, Experimental

Many dietary constituents are chemopreventive in animal models, and experiments with cultured cells are revealing various potential mechanisms of action. Compounds classified as blocking agents can prevent, or greatly reduce, initiation of carcinogenesis, while suppressing agents affect later stages of the process by reducing cell proliferation. Many compounds have both types of activity. Blocking mechanisms include alteration of drug metabolising activities and scavenging of reactive oxygen species. Mechanisms which suppress tumorigenesis often involve modulation of signal transduction pathways, leading to altered gene expression, cell cycle arrest or apoptosis. As our knowledge of how these dietary components affect cell biochemistry improves, so the likelihood of success in chemoprevention trials and in provision of dietary advice to the general population to optimise the chances of preventing disease is increased.

Topics: Anticarcinogenic Agents; Apoptosis; Arachidonic Acid; Cell Cycle; Curcumin; Diet; Enzyme Inhibitors; Free Radical Scavengers; Humans; Indoles; Neoplasms; Signal Transduction

Recently, considerable attention has been focused on identifying naturally occurring chemopreventive substances capable of inhibiting, retarding, or reversing the multi-stage carcinogenesis. A wide array of phenolic substances, particularly those present in dietary and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of these naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a pungent ingredient of hot chili pepper, protects against experimentally-induced mutagenesis and tumorigenesis. It also induces apoptosis in various immortalized or malignant cell lines. Plants of ginger family (Zingiberaceae) have been frequently and widely used as spices and also, in traditional oriental medicine. Curcumin, a yellow ingredient from turmeric (Curcuma longa L., Zingiberaceae), has been extensively investigated for its cancer chemopreventive potential. Yakuchinone A [1-(4'-hydroxy-3'-methoxyphenyl)-7-phenyl-3-heptanone] and yakuchinone B [1-(4'-hydroxy-3'-methoxyphenyl)-7-phenylhept-1-en-3-one] present in Alpinia oxyphylla Miquel (Zingiberaceae) have inhibitory effects on phorbol ester-induced inflammation and skin carcinogenesis in mice, and oxidative stress in vitro. These diarylheptanoids suppress phorbol ester-induced activation of ornithine decarboxylase and production of tumor necrosis factor-alpha or interleukin-1alpha and their mRNA expression. They also nullified the phorbol ester-stimulated induction of activator protein 1 (AP-1) in cultured human promyelocytic leukemia (HL-60) cells. In addition, both yakuchinone A and B induced apoptotic death in HL-60 cells. Ginger (Zingiber officinale Roscoe, Zingiberaceae) contains such pungent ingredients as [6]-gingerol and [6]-paradol, which also have anti-tumor promotional and antiproliferative effects. Resveratrol (3, 5,4'-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other dietary and medicinal plants, and (-)-epigallocatechin gallate, a major antioxidative green tea polyphenol, exert striking inhibitory effects on diverse cellular events associated with multi-stage carcinogenesis. In addition, these compounds have ability to suppress proliferation of human cancer cells via induction of apoptosis.

Topics: Animals; Capsaicin; Catechin; Catechols; Curcumin; Diet; Fatty Alcohols; Humans; Mice; Neoplasms; Neoplasms, Experimental; Phenols; Plants, Edible; Plants, Medicinal; Resveratrol; Stilbenes

The concept that cancer can be prevented, or its onset postponed, by certain diet-derived substances is currently eliciting considerable interest. Agents which interfere with tumour development at the stage of promotion and progression in particular are of potential clinical value. As chemopreventive agents have to be administered over a long period of time in order to establish whether they possess efficacy in humans, it is of paramount importance to establish their lack of toxicity. The desire to select the best chemopreventive drug candidates for clinical trial, and the necessity to monitor efficacy in the short and intermediate term, render the identification of specific mechanism-based in vivo markers of biological activity a high priority. Antioxidation, inhibition of arachidonic acid metabolism, modulation of cellular signal transduction pathways, inhibition of hormone and growth factor activity and inhibition of oncogene activity are discussed as mechanisms by which the soya constituent genistein, the curry ingredient curcumin and the vitamin A analogue 13-cis retinoic acid exert tumour suppression. A better understanding of these mechanisms will help the establishment of screens for the discovery of new and better chemopreventive agents and the identification of surrogate markers to assess the outcome of clinical chemoprevention trials.

Topics: Anticarcinogenic Agents; Antioxidants; Chemoprevention; Clinical Trials as Topic; Curcumin; Diet; Genistein; Humans; Neoplasms; Tretinoin

Topics: Antioxidants; Curcuma; Diet; Food; Health Promotion; Humans; India; Neoplasms; Plant Extracts; Spices

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Curcumin; Humans; Irinotecan; Maximum Tolerated Dose; Neoplasms

We aim to investigate the effect of curcumin on preventing cancer anorexia-cachexia syndrome (CACS) via through mechanism of inhibition on NF-kB signal pathway. Outcome measurement for primary end point was improvement of body tissue composition, and the secondary end points were body weight and body mass index, hand grip muscle strengthening, and safety.. This is randomized, double-blind, placebo-controlled phase ll a study, 33 patients with CACS in solid malignancy were enrolled and randomized in 1:1 to receive oral curcumin (at a dose of 800 mg twice daily) or placebo for 8 weeks.. All parameters of body compositions were not statistically significant different between two groups, which were consist body fat mass [-1.25(SEM 0.87) vs. +0.63(SEM 0.55); p=0.119], skeletal muscle mass [-0.35(SEM 0.60) vs.+0.33(SEM 0.42); p=0.408] and percent body fat [-0.47(SEM 0.95) vs. -0.29(SEM 0.82); p=0.893] including with basal metabolic rate [-13.47(SEM 21.94) vs. +15.30(13.76); p=0.336]. The average of weight loss was also not statistically significant different between two groups. [-1.4 kg(SEM 0.89) in curcumin vs-1.12 kg(SEM 0.73), p=0.810]. Notably, patient with curcumin had less reduction of hand-grip muscle strength on both hands [Rt. handed: -2.47 in curcumin vs. -5.36 in placebo; p=0.318] [Lt. handed: -1.98 vs. -5.43; p=0.317], and basal metabolic rate than placebo group. Most adverse events were grade 1 on both groups similarly.. Curcumin was not shown to be superior to placebo with regard to increasing the body composition in cancer patients with CACS. However, curcumin might show some clinical benefits, including slow progression of hand-grip muscle strength loss, and basal metabolic rate. Further investigations should be explored.

Topics: Anorexia; Cachexia; Curcumin; Double-Blind Method; Hand Strength; Humans; Neoplasms

Oral mucositis refers to erythematous and ulcerative lesions of oral mucosa during chemo/radiotherapy. Treatment modalities were directed towards reduction in severity of oral mucositis. Zinc plays an important role to retard oxidative processes and is considered as the critical component in wound healing. To compare the efficacy of zinc alone with improvised zinc preparation in reducing the severity of oral mucositis. Improvised zinc was a combination of zinc oxide, amla, tulsi and curcumin at 1% therapeutic concentrations. Seventy-five subjects undergoing chemo/radiotherapy were randomly divided into three groups: Group A (25 subjects) had received topical 5% zinc oxide paste trice daily application after food for entire treatment period, initiated 2 d prior to radiotherapy. Group B (25) received improvised zinc preparations (1%) and instructed to apply same as group A. Group C (25) received standard treatment offered by cancer hospital. All the groups were assessed for oral mucositis using WHO grading system at 7th, 14th, 21st, 28th, 35th day by the oncologist and results were tabulated for statistical analysis. Severity of oral mucositis reduced in zinc and improvised zinc group (p=0.096) when compared with controls with significant p value (0.037). Comparison of improvised zinc preparation (1%) group with only zinc group revealed that severity of overall mucositis though was not significant, was less in improvised zinc group with p value (0.029, 0.013) at 28 and 35 d respectively. Improvised zinc administration during radiation therapy was beneficial in reduction of oral mucositis during cancer treatment.

Topics: Administration, Topical; Adult; Aged; Antioxidants; Curcuma; Curcumin; Female; Humans; Male; Middle Aged; Mouth Mucosa; Neoplasms; Ocimum sanctum; Phyllanthus emblica; Phytotherapy; Plant Extracts; Radiation; Radiation Injuries; Radiotherapy; Stomatitis; Treatment Outcome; Wound Healing; Zinc; Zinc Oxide

We investigated whether personalized dietary intervention could improve clinical measurements such as immune cell-mediated cytotoxicity, serum albumin, derivatives of reactive oxygen metabolites (D-ROMS), D-dimer, and fibrinogen. Cancer patients received either a treatment support diet (TD, for those with chemotherapy), or a remission support diet (RD; for those in remission) for at least 3 wk (21-61 days). Both diets were low glycemic, low fat, and high plant protein diets; the diet for the TD group contained an additional 0.5 servings of protein. Based on clinical values, additional amounts of garlic, onion, tomato, shiitake, rice bran, kale, blueberry, pineapples, and/or turmeric powder were provided in regular meals. Estimated daily intake of protein, plant fat, garlic, onion, allicin, and quercetin was greater in the TD compared to the RD. An increased intake of vitamin A, vitamin C, vitamin E and selenium and a reduction in D-dimer were noted compared to baseline diets in both groups. A decrease in D-ROMS in the RD and an increase in albumin and an increased tendency in cytotoxicity in the TD were observed. In conclusion, personalized diets with supplemented functional ingredients improved antioxidant status and/or anticoagulant activity in cancer patients undergoing chemotherapy and in remission.

Topics: Adult; Aged; Anticoagulants; Antioxidants; Bromelains; Curcumin; Diet; Dietary Supplements; Eating; Female; Fibrin Fibrinogen Degradation Products; Fruit; Humans; Male; Middle Aged; Neoplasms; Precision Medicine; Quercetin; Vegetables

A proprietary lecithin delivery system of curcumin (Meriva) was evaluated in a controlled study to assess its efficacy in alleviating the side effects of cancer chemo- and radiotherapy in 160 patients undergoing these treatments. In both cases, a semi-quantitative evaluation of the side effects was carried out using a visual analogue scale, assessing also the plasma free radical status in all patients. Results showed that lecithinized curcumin might alleviate the burden of side effects associated to chemo- and radiotherapy, suggesting that the anecdotal use of various preparations of curcumin as a supportive agent for cancer treatment is well worth a systematic investigation in larger scale clinical trials. The capacity of curcumin to upregulate anti-oxidative responses and downregulate inflammatory pathways could explain its beneficial effect in tempering the prolonged and systemic oxidative and inflammatory effects of cancer treatment, and the beneficial effects observed in the plasma oxidative status in all patients of the treatment group support this view.

Topics: Adult; Aged; Antineoplastic Agents; Curcumin; Female; Humans; Lecithins; Male; Middle Aged; Neoplasms; Pain Measurement; Radiotherapy

Curcuminoids are bioactive polyphenolics with potent antiinflammatory properties. Although several lines of in vitro and preclinical evidence suggest potent anticancer effects of curcuminoids, clinical findings have not been conclusive. The present randomized double-blind placebo-controlled trial aimed to evaluate the efficacy of curcuminoids as adjuvant therapy in cancer patients. Eighty subjects with solid tumors who were under standard chemotherapy regimens were randomly assigned to a bioavailability-boosted curcuminoids preparation (180 mg/day; n = 40) or matched placebo (n = 40) for a period of 8 weeks. Efficacy measures were changes in the health-related quality of life (QoL) score (evaluated using the University of Washington index) and serum levels of a panel of mediators implicated in systemic inflammation including interleukins 6 (IL-6) and 8 (IL-8), TNF-α, transforming growth factor-β (TGFβ), high-sensitivity C-reactive protein (hs-CRP), calcitonin gene-related peptide (CGRP), substance P and monocyte chemotactic protein-1 (MCP-1). Curcuminoid supplementation was associated with a significantly greater improvement in QoL compared with placebo (p < 0.001). Consistently, the magnitude of reductions in TNF-α (p < 0.001), TGFβ (p < 0.001), IL-6 (p = 0.061), substance P (p = 0.005), hs-CRP (p < 0.001), CGRP (p < 0.001) and MCP-1 (p < 0.001) were all significantly greater in the curcuminoids versus placebo group. In contrast, the extent of reduction in serum IL-8 was significantly greater with placebo versus curcuminoids (p = 0.012). Quality of life variations were associated with changes in serum TGFβ levels in both correlation and regression analyses. Adjuvant therapy with a bioavailable curcuminoid preparation can significantly improve QoL and suppress systemic inflammation in patients with solid tumors who are under treatment with standard chemotherapy protocols.

Topics: Adult; Aged; Biological Availability; C-Reactive Protein; Calcitonin Gene-Related Peptide; Chemokine CCL2; Chemotherapy, Adjuvant; Curcuma; Curcumin; Double-Blind Method; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Iran; Male; Middle Aged; Neoplasms; Quality of Life; Tumor Necrosis Factor-alpha

Humans typically consume "natural agents" that are believed to be chemoprotective and are known to decrease inflammation biomarker NF-kappaB in vitro; however, no intervention studies in humans have been done to date. This commentary documents the in vivo results as a powerful example for supporting the superiority of a complex mixture of natural agents. Human volunteers consumed two 500 mg capsules (BID) containing a mixture of natural agents for a period of 2 weeks, and blood samples were collected pre- and post-intervention. The purified lymphocytes were subjected to ex-vivo exposure to TNF-alpha or kept as untreated control. The mean NF-kappaB DNA binding activity was increased upon TNF-alpha treatment in pre-intervention samples; however, TNF-alpha was unable to induce NF-kappaB in post-intervention samples, suggesting that the mixture of four important natural agents could be useful to protect humans against oxidative stress.

Topics: Adult; Biological Products; Catechin; Curcumin; DNA; Female; Humans; Isoflavones; Lymphocytes; Male; Middle Aged; Neoplasms; NF-kappa B; Oxidative Stress; Tumor Necrosis Factor-alpha; Young Adult

Epidemiological studies have shown that consumption of green tea, coffee, wine, and curry may contribute to a reduced risk of various cancers. However, there are some cancer site-specific differences in their effects; for example, the consumption of tea or wine may reduce bladder cancer risk, whereas coffee consumption may increase the risk. Animal and cell-based experiments have been used to elucidate the anticancer mechanisms of these compounds, with reactive oxygen species (ROS)-based mechanisms emerging as likely candidates. Chlorogenic acid (CGA), curcumin (CUR), epigallocatechin gallate (EGCG), and resveratrol (RSV) can act as antioxidants that activate AMP-activated protein kinase (AMPK) to downregulate ROS, and as prooxidants to generate ROS, leading to the downregulation of NF-κB. Polyphenols can modulate miRNA (miR) expression, with these dietary polyphenols shown to downregulate tumor-promoting miR-21. CUR, EGCG, and RSV can upregulate tumor-suppressing miR-16, 34a, 145, and 200c, but downregulate tumor-promoting miR-25a. CGA, EGCG, and RSV downregulate tumor-suppressing miR-20a, 93, and 106b. The effects of miRs may combine with ROS-mediated pathways, enhancing the anticancer effects of these polyphenols. More precise analysis is needed to determine how the different modulations of miRs by polyphenols relate to the cancer site-specific differences found in epidemiological studies related to the consumption of foods containing these polyphenols.

Topics: Animals; Catechin; Coffee; Curcumin; MicroRNAs; Neoplasms; Polyphenols; Reactive Oxygen Species; Resveratrol; Tea; Wine

The tumor microenvironment (TME) is a complex network of cellular and non-cellular components surrounding the tumor. The cellular component includes fibroblasts, adipocytes, endothelial cells, and immune cells, while non-cellular components are tumor vasculature, extracellular matrix and signaling molecules. The tumor cells have constant close interaction with their surrounding TME components that facilitate their growth, survival, and metastasis. Targeting a complex TME network and its interaction with the tumor can offer a novel strategy to disrupt cancer cell progression. Curcumin, from turmeric rhizome, is recognized as a safe and effective natural therapeutic agent against multiple diseases including cancer. Here the effects of curcumin and its metabolites on tumor-TME interaction modulating ability have been described. Curcumin and its metabolites regulate TME by inhibiting the growth of its cellular components such as cancer-associated adipocytes, cancer-associated fibroblast, tumor endothelial cells, tumor-stimulating immune cells, and inducing anticancer immune cells. They also inhibit the interplay of tumor cells to TME by suppressing non-cellular components such as extracellular matrix, and associated tumor promoting signaling-pathways. In addition, curcumin inhibits the inflammatory environment, suppresses angiogenic factors, and increases antioxidant status in TME. Overall, curcumin has the capability to regulate TME components and their interaction with tumor cells.

Topics: Curcumin; Endothelial Cells; Fibroblasts; Humans; Neoplasms; Tumor Microenvironment

Multifunctional nanoplatforms based on novel bimetallic nanoparticles have emerged as effective radiosensitizers owing to their potential capability in cancer cells radiosensitization. Implementation of chemotherapy along with radiotherapy, known as synchronous chemoradiotherapy, can augment the treatment efficacy. Herein, a tumor targeted nanoradiosensitizer with synchronous chemoradiotion properties, termed as CuFe

Topics: Animals; Antineoplastic Agents; Chemoradiotherapy; Curcumin; Drug Carriers; Mice; Nanoparticles; Neoplasms

Tumor microenvironment (TME) plays an important role in the growth, invasion, and metastasis of tumor cells. The pH of TME is more acidic in solid tumors than in normal tissues. Although targeted delivery in TME has progressed, the complex and expensive construction of delivery systems has limited their application. F

Topics: Antineoplastic Agents; Chromatophores; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Proton-Translocating ATPases; Tumor Microenvironment

Cachexia is a multifactorial debilitating syndrome that is responsible for 22% of mortality among cancer patients, and there are no effective therapeutic agents available. Curcumin, a polyphenolic compound derived from the plant turmeric, has been shown to have anti-inflammatory, antioxidant, anti-autophagic, and antitumor activities. However, its function in cancer cachexia remains largely unexplored.. This study aimed to elucidate the mechanisms by which curcumin improves adipose atrophy in cancer cachexia.. C26 tumor-bearing BALB/c mice and β3-adrenoceptor agonist CL316243 stimulated BALB/c mice were used to observe the therapeutic effects of curcumin on the lipid degradation of cancer cachexia in vivo. The effects of curcumin in vitro were examined using mature 3T3-L1 adipocytes treated with a conditioned medium of C26 tumor cells or CL316243.. Mice with C26 tumors and cachexia were protected from weight loss and adipose atrophy by curcumin (50 mg/kg, i.g.). Curcumin significantly reduced serum levels of free fatty acids and increased triglyceride levels. In addition, curcumin significantly inhibited PKA and CREB activation in the adipose tissue of cancer cachectic mice. Curcumin also ameliorated CL316243-induced adipose atrophy and inhibited hormone-mediated PKA and CREB activation in mice. Moreover, the lipid droplet degradation induced by C26 tumor cell conditioned medium in mature 3T3-L1 adipocytes was ameliorated by curcumin (20 µM) treatment. Curcumin also improved the lipid droplet degradation of mature 3T3-L1 adipocytes induced by CL316243.. Curcumin might be expected to be a therapeutic supplement for cancer cachexia patients, primarily through inhibiting adipose tissue loss via the cAMP/PKA/CREB signaling pathway.

Topics: Animals; Atrophy; Cachexia; Culture Media, Conditioned; Curcumin; Lipolysis; Mice; Neoplasms; Obesity; Signal Transduction

Using small molecules to inhibit the PD-1/PD-L1 pathway is an important approach in cancer immunotherapy. Natural compounds such as capsaicin, zucapsaicin, 6-gingerol and curcumin have been proposed to have anticancer immunologic functions by downregulating the PD-L1 expression. PD-L1 dimerization promoted by small molecules was recently reported to be a potential mechanism to inhibit the PD-1/PD-L1 pathway. To clarify the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and molecular dynamics simulations were performed. The results evidenced that these compounds could inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. Binding free energy calculations showed that capsaicin, zucapsaicin, 6-gingerol and curcumin have strong binding ability with the PD-L1 dimer, where the affinities of them follow the trend of zucapsaicin > capsaicin > 6-gingerol ≈ curcumin. Analysis by residue energy decomposition, contact numbers and nonbonded interactions revealed that these compounds have a tight interaction with the C-sheet, F-sheet and G-sheet fragments of the PD-L1 dimer, which were also involved in the interactions with PD-1. Moreover, non-polar interactions between these compounds and the key residues Ile54, Tyr56, Met115 and Ala121 play a key role in stabilizing the protein−ligand complexes in solution, in which the 4′-hydroxy-3′-methoxyphenyl group and the carbonyl group of zucapsaicin, capsaicin, 6-ginger and curcumin were significant for the complexation of small molecules with the PD-L1 dimer. The conformational variations of these complexes were further analyzed by free energy landscape (FEL) and principal component analysis (PCA) and showed that these small molecules could make the structure of dimers more stable. This work provides a mechanism insight for food-derived small molecules blocking the PD-1/PD-L1 pathway via directly targeting the PD-L1 dimerization and offers theoretical guidance to discover more effective small molecular drugs in cancer immunotherapy.

Topics: B7-H1 Antigen; Capsaicin; Curcumin; Dimerization; Humans; Immunotherapy; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Programmed Cell Death 1 Receptor

Despite the attractive anti-cancer effects, poor solubility and low bioavailability have restricted the clinical application of Curcumin. Recent findings show that Gemini nano-curcumin (Gemini-Cur) significantly improves the cellular uptake of Curcumin and its anti-cancer effect in tumor cells. Here, we aimed to assess the suppressive effect of Gemini-Cur on 4T1 breast cancer cells in vitro and, subsequently, in BALB/c mouse models.. Fluorescence microscopy was employed to visualize cellular uptake and morphological changes of 4T1 cells during treatment with Gemini-Cur and void curcumin. MTT and annexin V/FITC assays were performed to study the toxic effect of Gemini-Cur on mouse cancer cells. For in vivo studies, BALB/c tumor-bearing mice were used to evaluate the inhibitory effect of Gemini-Cur in comparison with mice receiving free Curcumin and nanoparticles.. Our data showed that Gemini-Cur enters the cells and inhibits proliferation in a time- and dose-dependent manner. Annexin V/FITC confirmed apoptotic effect on 4T1 cells. In vivo studies also illustrated that tumor growth is suppressed in Gemini-Cur treated mice rather than controls. Expression studies demonstrated the modulation of apoptotic and metastatic genes, including Bax, Bcl-2, MMP-9, VEGF, and COX-2 in treated mice.. In conclusion, these data demonstrate the promising anti-cancer properties of Gemini-Cur on mice models. However, further studies at molecular and cellular levels are required to conclude this therapeutic advantage.

Topics: Animals; Annexin A5; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Fluorescein-5-isothiocyanate; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasms

Topics: Biotin; Chitosan; Curcumin; Drug Carriers; Gallium Radioisotopes; Nanocomposites; Nanoparticles; Neoplasms; Spectroscopy, Fourier Transform Infrared

Combination nanomedicine is a potent strategy for cancer treatment. Exploiting different mechanisms of action, a novel triple drug delivery system of 5-fluorouracil, curcumin, and piperine co-loaded human serum albumin nanoparticles (5FU-CUR-PIP-HSA-NPs) was developed via the self-assembly method for suppressing breast tumor. Both hydrophobic and hydrophilic drugs were successfully encapsulated in the HSA NPs with a high drug loading efficiency (DLE) of 10%. Successful clinical translation of nanomedicines, however, is a challenging process requiring considerable preclinical in vitro and in vivo animal tests. The aim of this study was to develop a homemade preclinical 3D culture model in the standard 96-well plates in a cost and time-effective novel approach for the rapid generation of homogenous compact tumor spheroids for disease modeling, and anticancer therapeutic/nanomedicine screening. The knowledge of drug screening can be enhanced by employing such a model in a high-throughput manner. Accordingly, to validate the formulated drug delivery system and investigate the cellular uptake and cytotoxicity effect of the nanoformulation, 3D tumor spheroids were employed. The practicality of the nanomedicine system was substantiated in different tests. The in vitro uptake of the NPs into the tight 3D tumor spheroids was facilitated by the semi-spherical shape of the NPs with a proper size and surface charge. 5FU-CUR-PIP-HSA-NPs demonstrated high potency of migration inhibition as a part of successful anti-metastatic therapy as well. The remarkable differences in 2D and 3D cytotoxicities emphasize the importance of employing 3D tumor models as an intermediate step prior to in vivo animal experiments for drug/nanomedicine screening.

Topics: Animals; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Fluorouracil; High-Throughput Screening Assays; Humans; Nanomedicine; Nanoparticles; Neoplasms

Synergistic chemotherapy has been proved as an effective antitumor means in clinical practice. However, most co-administration treatment often lacks simultaneous control over the release of different chemotherapeutic agents.. These BNs had a spherical structure with the particle size of 299 ± 15.17 nm, while the synchronized release behaviour of those two drugs was proved in the medium with the pH value of 5.5 and 20 mM GSH. The co-delivery of DOX and CUR reduced the IC. The designed bilayer nanoparticle could be considered as potential chemotherapeutic co-delivery platform for efficient synchronized microenvironment respond and drug release. Furthermore, the simultaneous and synergistic drug release guaranteed the enhanced antitumor effects during the co-administration treatment.

Topics: Animals; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogen-Ion Concentration; Mice; Nanoparticles; Neoplasms; Tumor Microenvironment

Cancer development is associated with the deregulation of various cell signaling pathways brought on by certain genetic and epigenetic alterations. Therefore, novel therapeutic strategies have been developed to target those pathways. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) pathway is one major deregulated pathway in various types of cancer. Several anticancer drug candidates are currently being investigated in preclinical and/or clinical studies to target this pathway. Natural bioactive compounds provide an excellent source for anticancer drug development. Curcumin and plumbagin are two potential anticancer compounds that have been shown to target the PI3K/Akt/mTOR pathway individually. However, their combinatorial effect on cancer cells is still unknown. This study aims to investigate the synergistic effect of these two compounds on the PI3K/Akt/mTOR pathway by employing a sequential molecular docking and molecular dynamics (MD) analysis. An increase in binding affinity and a decrease in inhibition constant have been observed when curcumin and plumbagin were subjected to sequential docking against the key proteins PI3K, Akt, and mTOR. The MD simulations and molecular mechanics combined with generalized Born surface area (MM-GBSA) analyses validated the target proteins' more stable conformation when interacting with the curcumin and plumbagin combination. This indicates the synergistic role of curcumin and plumbagin against cancer cells and the possible dose advantage when used in combination. The findings of this study pave the way for further investigation of their combinatorial effect on cancer cells in vitro and in vivo models.

Topics: Curcumin; Humans; Molecular Docking Simulation; Neoplasms; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases

Nanomedicine represents a promising way to devise better drug delivery systems (DDSs), and the development of cell/tissue-based lipid carriers is a promising strategy. In this study, the author proposes the concept of reconstituted lipid nanoparticles (rLNPs) and offers a facile preparation method. The results demonstrated that the preparation of ultrasmall (∼20 nm) rLNPs can be highly reproducible from both cells (a mouse breast cancer cell line, 4T1) and tissue (mouse liver tissue). As a selected model platform, rLNPs derived from mouse liver tissue can be further labeled with imaging molecules (indocyanine green and coumarin 6) and modified with targeting moiety (biotin). Moreover, rLNPs were proved to be highly biocompatible and able to load various drugs, such as doxorubicin hydrochloride (Dox) and curcumin (Cur). Most importantly, Dox-loaded rLNPs (rLNPs/Dox) exerted good in vitro and in vivo anticancer performances

Topics: Animals; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Liposomes; Mice; Nanoparticles; Neoplasms

Photodynamic therapy (PDT) is one common ROS-generating therapeutic method with high tumor selectivity and low side effects. But the GSH-upregulation often alleviates its therapeutic efficiency. Here, we proposed a new strategy of jointly depleting GSH to enhance the therapeutic effect of PDT by preparing a nanomicelle by self-assembly method from GSH-activated photosensitizer DMT, curcumin, and amphiphilic polymer TPGS.

Topics: Cell Line, Tumor; Curcumin; Glutathione; Humans; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents

Curcumin has long been recognized for its anti-inflammatory properties. An antitumor effect has been recently reported in curcumin and clinical trials are being conducted. However, a large amount of required intake to obtain the antitumor effect of curcumin has been regarded as a problem. Therefore, curcumin analogs have been created by many researchers to enhance the effects of curcumin. We have synthesized >50 curcumin analogs and revealed greater growth suppression of various tumor cells with mono-carbonyl analogs than curcumin. Mechanistically, mono-carbonyl analogs inhibited transcriptional activity (e.g., nuclear factor kappa B, signal transducer, and activator of transcription 3) or activated caspase-3. Additionally, mono-carbonyl analogs of curcumin control tumor cell metabolism. Herein, we summarize the current knowledge about mono-carbonyl curcumin analogs and discuss their potential clinical applications.

Topics: Anti-Inflammatory Agents; Cell Line, Tumor; Curcumin; Humans; Neoplasms; NF-kappa B

Curcumin is a natural polyphenol that is extracted from the rhizomes of the turmeric plant (Curcuma longa), a member of the ginger family. It has been used for centuries in traditional Indian and Chinese medicine for its medicinal properties, including anti-inflammatory, antioxidant and antitumor effects. SVCT2 (Solute Carrier Family 23 Member 2, also known as SLC23A2) is a protein that plays a role in the transport of Vitamin C (Ascorbic Acid) into cells. SVCT2 plays an important role in tumor progression and metastasis, however, the molecular mechanisms of curcumin on SVCT2 have not been studied to date. Curcumin treatment inhibited proliferation and migration of cancer cells in a dose dependent manner. We found that curcumin reduced the expression of SVCT2 in cancer cells with a wild type p53, but not in those with a mutant type of p53. SVCT2 downregulation also reduced the MMP2 activity. Taken together, our results indicate that curcumin inhibited human cancer cell growth and migration by regulating SVCT2 through a downregulating p53. These findings provide new insights into the molecular mechanisms of curcumin's anticancer effects and potential therapeutic strategies for the treatment of metastatic migration.

Topics: Anti-Inflammatory Agents; Antioxidants; Curcumin; Down-Regulation; Humans; Neoplasms; Sodium-Coupled Vitamin C Transporters; Tumor Suppressor Protein p53

The aim of this study was to develop the ranostic nanocomposite by conjugating quantum dots with functional, therapeutic and targeting moieties. The quantum dots nanoparticles were used to diagnose and deliver anti-tumor drugs in a controlled manner to cancerous cells by fusing with tumor cell surfaces. To enhance the attachment of the nano-composite to specific tumor cells without harming neighboring normal cells, folic acid was conjugated with the nano-composite as folate receptors are over expressed in different kinds of tumors. The study was conducted for one year at the University of Punjab. The quantum dots were synthesized by a hydrothermal process using cadmium acetate and sodium sulfide. The response was evaluated on breast tumor samples for binding and nano-composite delivery under a fluorescent microscope. Fourier-transform infrared analysis was performed to confirm CdS conjugation with cysteine, folic acid and curcumin. The results showed that the quantum dot conjugate provides a two-way attack on cancer cells and causes increased cellular apoptosis. Further testing on murine animal models is required to confirm the results of this research study.

Topics: Animals; Curcumin; Folic Acid; Mice; Neoplasms; Quantum Dots

The increased stability of mutant p53 (Mutp53) plays a crucial role in its gain of function, making proteins involved in its stabilization promising targets for drug intervention. Although curcumin is known to exhibit anti-cancer effects, its role as a deubiquitinase (DUB) inhibitor in Mutp53 destabilization remains poorly explored. Our study demonstrates that curcumin treatment induced ubiquitination and destabilization of Mutp53 but not Wild-type p53 (WTp53) in cancer cells. Furthermore, proteasome and lysosome inhibitors failed to reverse the effect of curcumin, indicating Mutp53 destabilization is possibly via an alternate mechanism. Intriguingly, curcumin treatment also resulted in the nuclear aggregation of the Mutp53 protein, which was rescued by combined Dithiothreitol (DTT) treatment. Similar to curcumin, a broad-spectrum deubiquitinase inhibitor induced Mutp53 aggregation implying curcumin possibly acts by inhibiting deubiquitinases. Additionally, curcumin treatment inhibited colony-forming abilities, induced cytoplasmic vacuolation, and cell death selectively in Mutp53-expressing cells. Collectively, our study highlights the potential of curcumin as a promising therapeutic agent for targeting Mutp53-expressing cancer cells.

Topics: Cell Line, Tumor; Curcumin; Deubiquitinating Enzymes; Mutation; Neoplasms; Proteasome Endopeptidase Complex; Tumor Suppressor Protein p53

Stimuli-responsive cross-linked micelles (SCMs) are ideal nanocarriers for anti-cancer drugs. Compared with non-cross-linked micelles, SCMs exhibit superior structural stability. At the same time, the introduction of an environmentally sensitive crosslinker into a drug delivery system allows SCMs to respond to single or multiple stimuli in the tumor microenvironment, which can minimize drug leakage during the blood circulation process. In this study, curcumin (CUR) was modified as the hydrophobic core crosslinker by utilizing the bisphenol structure, and redox sensitive disulfide bonds were introduced to prepare the glutathione (GSH) stimulated responsive core crosslinker (abbreviated as N

Topics: Antibodies, Monoclonal; Curcumin; Micelles; Neoplasms; Polymers; Prodrugs; Spectroscopy, Fourier Transform Infrared

Multicomponent deoxyribozymes (MNAzymes) have great potential in gene therapy, but their ability to recognize disease tissue and further achieve synergistic gene regulation has rarely been studied. Herein, Arginylglycylaspartic acid (RGD)-modified Distearyl acylphosphatidyl ethanolamine (DSPE)-polyethylene glycol (PEG) (DSPE-PEG-RGD) micelle is prepared with a DSPE hydrophobic core to load the photothermal therapy (PTT) dye IR780 and the calcium efflux pump inhibitor curcumin. Then, the MNAzyme is distributed into the hydrophilic PEG layer and sealed with calcium phosphate through biomineralization. Moreover, RGD is attached to the outer tail of PEG for tumor targeting. The constructed nanomachine can release MNAzyme and the cofactor Ca

Topics: Cell Line, Tumor; Curcumin; DNA, Catalytic; Humans; MicroRNAs; Nanoparticles; Neoplasms; Oligopeptides; Pancreatic Neoplasms; Phototherapy; Photothermal Therapy; Polyethylene Glycols

The autoluminescence nanoplatform based on a single-atom catalyst has the potential to achieve accurate tumor diagnosis and treatment. Taking advantage of this, glycyrrhetinic acid (GA) and chitosan-modified single Fe-N-C atom catalysts (SAF NPs) loaded with luminol-curcumin (Cur) were fabricated (SAF-LCCG). Once delivered to the tumor, this autoluminescence SAF-LCCG could target the mitochondria to restrain tumor metastasis and promote the production of hydrogen peroxide (H

Topics: Curcumin; Humans; Hydrogen Peroxide; Luminol; Mitochondria; Neoplasms; Reactive Oxygen Species

Apoptosis is a naturally occurring process during the growth and development of multicellular organisms and is increasingly active during times of cellular stress such as in response to intracellular DNA damage when removal of the host cell is paramount to prevent cancer. Unfortunately, once formed, cancer cells become impervious to apoptosis, creating a desperate need to identify an approach to induce apoptosis in these cells. An attractive option is to focus efforts on developing and locating compounds which activate apoptosis using natural compounds. Curcumin is a natural component in turmeric and is well-known for its pharmacological effects in preventing and combating many ailments and has been shown to decrease the rapid proliferation of a wide variety of tumor cells. However, to date, the apoptotic intermediates and interactions through which curcumin exerts its cytotoxic effects are unknown. Motivated by reports linking the intracellular modulation of the concentrations of Bid and Bcl-xL, following curcumin administration to cancer cells, we set out to probe for potential intermolecular interactions of these proteins with curcumin. Using several biophysical techniques, most notably, fluorescence, circular dichroism and nuclear magnetic resonance spectroscopy, we reveal binding interactions of curcumin with both Bcl-xLΔC and full-length Bid (Bid-FL) and prove that this binding is hydrophobically driven and localized to well-known functional regions of each protein. Specifically, our NMR studies show that while Bid-FL interacts with curcumin through its hydrophobic and pore forming helices (α6-α7), Bcl-xLΔC interacts with curcumin via its BH3 binding pocket (α2-α3-α4-α5), a critical region for mediating apoptosis.

Topics: Apoptosis; bcl-X Protein; BH3 Interacting Domain Death Agonist Protein; Curcumin; Humans; Neoplasms

An optimal radiosensitizer with improved tumor retention has an important effect on tumor radiation therapy. Herein, gold nanoparticles (Au NPs) and drug-containing, mPEG-conjugated CUR (mPEG-CUR), self-assembled NPs (mPEG-CUR@Au) are developed and evaluated as a drug carrier and radiosensitizer in a breast cancer mice model. As a result, cancer therapy efficacy is improved significantly by applying all-in-one NPs to achieve synchronous chemoradiotherapy, as evidenced by studies evaluating cell viability, proliferation, and ROS production. In vivo anticancer experiments show that the mPEG-CUR@Au system improves the radiation sensitivity of 4T1 mammary carcinoma and completely abrogates breast cancer.

Topics: Animals; Cell Line, Tumor; Curcumin; Gold; Metal Nanoparticles; Mice; Nanoconjugates; Nanoparticles; Neoplasms; Prodrugs; X-Rays

The purpose of this study was to investigate in vitro drug release kinetics and to develop diffusion model of curcumin loaded Pluronic F127/Oleic acid(OA)-Fe

Topics: Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Kinetics; Magnetic Iron Oxide Nanoparticles; Nanoparticles; Neoplasms

In this project, a biocompatible block copolymer including poly ethylene glycol and poly caprolactone was synthesized using ring-opening reaction. Then, the copolymer was conjugated to folic acid using lysine as a linker. Also, curcumin (CUR) was used as a therapeutic anticancer agent. Nanoprecipitation method was used to prepare CUR-loaded polymeric micelles. Different methods including Fourier-transform infrared spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS) were used to characterize the prepared nanocarriers (NCs). MTT assay and hemolysis assay were used to evaluate

Topics: Animals; Curcumin; Drug Carriers; Drug Delivery Systems; Folic Acid; Mice; Micelles; Neoplasms; Polyethylene Glycols; Polymers

Topics: Animals; Curcumin; Humans; Indoles; Mice; Nanofibers; Nanoparticles; Neoplasms; Polymers

Topics: Alginates; Animals; Chitosan; Curcumin; Folic Acid; Mice; Nanoparticles; Neoplasms

The inflammation is tightly associated with tumor development, promoting or inhibiting tumorigenesis. And mutant p53 is speculated to promote inflammation and tumorigenesis. The tumor associated macrophages are usually educated to present the anti-inflammatory profile to tune down antitumor immunity. However, the impact of p53 mutants on macrophages is not clear. Here, we compared the basal inflammatory level and macrophage profiles in tumor cells and tumor samples with different p53 mutations. Data revealed that a lower inflammatory level was maintained in immune organs and tumor cells with p53 point mutations than those with p53 null mutation. Using the tumor cell-derived conditional media to culture macrophages, we found that the media from cells with p53 mutations, especially the point mutations, could decrease M1 markers and inhibit phagocytosis, suggesting the p53 mutation promoted M2 profile polarization. To target the p53 mutation induced M2 macrophage polarization, we applied low-concentration curcumin to the tumor cells with different p53 mutations. The data showed that curcumin could inhibit STAT3 signal and decrease PPARγ and CSF1 in tumor cells and tumor samples. In vitro, the co-culture assays showed that the curcumin treatment shifted p53 mutation educated macrophages back towards M1 profile. In vivo, the curcumin-treated MEFs showed obvious tumor inhibition, and the tumor samples displayed inhibited M2 markers. Results suggested that curcumin could inhibit p53 mutation educated macrophage induction and suppress M2-promoted tumorigenesis. Our study illustrated the inflammatory level under different p53 status and the inflammatory regulated role of curcumin in tumor environment. This study might provide a potential method in tumor personalized treatment aiming immune therapy in different p53 status.

Topics: Carcinogenesis; Curcumin; Humans; Inflammation; Mutation; Neoplasms; Tumor Microenvironment; Tumor Suppressor Protein p53

The limited tissue penetration depth and tumor hypoxic microenvironment have become the two pivotal obstacles that alleviate the antineoplastic efficacy in tumor photodynamic therapy (PDT). In the research, MnO

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Humans; Hydrogen Peroxide; Manganese; Manganese Compounds; Nanoparticles; Neoplasms; Oxides; Oxygen; Photochemotherapy; Photosensitizing Agents; Silicon Dioxide; Singlet Oxygen

Nowadays, the usage of nanoparticles in various fields such as drug delivery, attracts the attention of many researchers in the treatment of cancers. Graphene oxide (GO) is one of the novel drug delivery systems which is used broadly owing to its unique features. In this survey, doxorubicin (DOX) was accompanied by natural medicine, curcumin (CUR), to diminish its side effects and enhance its efficiency. Cytotoxicity assay in human gastric cancer (AGS), prostate cancer (PC3), and ovarian cancer (A2780), was evaluated. Also, the uptake of DOX and CUR into cells, was assessed using a fluorescence microscope. Moreover, real-time PCR was applied for the evaluation of the expression of RB1 and CDK2 genes, which were involved in the cell cycle. In both separate and simultaneous forms, DOX and CUR were loaded with high efficiency and the release behavior of both drugs was pH-sensitive. The higher release rate was attained at pH 5.5 and 42 °C for DOX (80.23%) and CUR (13.06), respectively. The intensity of fluorescence in the free form of the drugs, was higher than the loaded form. In the same concentration, the free form of CUR and DOX were more toxic than the loaded form in all cell lines. Also, free drugs showed more impact on the expression of RB1 and CDK2 genes. Co-delivery of CUR and DOX into the mentioned cell lines, was more effective than the free form of CUR and DOX due to its lower toxicity to normal cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Curcumin; Cyclin-Dependent Kinase 2; Doxorubicin; Drug Carriers; Drug Compounding; Drug Liberation; Female; Graphite; Humans; Hydrogen-Ion Concentration; Kinetics; Male; Neoplasms; Retinoblastoma Binding Proteins; Stimuli Responsive Polymers; Ubiquitin-Protein Ligases

Biomimetic therapeutics offer great potential for drug delivery that avoids immune recognition. However, the coated cell membrane usually hinders the cellular uptake of nanoparticles; thus, structure-changeable formulations have attracted increasing attention. Herein, we report photolytic pyropheophorbide a (PA)-inserted red blood cell (RBC) membrane-camouflaged curcumin dimeric prodrug (CUR

Topics: Cell Line, Tumor; Curcumin; Erythrocyte Membrane; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species

Recently, the world has been witnessing a global pandemic with no effective therapeutics yet, while cancer continues to be a major disease claiming many lives. The natural compound curcumin is bestowed with multiple medicinal applications in addition to demonstrating antiviral and anticancer activities. In order to elucidate the impact of curcumin on COVID-19 and cancer, the current investigation has adapted several computational techniques to unfold its possible inhibitory activity. Accordingly, curcumin and similar compounds and analogues were retrieved and assessed for their binding affinities at the binding pocket of SARS-CoV-2 main protease and DDX3. The best binding pose was escalated to molecular dynamics simulation (MDS) studies to assess the time dependent stability. Our findings have rendered one compound that has demonstrated good molecular dock score complemented by key residue interactions and have shown stable MDS results inferred by root mean square deviation (RMSD), radius of gyration (Rg), binding mode, hydrogen bond interactions, and interaction energy. Essential dynamics results have shown that the systemadapts minimum energy conformation to attain a stable state. The discovered compound (curA) could act as plausible inhibitor against SARS-CoV-2 and DDX3. Furthermore, curA could serve as a chemical scaffold for designing and developing new compounds.

Topics: Antiviral Agents; Computational Biology; COVID-19 Drug Treatment; Curcumin; Drug Evaluation, Preclinical; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Protease Inhibitors; Protein Binding; SARS-CoV-2

In cancer therapy, stimulus-responsive drug delivery systems are of particular interest for reducing side effects in healthy tissues and improving drug selectivity in the tumoral ones. Here, a strategy for the preparation of a photo-responsive cross-linked trilayer deposited onto an oil-in-water nanoemulsion via a layer-by-layer technique is reported. The system is made of completely biocompatible materials such as soybean oil, egg lecithin and glycol chitosan, with heparin as the polymeric shell. The oil core is pre-loaded with curcumin as a model lipophilic active molecule with anti-tumoral properties. The trilayer cross-linkage is performed via a photoinitiator-free thiol-ene 'click' reaction. In particular, the system is implemented with an

Topics: Animals; Biocompatible Materials; Curcumin; Humans; Mice; Nanocapsules; Neoplasms; Polymers

Topics: Animals; Apoptosis; Curcumin; Mice; Mice, Nude; Mitochondria; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species

The functional activity among STAT3 and PIM1, are key signaling events for cancer cell function. Curcumin, a diarylheptanoid isolated from turmeric, effectively inhibits STAT3 signaling. Selectively, we attempted to address interactions of STAT3, PIM1 and Curcumin for therapeutic intervention using in silico and in vitro experimental approaches. Firstly, protein-protein interactions (PPI) between STAT3-PIM1 by molecular docking studies reflected salt bridges among Arg279 (STAT3)-Glu140 (PIM1) and Arg282 (STAT3)-Asp100 (PIM1), with a binding affinity of -38.6 kcal/mol. Secondly, molecular dynamics simulations of heterodimeric STAT3-PIM1 complex with curcumin revealed binding of curcumin on PIM-1 interface of the complex through hydrogen bonds (Asp155) and hydrophobic interactions (Leu13, Phe18, Val21, etc.) with a binding energy of -7.3 kcal/mol. These PPIs were confirmed in vitro by immunoprecipitation assays in MDA-MB-231 cells. Corroborating our results, expression levels of STAT3 and PIM1 decreased after curcumin treatment. We observed that PIM1 interacts with STAT3 and these functional interactions are disrupted by curcumin. The calculated band energy gap of heterodimeric STAT3-PIM1-Curcumin complex was of 9.621 kcal/mol. The present study revealed the role of curcumin in STAT3/PIM1 signaling and its binding affinity to the complex for design of advanced cancer therapeutics.

Topics: Curcumin; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Proto-Oncogene Proteins c-pim-1; Signal Transduction; STAT3 Transcription Factor

Curcumin as a hydrophobic polyphenol has great potential for tumor therapy, yet its rapid degradation and hydrophobicity severely impair its therapeutic effect in the clinic. Herein, we report a novel strategy for the formation of curcumin doped zeolitic imidazolate framework nanoparticles (Cur-ZIF NPs) by zinc ion driven simultaneous coordination of curcumin and 2-methylimidazole. The resultant Cur-ZIF NPs with a uniform nanosize exhibit favorable stability and dispersibility in water, as well as high drug-loading capacities. The pH and redox sensitivity of ZIF NPs enable the controlled release of curcumin

Topics: Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Immunotherapy; Nanoparticles; Neoplasms; Zeolites

The improvement of cancer chemotherapy remains a major challenge, and thus new drugs are urgently required to develop new treatment regimes. Curcumin, a polyphenolic antioxidant derived from the rhizome of turmeric (Curcuma longa L.), has undergone extensive preclinical investigations and, thereby, displayed remarkable efficacy in vitro and in vivo against cancer and other disorders. However, pharmacological limitations of curcumin stimulated the synthesis of numerous novel curcumin analogs, which need to be evaluated for their therapeutic potential. In the present study, we calculated the binding affinities of 50 curcumin derivatives to known cancer-related target proteins of curcumin, i.e., epidermal growth factor receptor (EGFR) and nuclear factor κB (NF-κB) by using a molecular docking approach. The binding energies for EGFR were in a range of −12.12 (±0.21) to −7.34 (±0.07) kcal/mol and those for NF-κB ranged from −12.97 (±0.47) to −6.24 (±0.06) kcal/mol, indicating similar binding affinities of the curcumin compounds for both target proteins. The predicted receptor-ligand binding constants for EGFR and curcumin derivatives were in a range of 0.00013 (±0.00006) to 3.45 (±0.10) µM and for NF-κB in a range of 0.0004 (±0.0003) to 10.05 (±4.03) µM, indicating that the receptor-ligand binding was more stable for EGFR than for NF-κB. Twenty out of 50 curcumin compounds showed binding energies to NF-κB smaller than −10 kcal/mol, while curcumin as a lead compound revealed free binding energies of >−10 kcal/mol. Comparable data were obtained for EGFR: 15 out of 50 curcumin compounds were bound to EGFR with free binding energies of <−10 kcal/mol, while the binding affinity of curcumin itself was >−10 kcal/mol. This indicates that the derivatization of curcumin may indeed be a promising strategy to improve targe specificity and to obtain more effective anticancer drug candidates. The in silico results have been exemplarily validated using microscale thermophoresis. The bioactivity has been further investigated by using resazurin cell viability assay, lactate dehydrogenase assay, flow cytometric measurement of reactive oxygen species, and annexin V/propidium iodide assay. In conclusion, molecular docking represents a valuable approach to facilitate and speed up the identification of novel targeted curcumin-based drugs to treat cancer.

Topics: Curcumin; ErbB Receptors; Humans; I-kappa B Proteins; Ligands; Molecular Docking Simulation; Neoplasms; NF-kappa B

By hindering energy supply pathway for cancer cells, an alternative therapeutic strategy modality is put forward: tumor starvation therapy. And yet only in this blockade of glucose supply which is far from enough to result in sheer apoptosis of cancer cells.. In an effort to boost nutrient starvation-dominated cancer therapy, here a novel mitochondrial Ca. Here, a promising complementary modality for the trebling additive efficacy of starvation therapy was described for cutting off the existing energy sources in starvation therapy through Curcumin-augmented mitochondrial Ca

Topics: Apoptosis; Autophagy; Cell Line, Tumor; Curcumin; Glucose; Humans; Indoles; Neoplasms; Nutrients; Pyrroles; Starvation

Liposomes have been widely used in nanomedicine for the delivery of hydrophobic and hydrophilic anticancer agents. The most common applications of these formulations are vaccines and anticancer formulations (e.g., mRNA, small molecule drugs). However, large-scale production with precise control of size and size distribution of the lipid-based drug delivery systems (DDSs) is one of the major challenges in the pharmaceutical industry. In this study, we used newly designed microfluidic swirl mixers with simple 3D mixing chamber structures to prepare liposomes at a larger scale (up to 320 mL/min or 20 L/h) than the commercially available devices. This design demonstrated high productivity and better control of liposome size and polydispersity index (PDI) than conventional liposome preparation methods. The microfluidic swirl mixer devices were used to produce curcumin-loaded liposomes under different processing conditions which were later characterized and studied in vitro to evaluate their efficiency as DDSs. The obtained results demonstrated that the liposomes can effectively deliver curcumin into cancer cells. Therefore, the microfluidic swirl mixers are promising devices for reproducible and scalable manufacturing of DDSs.

Topics: Curcumin; Drug Delivery Systems; Liposomes; Microfluidics; Nanomedicine; Neoplasms; Particle Size

Curcumin is one of the most interesting plant-derived polyphenols with a high potential for therapeutic, and even diagnostic, application in various diseases [...].

Topics: Curcumin; Humans; Neoplasms; Polyphenols

Pyroptosis provides a new direction and broad prospects for cancer immunotherapy. However, the development of a nanoplatform as a pyroptosis inducer is limited, and the discovery of a new type of nano-pyroptosis inducer for cancer immunotherapy is still imminent. Herein, biodegradable Ca

Topics: Curcumin; Immunotherapy; Mitochondria; Neoplasms; Pyroptosis

(1) Background: Curcumin (CUR) and tetrandrine (TET) are natural compounds with various bioactivities, but have problems with low solubility, stability, and absorption rate, resulting in low bioavailability, and limited applications in food, medicine, and other fields. It is very important to improve the solubility while maintaining the high activity of drugs. Liposomes are micro-vesicles synthesized from cholesterol and lecithin. With high biocompatibility and biodegradability, liposomes can significantly improve drug solubility, efficacy, and bioavailability. (2) Methods: In this work, CUR and TET were encapsulated with nano-liposomes and g DSPE-MPEG 2000 (DP)was added as a stabilizer to achieve better physicochemical properties, biosafety, and anti-tumor effects. (3) Results: The nano-liposome (CT-DP-Lip) showed stable particle size (under 100 nm) under different conditions, high solubility, drug encapsulation efficiency (EE), loading capacity (LC), release rate in vitro, and stability. In addition, in vivo studies demonstrated CT-DP-Lip had no significant toxicity on zebrafish. Tumor cytotoxicity test showed that CT-DP-Lip had a strong inhibitory effect on a variety of cancer cells. (4) Conclusions: This work showed that nano-liposomes can significantly improve the physical and chemical properties of CUR and TET and make them safer and more efficient.

Topics: Animals; Benzylisoquinolines; Chemical and Drug Induced Liver Injury; Curcumin; Drug Carriers; Liposomes; Neoplasms; Particle Size; Zebrafish

Curcumin was found to possess numerous pharmacological activities in clinical research, however, its biological effects together with radiation are yet to be addressed. The present study investigated whether the combined treatment of dendrosomal nanoformulation of curcumin (DNC) and gamma radiation can enhance the radiosensitivity of U87MG and MDA-MB-231 cell lines.. U87MG and MDA-MB-231 cell lines were exposed to 2 Gray (Gy) and 10 μM DNC determined by MTT assay, then subjected to clonogenic assay, cell cycle assay, and flow cytometric apoptosis analysis. Acridine Orange/Ethidium Bromide (AO/EB) and 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) stained cells were used to study morphologic changes. The expression evaluation of putative cell cycle genes, i.e., P53, P21, CCND1, and CCNB1 was carried out by RT-qPCR.. Our findings indicated that the combined treatment with DNC and radiation might cooperatively augment the efficacy of ionizing radiation in the cancer cells and notably decrease the survival and viability of the cells in a time- and concentration-dependent manner. In addition to a synergistic effect deducted by sensitizer enhancement ratio (SER) assessment, co-treatment resulted in greater apoptotic cells than the individual treatments. Further experiments then indicated that DNC could effectively induce G2/M phase cell cycle arrest and apoptosis following irradiation. Conformably, there was a decrement of CCND1 and CCNB1 expression, and an increment of P53, P21 expression.. The data implied that DNC as a radiosensitizer can enhance the lethal effect of ionizing radiation on cancer cells which could be a promising adjuvant therapy in clinical treatments.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Curcumin; Neoplasms; Radiation-Sensitizing Agents; Tumor Suppressor Protein p53

We herein fabricated a cancer nanotheranostics platform based on Graphene Oxide Quantum Dot-Chitosan-polyethylene glycol nanoconjugate (GOQD-CS-PEG), which were targeted with MUC-1 aptamer towards breast and colon tumors. The interaction between aptamer and MUC-1 receptor on the desired cells was investigated utilizing molecular docking. The process of curcumin release was investigated, as well as the potential of the produced nanocomposite in targeted drug delivery, specific detection, and photoluminescence imaging. The fluorescence intensity of GOQD-CS-PEG was reduced due to transferred energy between (cytosine-guanin) base pairs in the hairpin structure of the aptamer, resulting in an "on/off" photoluminescence bio-sensing. Interestingly, the integration of pH-responsive chitosan nanoparticles in the nanocomposite results in a smart nanocomposite capable of delivering more curcumin to desired tumor cells. When selectively binds to the MUC-1 receptor, the two strands of aptamer separate in acidic conditions, resulting in a sustained drug release and photoluminescence recovery. The cytotoxicity results also revealed that the nanocomposite was more toxic to MUC-1-overexpressed tumor cells than to negative control cell lines, confirming its selective targeting. As a result, the proposed nanocomposite could be used as an intelligent cancer nanotheranostic platform for tracing MUC-1-overexpressed tumor cells and targeting them with great efficiency and selectivity.

Topics: Chitosan; Curcumin; Graphite; Humans; Hydrogen-Ion Concentration; Molecular Docking Simulation; Neoplasms; Quantum Dots; Theranostic Nanomedicine

Topics: Cell Cycle Checkpoints; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Flavonoids; Flavonols; Heterochromatin; Neoplasms; Quercetin

A series of novel cobalt bis(dicarbollide)-curcumin conjugates were synthesized. Two conjugates were obtained through the nucleophilic ring-opening reaction of the 1,4-dioxane and tetrahydropyran derivatives of cobalt bis(dicarbollide) with the OH group of curcumin, and using two equiv. of the oxonium derivatives, two other conjugates containing two cobalt bis(dicarbollide) units per molecule were obtained. In contrast to curcumin, the conjugates obtained were found to be non-cytotoxic against both tumor and normal cell lines. The analysis of the intracellular accumulation of the conjugates by flow cytometry showed that all cobalt bis(dicarbollide)-curcumin conjugates entered HCT116 colorectal carcinoma cells in a time-dependent manner. New non-cytotoxic conjugates contain a large amount of boron atoms in the biomolecule and can potentially be used for further biological research into boron neutron capture therapy (BNCT).

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Cobalt; Curcumin; Humans; Neoplasms

The development of effective carriers enabling combination cancer therapy is of practical importance due to its potential to enhance the effectiveness of cancer treatment. However, most of the reported carriers are monofunctional in nature. The carriers that can be applied to concomitantly mediate multiple treatment modalities are highly deficient. This study fills this gap by reporting the design and fabrication of ROS-generating carbohydrate-based pH-responsive beads with intrinsic anticancer therapy and multidrug co-delivery capacity for combination cancer therapy. Sodium alginate (SA) microspheres and reduced graphene oxide (rGO)-embedded chitosan (CS) beads are developed via emulsion-templated ionic gelation for a combination therapy involving co-delivery of curcumin (CUR) and 5-fluororacil (5-FU). Drug-encapsulated microbeads are characterized by FTIR, DSC, TGA, XRD, and SEM. 5-FU and CUR-encapsulated microbeads are subjected to

Topics: Alginates; Chitosan; Curcumin; Drug Carriers; Drug Liberation; Fluorouracil; Graphite; Humans; Hydrogen-Ion Concentration; Microspheres; Neoplasms; Reactive Oxygen Species

In this project, different photosensitizers were prepared using different ratios of nickel, manganese, and iron. Then, multiple analysis were performed to evaluate their efficiency, and the most suitable one was used to be coated by hyaluronic acid to improve the nano-platform's biocompatibility and target ability. Moreover, another chemical targeting agent (riboflavin) was used to further improve the target ability of the prepared nano-platform. Different spectroscopies and thermal analysis were used to determine the physical and chemical characteristics of the prepared nano-platform. Also, in order to determine the biocompatibility of the nano-platform, in vitro and in vivo tests such as blood hemolysis, blood aggregation and lethal dose were performed. Then, an anti-cancer agent (curcumin) was loaded on the selected nano-platform to makes us able utilizing the synergistic effect of chemotherapy and photodynamic therapy simultaneously. Finally, the cell cytotoxicity results showed that the prepared nano-platform had a great anti-cancer potential which can make it a great candidate as a dual photo and chemo therapy agent for treatment of breast cancers.

Topics: Aluminum Oxide; Cell Line, Tumor; Curcumin; Doxorubicin; Ferric Compounds; Humans; Hyaluronic Acid; Iron; Magnesium Oxide; Manganese; Nanoparticles; Neoplasms; Nickel; Photochemotherapy; Photosensitizing Agents; Riboflavin

Efficient drug loading, tumor targeting, intratumoral penetration, and cellular uptake are the main factors affecting the effectiveness of drug delivery systems in oncotherapy. Based on the tumor microenvironment, we proposed to develop Curcumin (Cur)-loaded matrix metalloproteinase (MMP)-responsive nanoparticles (Cur-P-NPs) by static electricity, to enhance tumor targeting, cellular uptake, and drug loading efficiency. These nanoparticles combine the properties of both PEG-peptides (cleaved peptide + penetrating peptide) and star-shaped polyester (DPE-PCL) nanoparticles. Cur-P-NPs displayed good entrapment efficiency, drug loading and biocompatibility. Additionally, they showed an enhanced release rate, cellular uptake, and anti-proliferative activity by activating peptides under the simulated tumor microenvironment. Furthermore, intraperitoneal injection of losartan (LST) successfully enhanced intratumoral drug penetration by collagen I degradation. In vivo studies based on the systematic administration of the synergistic LST + Cur-P-NPs combination to mice confirmed that combined antitumor therapy with LST and Cur-P-NPs could further improve intratumor distribution, enhance anticancer efficacy, and reduce the toxicity and side effects. Therefore, LST + Cur-P-NPs represent a new and efficient system for clinical oncotherapy.

Topics: Animals; Cell Line, Tumor; Collagen; Curcumin; Drug Delivery Systems; Losartan; Matrix Metalloproteinases; Mice; Nanoparticle Drug Delivery System; Nanoparticles; Neoplasms; Particle Size; Polyesters; Tumor Microenvironment

Resveratrol, a natural polyphenol, exhibits beneficial health properties and has been touted as a potential anti-tumor agent. Here, we demonstrate potent anti-cancer effects of carbon dots (C-dots) synthesized from resveratrol. The mild synthesis conditions retained resveratrol functional moieties upon the carbon dots' (C-dots) surface, an important requisite for achieving specificity toward cancer cells and biological activities. Indeed, the disruptive effects of the resveratrol-C-dot were more pronounced in several cancer cell types compared to normal cells, underscoring targeting capabilities of the C-dots, a pertinent issue for the development of cancer therapeutics. In particular, we observed impairment of mitochondrial functionalities, including intracellular calcium release, inhibition of cytochrome-C oxidase enzyme activity, and mitochondrial membrane perturbation. Furthermore, the resveratrol C-dots were more potent than either resveratrol molecules alone, known anti-cancer polyphenolic agents such as curcumin and triphenylphosphonium, or C-dots prepared from different carbonaceous precursors. This study suggests that resveratrol-synthesized C-dots may have promising therapeutic potential as anti-cancer agents.

Topics: Antineoplastic Agents; Apoptosis; Calcium; Carbon; Curcumin; Electron Transport Complex IV; Mitochondria; Neoplasms; Polyphenols; Resveratrol; Stilbenes

Curcumin (CUR) manifests anti-colon cancer activity but suffers from low solubility, bioavailability, and instability, rendering it not as effective as its chemotherapeutic cousins. Here, we conjugate CUR to succinic anhydride (SA), (CUR.SA conjugate), subsequently formulated in mannose-conjugated chitosan nanoparticles (CUR-NPs and CUR.SA-NPs). Instrumental analyses confirmed formation of CUR.SA and mannosylated chitosan (CM) conjugates, with CUR.SA being less crystalline thus, more soluble. Average particle size of CUR-NPs and CUR.SA-NPs were 268 ± 6 nm and 342 ± 4.6 nm, with drug entrapment of 93.34 ± 0.40 % and 98.46 ± 0.06 % respectively. In vitro releases of CUR and CUR.SA from nanoparticles in pH 1.2 and 6.8 media were slow and sustained over 2 h and 72 h, respectively. The physical characteristics of the nanoparticles were unchanged over 3 weeks of storage. Thus, a successful CUR.SA conjugate has been developed, couriered in CM nanoparticles, with favorable attributes that warrant further anti-colon cancer studies, which is ongoing.

Topics: Chitosan; Curcumin; Drug Carriers; Humans; Mannose; Nanoparticles; Neoplasms; Particle Size; Succinic Anhydrides

Turmeric spice contains curcuminoids, which are polyphenolic compounds found in the Curcuma longa plant's rhizome. This class of molecules includes curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Using prostate cancer cell lines PC3, LNCaP, DU145, and C42B, we show that curcuminoids inhibit cell proliferation (measured by MTT assay) and induce apoptosis-like cell death (measured by DNA/histone ELISA). A copper chelator (neocuproine) and reactive oxygen species scavengers (thiourea for hydroxyl radical, superoxide dismutase for superoxide anion, and catalase for hydrogen peroxide) significantly inhibit this reaction, thus demonstrating that intracellular copper reacts with curcuminoids in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitize normal breast epithelial cells (MCF-10A) to curcumin-mediated growth inhibition, as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters CTR1 and ATP7A in MCF-10A cells, which is attenuated by the addition of curcumin in the medium. We propose that the copper-mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of curcuminoids.

Topics: Apoptosis; Copper; Curcuma; Curcumin; Diarylheptanoids; Genomics; Humans; Hydrogen Peroxide; Male; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species

A tumor-targeting therapy strategy is urgently needed to increase the accumulation of drugs in tumors and reduce the side effects in normal tissues. Herein, we developed an esterase-activatable curcumin prodrug Cur-RGD for tumor-targeting therapy. Armed with the tumor-targeting RGD peptide and

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Carriers; Esterases; Humans; Nanoparticles; Neoplasms; Oligopeptides; Prodrugs

Oral cancer, one of the most common cancers, has unimproved 5-years survival rate in the last 30 years and the chemo/radiotherapy-associated morbidity. Therefore, intervention strategies that evade harmful side effects of the conventional treatment modalities are of need. Herbal therapy as a complementary preventive/therapeutic modality has gained attention. Curcumin is one of the herbal compounds possessing unique anticancer activity and luminescent optical properties. However, its low water solubility limits its efficacy. In contrast, curcumin at the nanoscale shows altered physical properties with enhancing bioavailability.. The current study evaluated the impact of nanocurcumin as an anti-oral cancer herbal remedy, comparing its efficacy against the native curcumin complement and conventional chemotherapeutic. An optimized polymeric-stabilized nanocurcumin was synthesized using the solvent-antisolvent precipitation technique. After assuring the solubility and biocompatibility of nanocurcumin, we determined its cytotoxic dose in treating the squamous cell carcinoma cell line. We then evaluated the anti-tumorigenic activity of the nano-herb in inhibiting wound closure and the cytological alterations of the treated cancer cells. Furthermore, the cellular uptake of the nanocurcumin was assessed depending on its autofluorescence.. The hydrophilic optimized nanocurcumin has a potent cancerous cytotoxicity at a lower dose (60.8 µg/mL) than the native curcumin particles (212.4 µg/mL) that precipitated on high doses hindering their cellular uptake. Moreover, the nanocurcumin showed differential targeting of the cancer cells over the normal fibroblasts with a selectivity index of 4.5. With the confocal microscopy, the luminescent nanoparticles showed gradual nuclear and cytoplasmic uptake with apparent apoptotic cell death, over the fluorescent doxorubicin with its necrotic effect. Furthermore, the nanocurcumin superiorly inhibited the migration of cancer cells by -25%.. The bioavailable nanocurcumin has better apoptotic cytotoxicity. Moreover, its superior luminescence promotes the theranostic potentialities of the nano-herb combating oral cancer.

Topics: Administration, Oral; Curcumin; Humans; Nanoparticles; Neoplasms; Precision Medicine

Modulation of proteasome function by pharmacological interventions and molecular biology tools is an active area of research in cancer biology and neurodegenerative diseases. Curcumin (diferuloylmethane) is a naturally occurring polyphenol that affects multiple signaling pathways. Curcumin shows anti-inflammatory, antioxidant, anti-angiogenic, or anti-apoptotic properties. Recent research suggests that the therapeutic efficacy of curcumin may be due to its activity as a potent inhibitor of the proteasome. Using in vitro cell culture and molecular docking methods, here we show that both curcumin and its synthetic polyphenolic derivative (didemethylcurcumin, CUIII) modulated proteasome activity in a biphasic manner. Curcumin and CUIII increased proteasome activity at nanomolar concentrations, but inhibited proteasome activity at micromolar concentrations. Curcumin was more effective than CUIII in increasing relative proteasome activity at nanomolar concentrations. Also, curcumin was more effective than CUIII in inhibiting relative proteasome activity at micromolar concentrations. Docking simulations of curcumin and didemethylcurcumin binding to the 20S proteasome catalytic subunit estimated

Topics: Antioxidants; Curcumin; Humans; Molecular Docking Simulation; Neoplasms; Polyphenols; Proteasome Endopeptidase Complex

Nowadays, the use of nanoparticle-based drug delivery systems has received much more attention. In this regard, here, graphene quantum dots (GQD) were used as drug carriers as well as imaging agents for cancer cells. In order to optimize the dose of the drug and reduce its side effects for healthy cells, hyaluronic acid was decorated on the surface of GQD to target cancer cells. The morphology and size of the synthesized nanoparticles alone and conjugated with hyaluronic acid were investigated using scanning electron microscopy (SEM) and transmission electron microscopy (TEM); TEM images revealed a particles size of ∼5.67 and ∼8.69 nm, respectively. In the presence of 1-ethyl-3-[3(dimethylamino)propyl]carbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS), hyaluronic acid was bounded to dopamine hydrochloride and was prepared to react with GQD. After synthesis of graphene quantum dot-hyaluronic acid nanocomposite, curcumin (CUR) as a drug model was loaded on the synthesized nanocarriers, and its loading percentage was measured. The results showed that 98.02% of the drug was loaded on the nanocarriers. Also, the conjugation of each agent on the nanocarrier was approved by photoluminescence spectroscopy, Fourier transform infrared spectroscopy (FTIR), and UV-visible absorption techniques, and the results showed that the reactions were performed correctly. The effect of GQD, graphene quantum dot-hyaluronic acid, CUR, graphene quantum dot-hyaluronic acid-CUR on the viability of HeLa and L929 cells was evaluated by the MTT test. The results showed that the synthesized nanocarrier is completely biocompatible, and the drug nanocarriers reduce HeLa cell viability significantly due to the mediation of hyaluronic acid-CD44 for drug cell uptake. Simultaneously with drug delivery, the other goal of these nanocarriers is to image cancer cells by emitting fluorescent light. Fluorescent microscopy showed that these nanocarriers were adsorbed on HeLa cells, unlike L929 cells.

Topics: Curcumin; Drug Delivery Systems; Graphite; HeLa Cells; Humans; Hyaluronic Acid; Nanocomposites; Neoplasms; Quantum Dots

Curcumin is an ingredient in the turmeric plant that gives yellow color to dishes and is used as a spice. It has been used locally/topically and systemically in the treatment of diseases in Far Eastern societies, especially in Indian and Chinese traditional medicine. Curcumin is a natural substance that does not show toxic properties in overdose. In addition to its anti-inflammatory, anti-oxidant, anti-neoplastic, anti-viral, anti-microbial, anti-angiogenic properties, platelet aggregation, apoptosis, and wound healing have been demonstrated in different studies. In recent years, it has been used as a radiosensitizing agent and a radioprotector in radiation therapy. Although curcumin has low bio-availability, it seems to be the ideal molecule due to its low molecular weight, high activity in inhibiting the growth of tumor cells and protecting normal tissues from the side effects of radiation.. Curcumin in combination with radiotherapy was discussed in the light of the literature.

Topics: Antineoplastic Agents, Phytogenic; Curcumin; Humans; Neoplasms; Radiation-Protective Agents; Radiation-Sensitizing Agents

Curcumin (CUR) is a bioactive natural compound with potent antioxidant and anticancer properties. However, its poor water solubility has been a major limitation against its widespread clinical use. The aim of this study was to develop a nanoscale formulation for CUR to improve its solubility and potentially enhance its bioactivity, by leveraging the self-assembly behavior of tannic acid (TA) and amphiphilic poloxamers to form CUR-entrapped nanoassemblies. To optimize drug loading, formulation variables included the CUR: TA ratio and the type of amphiphilic polymer (Pluronic® F-127 or Pluronic® P-123). The optimal CUR nanoparticles (NPs) were around 200 nm in size with a high degree of monodispersity and 56% entrapment efficiency. Infrared spectroscopy confirmed the presence of intermolecular interactions between CUR and the NP formulation components. X-ray diffraction revealed that CUR was entrapped in the NPs in an amorphous state. The NPs maintained excellent colloidal stability under various conditions. In vitro release of CUR from the NPs showed a biphasic controlled release pattern up to 72 h. Antioxidant and antiproliferative assays against a panel of human cancer cell lines revealed significantly higher activity for CUR NPs compared to free CUR, particularly in MCF-7 and MDA-MB-231 breast cancer cells. This was attributed to greater cellular uptake of the NPs compared to the free drug as verified by confocal microscopy imaging and flow cytometry measurements. Our findings present a highly promising NP delivery platform for CUR prepared via a simple self-assembly process with the ability to potentiate its bioactivity in cancer and other diseases where oxidative stress is implicated.

Topics: Antineoplastic Agents; Curcumin; Humans; Nanoparticles; Neoplasms; Particle Size; Poloxamer; Tannins

In our previous paper, we reported that amphiphilic Ir complex-peptide hybrids (IPHs) containing basic peptides such as KK(K)GG (K: lysine, G: glycine) (e.g., ASb-2) exhibited potent anticancer activity against Jurkat cells, with the dead cells showing a strong green emission. Our initial mechanistic studies of this cell death suggest that IPHs would bind to the calcium (Ca

Topics: A549 Cells; Apoptosis; Calcium; Calmodulin; Cell Death; Cell Line, Tumor; Curcumin; Endoplasmic Reticulum; HeLa Cells; Humans; Iridium; Jurkat Cells; K562 Cells; Membrane Potential, Mitochondrial; Mitochondria; Neoplasms; Pentacyclic Triterpenes; Signal Transduction; Triterpenes; U937 Cells

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogen-Ion Concentration; Mice; Micelles; Neoplasms

Topics: Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Humans; Nanotubes; Neoplasms; Pharmaceutical Preparations

Topics: Cell Line, Tumor; Curcumin; Drug Delivery Systems; Hyaluronic Acid; Micelles; Nanoparticles; Neoplasms

Curcumin (CUR) display promising antitumor effects, however, the poor water solubility severely limited its clinical application. To overcome this problem, polymeric nanocarriers have been adopted for targeted CUR delivery and enhanced cancer therapy. In this paper, utilizing an acid-labile hydrazone linkage, hydrophobic CUR was conjugated with hydrophilic hyaluronic acid (HA) to form amphiphilic HA-ADH-CUR conjugates, which could subsequently self-assemble to form nanoparticles (HA@CUR NPs) in aqueous. The in vitro drug release experiments showed that HA@CUR NPs exhibited a pH-responsive CUR release behavior, and the release rate of CUR was 73.5 % in pH 5.0. Further, in vitro cell experiments showed HA@CUR NPs could be efficiently internalized by 4T1 and MCF-7 cancer cells through CD44 receptor mediated endocytosis and successfully release CUR in acidic lysosome environment for chemotherapy. In vivo antitumor experiments showed that, compared to free CUR, HA@CUR NPs could efficiently cumulate in tumor site via EPR effect and CD44 mediated endocytosis, achieve superior therapeutic effect for tumor growth suppression. Therefore, HA@CUR NPs were a highly promising nanocarrier for hydrophobic CUR to realize enhanced cancer therapy with good biosafety.

Topics: Curcumin; Drug Delivery Systems; Drug Liberation; Humans; Hyaluronic Acid; Hydrogen-Ion Concentration; Nanoparticles; Neoplasms

Encapsulation of therapeutic molecules into nanocarrier is an extensively explored strategy to treat cancer more effectively. In this study, pH-responsive targeting dual-agent delivery nanoparticles were prepared, into which hydrophilic doxorubicin hydrochloride (DOX) and hydrophobic curcumin (CUR) were entrapped. Tyrosine (Tyr) was grafted onto poly(aspartic acid) (PASP) to produce PASP-Tyr, the following reaction between hyaluronic acid (HA) and ethylenediamine (EDA) modified PASP-Tyr formed the nanocarrier HA-EDA-PASP-Tyr (HEPT), and the loading capacity was up to 50.9 ± 4.3% for CUR and 26.0 ± 1.9% for DOX. The spherical HEPT with the mean particle size of 142.9 ± 11.4 nm expanded and deformed into petaloid pattern with an increased size of about 2 µm when triggered by the acidic microenvironment.

Topics: Aspartic Acid; Curcumin; Doxorubicin; Drug Delivery Systems; Humans; Hyaluronic Acid; Hydrogen-Ion Concentration; Nanoparticles; Neoplasms; Particle Size; Peptides; Tumor Microenvironment

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Autophagy; Cell Culture Techniques; Cell Death; Curcumin; Drug Development; Humans; Leucine Zippers; Lysosomes; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 9; Mitogen-Activated Protein Kinases; Neoplasms; Nerve Tissue Proteins; Protective Agents; Reactive Oxygen Species

The present work involves encapsulation of herbal drug nanocurcumin into the virosomes and compared with a liposome in terms of their in vitro anti-proliferative, anti-inflammatory, and anti-migratory efficacy.. The anti-proliferative, anti-inflammatory, and anti-migratory efficacy of virosome and liposome were compared in HepG2 and CaCo2 cells by using MTT, Nitric oxide scavenging, and Wound healing assay, respectively.. Size of the optimised NC-Virosome and NC-Liposome was 70.06 ± 1.63 and 265.80 ± 1.64 nm, respectively. The prepared NC-Virosome can be stored at -4 °C up to six months. The drug encapsulation efficiency of NC-Virosome and NC-Liposome was found to be 84.66 ± 1.67 and 62.15 ± 1.75% (w/w). The evaluated minimum inhibitory concentration (IC50 value) for NC-Virosome was 102.7 μg/ml and 108.1 μg/ml, while NC-Liposome showed 129.2 μg/ml and 160.1 μg/ml for HepG2 and CaCo2 cells, respectively. Morphological examination depicts detachment of the cells from substratum after exposure to NC-Virosome for 48 h.. The prepared NC-Virosome provides remarkable in vitro efficacy in both the cell lines with site-specific drug-targeting potential as compared to the liposome, results proved its potential as a drug delivery vehicle for future therapy with reduced toxicity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Caco-2 Cells; Cell Movement; Curcumin; Drug Delivery Systems; Excipients; Hep G2 Cells; Humans; Liposomes; Microbial Sensitivity Tests; Neoplasms; Nitric Oxide; Tetrazolium Salts; Thiazoles; Virosomes; Wound Healing

Two cationic ruthenium(II) 1,4,7-trithiacyclononane ([9]aneS

Topics: Alkanes; Antineoplastic Agents; Cell Survival; Coordination Complexes; Crystallography, X-Ray; Curcumin; Humans; Models, Molecular; Neoplasms; Ruthenium; Sulfur Compounds; Tumor Cells, Cultured

Telomerases are attractive targets for development of new anticancer agents. Most tumors express the enzyme telomerase that maintains telomere length and thus ensures indefinite cell proliferation, a hallmark of cancer. Curcumin has been shown to be effective against several types of malignancies and has also been shown to have inhibitory effects on telomerase activity. Hence, the aim of this chapter is to review the available investigations of curcumin on telomerase activity. Based on the findings obtained from the different studies here, we conclude that the telomerase inhibitory effects of curcumin are integral to its anticancer activity, and thus curcumin may be useful therapeutically in the cancer field.

Topics: Antineoplastic Agents; Cell Proliferation; Curcumin; Humans; Neoplasms; Telomerase; Telomere

Nanotechnology has many potential applications in cancer treatment. For example, nano-drug delivery systems (NDDS) with high bioavailability, biodegradability, and biocompatibility have been developed, in order to increase the therapeutic effects of anticancer drugs. Among these NDDS, high-performance hydroxyapatite (HA) nanoparticles are rapidly advancing in the targeted cancer treatment due to their numerous benefits. Curcumin is an herbal metabolite that acts as a chemical inhibitor through the inhibition of tumor cells and the progression of many cancers. However, the poor bioavailability of curcumin is the most important challenge in using this substance. In this study, HA nanoparticles coated by chitosan were used as a pH-sensitive biopolymer to improve the efficiency and bioavailability of curcumin. For this purpose, HA nanoparticles were first synthesized by the sol-gel method. Then, a layer of chitosan was coated on it, and the curcumin drug was encapsulated in the nanocarrier, under controlled conditions. Techniques such as scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to characterize the nanocarriers. In the second part, nano-drugs prepared by various bioassays were examined. For this purpose, the rate of cytotoxicity by the methyl-thiazol-tetrazolium (MTT) assay and the rate of apoptosis induction by the acridine orange and ethidium bromide (AO/EB) staining method on the brain carcinoma U87MG cell line were investigated.

Topics: Antineoplastic Agents; Chitosan; Curcumin; Drug Carriers; Durapatite; Nanoparticles; Neoplasms; Spectroscopy, Fourier Transform Infrared

Due to the shortcomings of nanocarriers, the development of carrier-free nanodelivery systems has attracted more and more attention in cancer treatment. However, there are few studies on carrier-free nanosystems that can simultaneously achieve monitoring functions. Here a multifunctional carrier-free nanosystem loaded with curcumin and irinotecan hydrochloride was established for the treatment and monitoring of gastric cancer.. In this study, an irinotecan hydrochloride-curcumin nanosystem in the early stage (the system is named SICN) was prepared. Based on the fluorescence of curcumin, flow cytometry, laser confocal microscopy, and zebrafish fluorescence imaging were used to study the monitoring function of SICN in vivo and in vitro. In addition, HGC-27 human gastric cancer cells were used to study SICN cytotoxicity.. Flow cytometry and zebrafish fluorescence imaging monitoring results showed that the uptake of SICN was significantly higher than free curcumin, and the excretion rate was lower. SICN had higher accumulation and retention in cells and zebrafish. Laser confocal microscopy monitoring results showed that SICN was internalized into HGC-27 cells through multiple pathways, including macropinocytosis, caveolin, and clathrin-mediated and clathrin -independent endocytosis, and distributed intracellularly throughout the whole cytoplasm, including lysosomes and Golgi apparatus. In vitro cell experiments showed that SICN nanoparticles were more toxic than single components, and HGC-27 cells had more absorption and higher toxicity to nanoparticles under slightly acidic conditions.. SICN is a promising carrier-free nanoparticle, and the combination of two single-component therapies can exert a synergistic antitumor effect. When exposed to a tumor acidic environment, SICN showed stronger cytotoxicity due to charge conversion. More importantly, the nanoparticles' self-monitoring function has been developed, opening up new ideas for combined tumor therapy.

Topics: Animals; Apoptosis; Cell Cycle; Cell Death; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Endocytosis; Fluorescence; Humans; Imaging, Three-Dimensional; Irinotecan; Nanoparticles; Neoplasms; Particle Size; Zebrafish

Phytochemicals are various compounds produced by plants. There is growing evidence on their potential health effects. Some of these compounds are considered as traditional medicines and used as painkillers, anti-inflammatory agents, and for other applications. One of these phytochemicals is curumin, a natural polyphenol derived from the turmeric plant (Curcuma longa L.). Curcumin is widely used as a food coloring, preservative and condiment. It has also been shown to have antioxidative and anti-inflammatory effects. Moreover, there is growing evidence that curcumin alters long noncoding RNAs (lncRNAs) in many kinds of cancer. These noncoding RNAs can cause epigenetic modulation in the expression of several genes. This study reviews reports of curcumin effects on lncRNAs in lung, prostate, colorectal, breast, pancreatic, renal, gastric, and ovarian cancers.

Topics: Anti-Inflammatory Agents; Curcumin; Humans; Male; Neoplasms; Phytochemicals; RNA, Long Noncoding

Topics: Curcumin; Doxorubicin; Drug Carriers; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glutathione; Humans; Nanoparticles; Neoplasms

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Curcumin; Drug Screening Assays, Antitumor; Flavanones; Humans; Lab-On-A-Chip Devices; Microfluidic Analytical Techniques; Microfluidics; Neoplasms; Polyphenols; Resveratrol; Tumor Microenvironment

Curcumin is a kind of anti-cancer chemotherapeutic drug and has been demonstrated to be able to produce reactive oxygen species (ROS) under the stimuli of ultrasound (US). Herein, gadolinium-doped hollow mesoporous silica nanospheres (Gd-HMSNs) loaded with curcumin (Cur) and conjugated with carboxymethyl dextran (CMD) have been facilely fabricated and applied for magnetic resonance imaging (MRI)-guided synergistic cancer sonodynamic-chemotherapy. The as-prepared multifunctional theranostic nanoplatform (Cur@Gd-HMSNs-CMD) shows high drug loading capacity, satisfactory biocompatibility, pH-responsive degradation, and US-triggered drug release. Due to the release of Gd

Topics: Curcumin; Gadolinium; Magnetic Resonance Imaging; Nanoparticles; Nanospheres; Neoplasms; Silicon Dioxide; Theranostic Nanomedicine

A chlorine e6 (Ce6) and curcumin (Cur) based self-delivery nanomedicine (CeCu) is prepared for chemotherapy sensitized photodynamic therapy (PDT). The chemotherapeutic agent of Cur could inhibit the TrxR activity to destroy the cellular ROS-defence system for enhanced PDT, which provides synergistic effects for tumor precision therapy in consideration of the unfavorable tumor microenvironments.

Topics: Animals; Cell Line; Cell Survival; Chlorophyllides; Curcumin; Humans; Mice; Microscopy, Confocal; Nanomedicine; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase; Transplantation, Heterologous; Tumor Microenvironment

A novel folate receptor-targeted β-cyclodextrin (β-CD) drug delivery vehicle was constructed to improve the bioavailability, biosafety, and drug loading capacity of curcumin. Controlled release and targeted delivery was achieved by modifying the nanoparticles with folic acid (FA).. Folate-conjugated β-CD-polycaprolactone block copolymers were synthesized and characterized. Curcumin-loaded nanoparticles (FA-Cur-NPs) were structured by self-assembly. The physicochemical properties, stability, release behavior and tumor-targeting ability of the fabricated nanoparticles were studied.. The average particle size and drug loading of FA-Cur-NPs was 151.8 nm and 20.27%, respectively. Moreover, the FA-Cur-NPs exhibited good stability in vitro for 72 h. The drug release profiles showed that curcumin from FA-Cur-NPs was released significantly faster in a pH 6.4 phosphate buffered solution (PBS) than in pH 7.4, indicating that curcumin can be enriched around the tumor site compared with normal cells. Additionally, the internalization of FA-Cur-NPs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. Furthermore, in vivo studies confirmed that FA-Cur-NPs exhibited marked accumulation in the tumor site and excellent antitumor activity.. These findings suggest that FA-Cur-NPs are a promising approach for improving cancer therapy through active targeting and controllable release.

Topics: Animals; Antineoplastic Agents; beta-Cyclodextrins; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Female; Folate Receptors, GPI-Anchored; Folic Acid; HeLa Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms; Particle Size; Polyesters; Tissue Distribution; Xenograft Model Antitumor Assays

Although first-line chemotherapy drugs, including 5-fluorouracil (5-FU), remain one of the major choice for cancer treatment, the clinical use is also accompanied with dose-depending toxicities, such as intestinal mucositis (IM), in cancer patients undergoing treatment. IM-induced gastrointestinal adverse reactions become frequent reason to postpone chemotherapy and have negative impacts on therapeutic outcomes and prognosis. Various studies have evidenced the anticancer role of curcumin in many cancers; except for this effect, studies also indicated a protective role of curcumin in intestinal diseases. Therefore, in this study, we investigated the effect of curcumin on inflammation, intestinal epithelial cell damage in an IM model. 5-FU was used to induce the model of IM in intestinal epithelial cells, and curcumin at different concentrations was administrated. The results showed that curcumin efficiently attenuated 5-FU-induced damage to IEC-6 cells, inhibited the levels of inflammatory cytokines, attenuated the 5-FU-induced inhibition on cell viability, and displayed antiapoptosis effect on IEC-6 cells. Further RNA-sequencing analysis and experiment validation found that curcumin displays its protective effect against 5-FU-induced IM in intestinal epithelial cells by the inhibition of IL-6/STAT3 signaling pathway. Taken together, these findings suggested that curcumin may be provided as a therapeutic agent in prevention and treatment of chemotherapy-induced IM.

Topics: Animals; Cell Line; Curcumin; Disease Models, Animal; Epithelial Cells; Fluorouracil; Gene Expression Regulation; Humans; Interleukin-6; Intestinal Mucosa; Mucositis; Neoplasms; Rats; RNA-Seq; Signal Transduction; STAT3 Transcription Factor

Breast cancer consists of heterogenic subpopulations, which determine the prognosis and response to chemotherapy. Among these subpopulations, a very limited number of cancer cells are particularly problematic. These cells, known as breast cancer stem cells (BCSCs), are thought responsible for metastasis and recurrence. They are thus major contributor to the unfavorable outcomes seen for many breast cancer patients. BCSCs are more prevalent in the hypoxic niche. This is an oxygen-deprived environment that is considered crucial to their proliferation, stemness, and self-renewal but also one that makes BCSCs highly refractory to traditional chemotherapeutic regimens. Here we report a small molecule construct,

Topics: Acetazolamide; Animals; Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IX; Carcinogenesis; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Curcumin; Diarylheptanoids; Fluorescent Dyes; Humans; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Neoplastic Stem Cells; Spheroids, Cellular; Thiophenes; Tumor Microenvironment; Xenograft Model Antitumor Assays

In this contribution, we report the fabrication of multifunctional nanoparticles with gold shell over an iron oxide nanoparticles (INPs) core. The fabricated system combines the magnetic property of INPs and the surface plasmon resonance of gold. The developed nanoparticles are coated with thiolated pectin (TPGINs), which provides stability to the nanoparticles dispersion and allows the loading of hydrophobic anticancer drugs. Curcumin (Cur) is used as the model drug and an encapsulation efficiency of approximately 80% in TPGINs is observed. Cytotoxicity study with HeLa cells shows that Cur-loaded TPGINs have better viability percent (~30%) than Cur alone (~40%) at a dose of 30 μg of TPGINs. Further, annexin V-PI assay demonstrated the enhanced anticancer activity of Cur-loaded TPGINs via induction of apoptosis. The use of TPGINs leads to a significant enhancement in generating reactive oxygen species (ROS) in HeLa cells through improved radiosensitization by gamma irradiation (0.5 Gy). TPGINs are further evaluated for imparting contrast in magnetic resonance imaging (MRI) with the r

Topics: Cell Death; Cell Survival; Curcumin; Diagnostic Imaging; Drug Liberation; Endocytosis; HeLa Cells; Humans; Hydrodynamics; Kinetics; Magnetic Resonance Imaging; Multifunctional Nanoparticles; Neoplasms; Particle Size; Pectins; Phantoms, Imaging; Photoelectron Spectroscopy; Radiation Tolerance; Reactive Oxygen Species; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman; Staining and Labeling; Thermogravimetry

Muscle wasting and cachexia are prominent comorbidities in cancer. Treatment with polyphenolic compounds may partly revert muscle wasting. We hypothesized that treatment with curcumin or resveratrol in cancer cachectic mice may improve muscle phenotype and total body weight through attenuation of several proteolytic and signaling mechanisms in limb muscles. In gastrocnemius and soleus muscles of cancer cachectic mice (LP07 adenocarcinoma cells, N = 10/group): (1) LC-induced cachexia, (2) LC-cachexia+curcumin, and (3) LC-cachexia + resveratrol, muscle structure and damage (including blood troponin I), sirtuin-1, proteolytic markers, and signaling pathways (NF-κB and FoxO3) were explored (immunohistochemistry and immunoblotting). Compared to nontreated cachectic mice, in LC-cachexia + curcumin and LC-cachexia + resveratrol groups, body and muscle weights (gastrocnemius), limb muscle strength, muscle damage, and myofiber cross-sectional area improved, and in both muscles, sirtuin-1 increased, while proteolysis (troponin I), proteolytic markers, and signaling pathways were attenuated. Curcumin and resveratrol elicited beneficial effects on fast- and slow-twitch limb muscle phenotypes in cachectic mice through sirtuin-1 activation, attenuation of atrophy signaling pathways, and proteolysis in cancer cachectic mice. These findings have future therapeutic implications as these natural compounds, separately or in combination, may be used in clinical settings of muscle mass loss and dysfunction including cancer cachexia.

Topics: Animals; Biomarkers; Cachexia; Cell Line; Curcumin; Female; Mice, Inbred BALB C; Muscle Proteins; Muscles; Muscular Atrophy; Neoplasms; Phenotype; Proteolysis; Resveratrol; Signal Transduction; Sirtuin 1

Zingiberaceae plants are well known for their use in ethnomedicine. Curcuma mutabilis Škorničk., M. Sabu & Prasanthk., is an endemic Zingiberaceae species from Western Ghats of Kerala, India. Here, we report for the first time, the anticancer potential of petroleum ether extract from C. mutabilis rhizome (CMRP) and a novel labdane diterpenoid, (E)-14, 15-epoxylabda-8(17), 12-dien-16-al (Cm epoxide) isolated from it. CMRP was found to be a mixture of potent bioactive compounds including Cm epoxide. Both the extract and the compound displayed superior antiproliferative activity against several human cancer cell lines, without any display of cytotoxicity towards normal human cells such as peripheral blood derived lymphocytes and erythrocytes. CMRP treatment resulted in phosphatidylserine externalization, increase in the levels of intracellular ROS, Ca

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Calcium; Cell Line, Tumor; Cell Proliferation; Curcuma; Diterpenes; DNA Fragmentation; Dose-Response Relationship, Drug; Epoxy Compounds; Humans; India; Membrane Potential, Mitochondrial; Mice; Neoplasms; Phosphatidylserines; Plant Extracts; Plant Roots; Reactive Oxygen Species

Plant derived products have steadily gained momentum in treatment of cancer over the past decades. Curcuma and its derivatives, in particular, have diverse medicinal properties including anticancer potential with proven safety as supported by numerous in vivo and in vitro studies. A defective Mis-Match Repair (MMR) is implicated in solid tumors but its role in haematologic malignancies is not keenly studied and the current literature suggests that it is limited. Nonetheless, there are multiple pathways interjecting the mismatch repair proteins in haematologic cancers that may have a direct or indirect implication in progression of the disease. Here, through computational analysis, we target proteins that are involved in rewiring of multiple signaling cascades via altered expression in cancer using various curcuma derivatives (Curcuma longa L. and Curcuma caesia Roxb.) which in turn, profoundly controls MMR protein function. These biomolecules were screened to identify their efficacy on selected targets (in blood-related cancers); aberrations of which adversely impacted mismatch repair machinery. The study revealed that of the 536 compounds screened, six of them may have the potential to regulate the expression of identified targets and thus revive the MMR function preventing genomic instability. These results reveal that there may be potential plant derived biomolecules that may have anticancer properties against the tumors driven by deregulated MMR-pathways.

Topics: Antineoplastic Agents, Phytogenic; Computational Biology; Curcuma; DNA Mismatch Repair; Gene Expression Regulation, Neoplastic; Humans; Molecular Structure; Neoplasms; Plant Extracts; Rhizome

In this study, amphiphilic conjugates were synthesized by conjugating curcumin (CUR) to a food-derived hydrophilic hydroxyethyl starch (HES) via an acid-labile ester linker. The self-assembly of the conjugates formed uniform micellar nanoparticles (HES-CUR NPs) with a desirable drug loading efficiency, excellent colloidal and storage stability, as well as acid-responsive release manner. Besides, the formation of the nanoparticles increased the solubility of CUR to thousands times higher than free CUR, and effectively protected the loaded CUR from degradation upon exposure to UV light and high temperature. In vitro cytotoxicity assay and radical scavenging experiments demonstrated that the HES-CUR NPs significantly improved the cytocompatibility, anticancer and antioxidant activity of CUR due to the enhanced solubility, stability, and bioavailability. The HES-CUR NPs reported herein have a great potential in developing functional food or pharmaceutical formulations for preventing or treating various diseases such as inflammatory diseases and cancer.

Topics: Antineoplastic Agents; Antioxidants; Caco-2 Cells; Curcumin; Drug Carriers; Drug Compounding; Drug Liberation; HeLa Cells; Humans; Micelles; Nanoparticles; Neoplasms; Solubility; Starch

Chemotherapeutic agents with different anticancer mechanisms could enhance therapeutic effect in cancer therapy by their combined application. In this study, redox-sensitive prodrug nanoparticles based on Xyl-SS-Cur conjugate were developed for co-delivery of curcumin and 5-FU in cancer therapy. The Xyl-SS-Cur conjugate was synthesized via covalent conjugation of curcumin to xylan through a disulphide (-S-S-) linkage. The Xyl-SS-Cur conjugate could self-assemble in aqueous medium into nanoparticles and the lipophilic 5-fluorouracil-stearic acid (5-FUSA) prodrug was encapsulated into the hydrophobic core of Xyl-SS-Cur NPs through dialysis membrane method. The obtained Xyl-SS-Cur/5-FUSA NPs had an appropriate size (∼217 ± 2.52 nm), high drug loading of curcumin (∼ 31.4 wt%) and 5-FUSA (∼ 11.8 wt%) and high stability. The interaction of Xyl-SS-Cur/5-FUSA NPs with blood components was investigated by hemolysis study. The cytotoxicity study demonstrated that Xyl-SS-Cur/5-FUSA NPs induced higher cytotoxicity than free drugs against the Human colorectal cancer cells (HT-29, HCT-15). These results indicate that Xyl-SS-Cur/5-FUSA NPs can serve as a promising drug delivery system in cancer therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Curcumin; Disulfides; Drug Delivery Systems; Drug Liberation; Drug Stability; Fluorouracil; Hemolysis; HT29 Cells; Humans; Nanoparticles; Neoplasms; Oxidation-Reduction; Particle Size; Prodrugs; Spectroscopy, Fourier Transform Infrared; Stearic Acids; Xylans

Supramolecular hydrogels are highly promising candidates as biomedical materials owing to their wide array of properties, which can be tailored and modulated. Additionally, their combination with plasmonic/magnetic nanoparticles to form plasmonic magnetogels further improves their potential in biomedical applications through the combination of complementary strategies, such as photothermia, magnetic hyperthermia, photodynamic therapy and magnetic-guided drug delivery. Here, a new dehydropeptide hydrogelator, Npx-l-Met-Z-ΔPhe-OH, was developed and combined with two different plasmonic/magnetic nanoparticle architectures, i.e., core/shell manganese ferrite/gold nanoparticles and gold-decorated manganese ferrite nanoparticles with ca. 55 nm and 45 nm sizes, respectively. The magnetogels were characterized via HR-TEM, FTIR spectroscopy, circular dichroism and rheological assays. The gels were tested as nanocarriers for a model antitumor drug, the natural compound curcumin. The incorporation of the drug in the magnetogel matrices was confirmed through fluorescence-based techniques (FRET, fluorescence anisotropy and quenching). The curcumin release profiles were studied with and without the excitation of the gold plasmon band. The transport of curcumin from the magnetogels towards biomembrane models (small unilamellar vesicles) was assessed via FRET between the fluorescent drug and the lipid probe Nile Red. The developed magnetogels showed promising results for photothermia and photo-triggered drug release. The magnetogels bearing gold-decorated nanoparticles showed the best photothermia properties, while the ones containing core/shell nanoparticles had the best photoinduced curcumin release.

Topics: Animals; Antineoplastic Agents; Curcumin; Drug Carriers; Ferric Compounds; Gold; Hydrogels; Manganese Compounds; Metal Nanoparticles; Mice; Neoplasms; RAW 264.7 Cells

Fungal chitosan (FCt) from Amylomyces rouxii, with 88.7% deacetylation degree and 112.4 kDa molecular weight, was utilized for nanoparticles (NPs) formation via ionic gelation. FCt-NPs were employed as carriers for curcumin (CUR) to augment its availability and anticancer bioactivity. The synthesis of CUR/FCt-NPs composite was succeeded as evidenced from their FTIR spectra. The scanning micrographs of synthesized CUR/FCt-NPs indicated their spherical shapes and well-distribution; they had average diameters of 115 ± 21 nm and positive zeta potentials of +33.8 mV. The NPs loading capacity for CUR was 21.6% and the encapsulation efficiency reached 83.8%. The CUR was vastly released in the beginning 5 h then gradually released up to 90 h, with higher release in pH 5.2 than in pH 7.0. The treatment of cancer cells, HCT-116 and A-549, with CUR/FCt NPs lead to time-dependent decrement of cells' viability; the dead cells were 67.6% from HCT-116 and 73.8% from A-546 after 96 h of exposure. Fluorescent imaging indicated that most cancer cells entered the apoptosis phase after treatment with 150 μM of CUR/FCt-NPs for 72 h. The efficiency of FCt-NPs was proved as carriers for loading CUR and augmenting its anticancer activity toward human cancer cells, using these natural and biosafe agents.

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Chitosan; Curcumin; Drug Carriers; HCT116 Cells; Humans; Mucorales; Nanoparticles; Neoplasms

Previous studies have established the antitumor activity of curcumin, a major component of turmeric. Increasing evidence indicates that curcumin induces autophagy, the activation of mitogen-activated protein kinase (MAPK) intracellular signaling pathways, and reactive oxygen species (ROS)-mediated cell death. The c-Jun NH

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Autophagy; Cell Death; Cell Line, Tumor; Curcumin; Humans; Neoplasms; Reactive Oxygen Species

Photobiomodulation therapy (PBM-T) can penetrate soft tissues and exert analgesic and healing effects, and is thus a promising alternative for prevention and treatment of oral mucositis (OM). The aim of this study was to evaluate the efficacy of PBM-T, alone or combined with photodynamic therapy (PDT), for treatment of OM in cancer patients.. Fifty-six patients were recruited from the Oncology Department of a teaching hospital. Patients underwent grading of OM and were divided into two groups (n = 28 each): PBM-T and PBM-T + PDT. In the PBM-T group, low-level laser was applied to 61 points in the oral cavity, once weekly for 4 weeks (wavelength 660 nm, power 100 mW, energy density 142 J/cm², spot energy 4 J, irradiation time 40 s). In the PBM-T + PDT group, in addition to PBM-T as described above, patients rinsed with 20 ml of photosensitizing mouthwash (curcumin 1.5 g/L) and the oral cavity was irradiated with a blue (468 nm) LED for 5 min.. Significant reductions in OM grade were observed after application of PBM-T or PBM-T + PDT (p < 0.0001). PBM-T + PDT resulted in a shorter time to resolution of lesions compared to PBM-T alone (p = 0.0005).. PBM-T, alone or combined with PDT, can be used for the treatment of OM. PDT + PBM-T in particular accelerated the OM healing process, reducing time to lesion remission from 15 to 11 days.

Topics: Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Curcumin; Female; Humans; Low-Level Light Therapy; Male; Middle Aged; Neoplasms; Photochemotherapy; Photosensitizing Agents; Stomatitis

Although supramolecular prodrug self-assemblies have been proven as efficient nanocarriers for cancer therapy, tedious synthesis procedures have made their practical applications more difficult. In this paper, β-cyclodextrin-based supramolecular self-assemblies (SSAs) were directly constructed by utilizing β-cyclodextrin trimer (β-CD

Topics: Apoptosis; beta-Cyclodextrins; Cell Proliferation; Curcumin; Delayed-Action Preparations; Doxorubicin; Drug Delivery Systems; Drug Liberation; HeLa Cells; Humans; MCF-7 Cells; Micelles; Neoplasms

Topics: Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Curcumin; HCT116 Cells; Humans; Hydroxyl Radical; Neoplasms; Oxidation-Reduction; Reactive Oxygen Species; Superoxides; Vitamin K 3

Topics: Adenosine Diphosphate Ribose; Animals; Apoptosis; Cisplatin; Curcumin; Humans; Mice; Mitochondria; Neoplasms; Optic Nerve; Optic Nerve Injuries; Oxidative Stress; Patch-Clamp Techniques; Reactive Oxygen Species; Signal Transduction; TRPM Cation Channels

Topics: Cell Line, Tumor; Curcumin; Cytotoxins; Humans; Liposomes; Neoplasms; Poloxamer

Cancer-associated fibroblasts (CAFs) are "activated" fibroblasts in the tumor microenvironment (TME) and play a vital role in all steps of cancer development. Increasing evidence focusing on the function of CAFs suggests that CAFs are candidate therapeutic targets and that drugs targeting the modification of CAFs would suppress tumor progression and be beneficial to tumor treatment and prevention. In the present study, we found that curcumin reversed the phenotype of CAFs to that of peri-tumor fibroblast (PTF)-like cells by downregulating the expression of α-SMA (a special marker for CAFs) and inhibiting the secretion of pro-carcinogenic cytokines, including transforming growth factor-β1 (TGF-β1), matrix metalloproteinases 2 (MMP2), and stromal cell-derived factor-1 (SDF-1). We further demonstrated that the conditioned medium (CM) derived from CAFs promoted the proliferation of Cal27, and this effect was confirmed by the xenograft model. More importantly, we found that curcumin blocked the CAF-mediated enhancement of Cal27 proliferation in vitro and in vivo. In conclusion, our data suggest that curcumin reverses cell phenotype from CAF to PTF-like cells and suppresses the CAF-mediated proliferation and tumorigenicity of Cal27 by inhibiting TSCC CAFs.

Topics: Cancer-Associated Fibroblasts; Cell Proliferation; Curcumin; Fibroblasts; Neoplasms; Tumor Microenvironment

In order to support uncontrolled proliferation, cancer cells need to adapt to increased energetic and biosynthetic requirements. One such adjustment is aerobic glycolysis or the Warburg effect. It is characterized by increased glucose uptake and lactate production. Curcumin, a natural compound, has been shown to interact with multiple molecules and signaling pathways in cancer cells, including those relevant for cell metabolism. The effect of curcumin and its solvent, ethanol, was explored on four different cancer cell lines, in which the Warburg effect varied. Vital cellular parameters (proliferation, viability) were measured along with the glucose consumption and lactate production. The transcripts of pyruvate kinase 1 and 2 (PKM1, PKM2), serine hydroxymethyltransferase 2 (SHMT2) and phosphoglycerate dehydrogenase (PHGDH) were quantified with RT-qPCR. The amount and intracellular localization of PKM1, PKM2 and signal transducer and activator of transcription

Topics: Cell Line, Tumor; Curcumin; Ethanol; Gene Expression Regulation, Neoplastic; Glucose; Humans; Isoenzymes; Lactic Acid; Neoplasms; Protein Kinases; RNA, Messenger; STAT3 Transcription Factor; Transcription, Genetic

Novel red Zn(ii) complex-based fluorescent probes featuring cryptolepine-curcumin derivatives, namely, [Zn(BQ)Cl

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Fluorescent Dyes; Humans; Indole Alkaloids; Mice; Molecular Probes; Neoplasms; Photochemotherapy; Quinolines; Zinc

Photodynamic therapy (PDT) has been extensively used to treat cancer and other malignant diseases because it can offer many unique advantages over other medical treatments such as less invasive, fewer side effects, lower cost, etc. Despite great progress, the efficiency of PDT treatment, as an oxygen-dependent therapy, is still limited by the hypoxic microenvironment in the human tumor region. In this work, we have developed a near-infrared (NIR) activated theranostic nanoplatform based on upconversion nanoparticles (UCNPs), which incorporates PDT photosensitizer (curcumin) and NO donor (Roussin's black salt) in order to overcome hypoxia-associated resistance by reducing cellular respiration with NO presence in the PDT treatment. Our results suggest that the photo-released NO upon NIR illumination can greatly decrease the oxygen consumption rate and hence increase singlet oxygen generation, which ultimately leads to an increased number of cancer cell deaths, especially under hypoxic condition. It is believed that the methodology developed in this study enables to relieve the hypoxia-induced resistance in PDT treatment and also holds great potential for overcoming hypoxia challenges in other oxygen-dependent therapies.

Topics: Animals; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Curcumin; Fluorides; HeLa Cells; Humans; Infrared Rays; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Neoplasms; Nitric Oxide; Oleic Acid; Photochemotherapy; Photosensitizing Agents; Porosity; Silicon Dioxide; Yttrium

Poly (lactic-co-glycolic acid)-graft-pullulan (PPLGA) based self-organized nanoparticles hold immense potential for synergistic thermo-chemotherapy of tumor. Herein, the biocompatible and biodegradable PPLGA were synthesized by a novel microwave-assisted solution polymerization. The polymers showed thermo-responsive properties, which was attributed to the change of polymer-water hydrogen bonding in controlling the macromolecular contraction, chain collapse as a result of changes in micro-rigidity of core. The curcumin loaded PPLGA nanoparticles (CUR-PPLGA-N), with impressively high drug loading (10.85 ± 0.27 %), exhibited temperature dependence in drug release kinetics. The results of both MTT and antitumor efficiency elucidated that the CUR-PPLGA-N under high temperature facilitated on-demand drug release from the nano-assembly and had a synergistic therapeutic effect for cancer. Thus the developed thermo-responsive PPLGA addressed concerns related to the low drug loading and inefficient drug release at target sites, and might be considered as a powerful nanoplatform for synergistic thermo-chemotherapy of tumor.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Carriers; Glucans; Hep G2 Cells; Humans; Mice; Nanomedicine; Nanoparticles; Neoplasms; Polylactic Acid-Polyglycolic Acid Copolymer; Temperature

Many solutions have been evaluated to deal with "chemotherapy and radiation-resistant cancer cells' as well as "severe complications of chemotherapy drugs". One of these solutions is the use of herbal compounds with antioxidant properties. Among these antioxidant compounds, curcumin is identified as the strongest one to inhibit cancerous cells proliferation. However, its clinical trials have encountered many constraints, because curcumin is insoluble in water and unstable in physiological conditions. To overcome these limitations, in this study, curcumin was conjugated with human serum albumin (HSA) and its effects on breast cancer cell lines were also measured.. After making of HSA-curcumin nanoparticles (NPs) by the desolvation technique, they were characterized by the FTIR, DLS, TEM, and SEM method. At the end, its anticancer effects have been examined using MTT test and apoptosis assay.. The FTIR graph confirmed that curcumin and HSA have been conjugated along with each other. Particles size was reported to be 220 nm and 180 nm by DLS and SEM, respectively. The zeta potential of HSA-curcumin NPs was -7 mV, while it was -37 mV for curcumin. The MTT and apoptosis assay results indicated that the toxicity of HSA-curcumin NPs on the normal cell are less than curcumin; however, its anti-cancer effects on the cancer cells are much greater, compared to curcumin.. HSA-curcumin NPs increase curcumin solubility in water as well as its stability in physiological and acidic conditions. These factors have the ability of overwhelming the limitations on using curcumin alone, and they could result in a significant increase in the toxicity of curcumin on the cancer cells without increasing its toxicity on the normal cells. Grapical abstract.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Drug Liberation; Humans; Nanoparticles; Neoplasms; Serum Albumin, Human

Phosphatidylcholines (PCs) have been widely used in pharmaceutical research. Unfortunately, our understanding of how PCs influence the in vivo lipolysis process of drug delivery systems is still limited. In this study, PCs with fatty acid chains of varying lengths and saturability were used as emulsifiers to prepare curcumin-loaded nanoemulsions (Cur-NEs). The differences in particle size as well as drug and free fatty acid release during the lipolysis process were studied in a simulated blood environment. Furthermore, the pharmacokinetics and antitumor efficacy of Cur-NEs were evaluated in mice. The prepared 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)-stabilized Cur-NEs showed similar particle size and stability during storage but exhibited different lipolysis behaviors in vitro and in vivo. Due to the gel state of DPPC in the physiological environment, DPPC-stabilized Cur-NEs had low binding affinity with proteins and maintained their integrity in plasma, leading to sustained drug release, prolonged circulation time and enhanced antitumor efficacy in 4T1 tumor-bearing mice. In contrast, DOPC and DSPC-stabilized Cur-NEs were prone to coalescence in the plasma, resulting in rapid drug release and elimination from circulation. Our findings demonstrated that proper use of PCs is beneficial for obtaining desired transport behavior and drug therapeutic effects, providing guiding principles for rational design of nanodelivery systems.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Drug Stability; Emulsions; Fatty Acids, Nonesterified; Female; Lipolysis; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Phosphatidylcholines; Rats, Sprague-Dawley

The balance between tumor accumulation and renal clearance has severely limited the efficacy of mesoporous silica-based drug nanocarriers in cancer therapy. Herein, a pH-responsive dissociable mesoporous silica-based nanoplatform with efficient dual-drug co-delivery, tumor accumulation and rapid clearance for cancer therapy is achieved by adjusting the wetting of the mesoporous silica surface. At pH 7.4, the synthesized spiropyran- and fluorinated silane-modified ultrasmall mesoporous silica nanoparticles (SP-FS-USMSN) self-assemble to form larger nanoclusters (denoted as SP-FS-USMSN cluster) via hydrophobic interactions, which can effectively co-deliver anticancer drugs, doxorubicin hydrochloride (Dox) and curcumin (Cur), based on the mesopores within SP-FS-USMSN and the voids among the stacked SP-FS-USMSN. At pH 4.5-5.5, the conformational conversion of spiropyran from a "closed" state to an "open" state causes the wetting of the SP-FS-USMSN surface, leading to the dissociation of the SP-FS-USMSN cluster for drug release and renal clearance. The in vitro and in vivo studies demonstrate that the Cur and Dox co-loaded SP-FS-USMSN cluster (Cur-Dox/SP-FS-USMSN cluster) possesses great combined cytotoxicity, and can accumulate into tumor tissue by its large size-favored EPR effect and potently suppress tumor growth in HepG2-xenografted mice. This research demonstrates that the SP-FS-USMSN cluster may be a promising drug delivery system for cancer therapy and lays the foundation for practical mesoporous silica-based nanomedicine designs in the future.

Topics: Animals; Antineoplastic Agents; Benzopyrans; Cell Survival; Curcumin; Doxorubicin; Drug Delivery Systems; Drug Liberation; Female; Hep G2 Cells; Humans; Indoles; Mice, Nude; Nanoparticles; Neoplasms; Nitro Compounds; Porosity; Silanes; Silicon Dioxide

Tumor progression and tumor response to anticancer therapies may be affected by activation of oncogenic pathways such as the antioxidant one induced by NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor and the pathways modified by deregulation of oncosuppressor p53. Often, oncogenic pathways may crosstalk between them increasing tumor progression and resistance to anticancer therapies. Therefore, understanding that interplay is critical to improve cancer cell response to therapies. In this study we aimed at evaluating NRF2 and p53 in several cancer cell lines carrying different endogenous p53 status, using a novel curcumin compound since curcumin has been shown to target both NRF2 and p53 and have anti-tumor activity.. We performed biochemical and molecular studies by using pharmacologic of genetic inhibition of NRF2 to evaluate the effect of curcumin compound in cancer cell lines of different tumor types bearing wild-type (wt) p53, mutant (mut) p53 or p53 null status.. We found that the curcumin compound induced a certain degree of cell death in all tested cancer cell lines, independently of the p53 status. At molecular level, the curcumin compound induced NRF2 activation, mutp53 degradation and/or wtp53 activation. Pharmacologic or genetic NRF2 inhibition further increased the curcumin-induced cell death in both mutp53- and wtp53-carrying cancer cell lines while it did not increase cell death in p53 null cells, suggesting a cytoprotective role for NRF2 and a critical role for functional p53 to achieve an efficient cancer cell response to therapy.. These findings underline the prosurvival role of curcumin-induced NRF2 expression in cancer cells even when cells underwent mutp53 downregulation and/or wtp53 activation. Thus, NRF2 inhibition increased cell demise particularly in cancer cells carrying p53 either wild-type or mutant suggesting that p53 is crucial for efficient cancer cell death. These results may represent a paradigm for better understanding the cancer cell response to therapies in order to design more efficient combined anticancer therapies targeting both NRF2 and p53.

Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Mutation; Neoplasms; NF-E2-Related Factor 2; Ruthenium; Tumor Cells, Cultured; Tumor Suppressor Protein p53

The combinational therapy is often considered as a desire in chemotherapy despite some limitations. This study aimed to encapsulate two natural-based drugs, curcumin (CUR), and piperine (PIP) into highly biocompatible albumin nanoparticles for anticancer applications.. A simultaneous exertion of CUR and PIP in a biocompatible drug delivery system with the minimum side effects and no limitations was achievable in this work for cancer treatment.. Curcumin and piperine co-loaded human serum albumin nanoparticles (CUR-PIP-HSA-NPs) were synthesized by the self-assembly method. The effectiveness of the codelivery system was evaluated physically, chemically, and pharmaceutically. Moreover, the anticancer activity of CUR-PIP-HSA-NPs was studied on MCF-7 cells by MTT assay.. CUR-PIP-HSA-NPs showed appropriate stability with an average particle size of 154.7 ± 5.2 nm. Loading of drugs was demonstrated by Fourier transform infrared (FT-IR) and differential scanning calorimetry (DSC) analyses. The drug encapsulation efficiencies (DEEs) of CUR and PIP in NPs were 85.3% ± 1.46% and 81.7%, ± 1.67%, respectively. Furthermore, the drug loading efficiency (DLE) of CUR-PIP-HSA-NPs was 8.71% ± 0.24%. The circular dichroism (CD) examination of the NPs confirmed that the conformational structure of albumin remained unchanged during the synthesis. In addition, the cytotoxicity experiments demonstrated the high potential of CUR-PIP-HSA-NPs against breast cancer (MCF-7) cells in the presence of PIP as both bioenhancer and anticancer drug with the capability of suppressing the effect of multidrug resistance (MDR).. The results suggest that CUR-PIP-HSA-NPs can be employed as a practical drug delivery system in cancer treatment with synergistic effects of both CUR and PIP.

Topics: Alkaloids; Benzodioxoles; Curcumin; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Particle Size; Piperidines; Polyunsaturated Alkamides; Serum Albumin, Human; Spectroscopy, Fourier Transform Infrared

Indocyanine green (ICG) has received considerable interest as a biocompatible organic photothermal agent, and curcumin (Cur) is considered an attractive natural chemopreventive and chemotherapeutic compound. However, the in vivo applicability of ICG and Cur is significantly restricted by their poor ability to target tumors and their extremely low solubility.. To address these problems, ICG/Cur-loaded albumin nanoparticles (ICG-BSA-Cur-NPs) based on the nab. The fabricated ICG-BSA-Cur-NPs were found to be spherical, ~150 nm in size and highly dispersible and stable in aqueous solution. Approximately 80% of the incorporated ICG and Cur were gradually released from the NPs over 48 h. All formulations of ICG-BSA-Cur-NPs (5~20 µg/mL) showed efficient hyperthermia profiles (up to 50-60°C within 5 min) in response to 808-nm NIR laser irradiation in vitro and in vivo. Notably, ICG-BSA-Cur-NPs illuminated with 808-nm laser irradiation (1.5 W/cm. We demonstrate that these hyperthermal chemotherapeutic ICG-BSA-Cur-NPs have potential as a future brain tumor treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line, Tumor; Curcumin; Humans; Hyperthermia, Induced; Indocyanine Green; Male; Mice, Inbred BALB C; Multifunctional Nanoparticles; Neoplasms; Neuroblastoma; Phototherapy; Serum Albumin, Bovine; Xenograft Model Antitumor Assays

Curcumin is highly effective against various types of cancers; however, its low aqueous solubility, high metabolism and non-specificity hinder its efficacy. This study reports the synthesis of three lactobionic acid containing bola-amphiphiles and their investigation for curcumin nano-vesicular delivery into cancer cells. Synthesized bola-amphiphiles were capable of forming nano-vesicles and curcumin loading in a lipophilicity dependent manner. Bola-amphiphile with higher lipophilicity (C12) caused 89.55 ± 5.52% drug encapsulation in its spherical shape nano-vesicles (195.90 ± 0.83 nm). Bola-amphiphile resulting increased curcumin encapsulation with minimum vesicles size was further investigated for cellular uptake and in-vitro anticancer activity. Anticancer activity of curcumin significantly increased against the tested cancer cells upon loading in bola-amphiphile nano-vesicles. Furthermore, nano-vesicular drug delivery of curcumin enhanced its cellular uptake even at the lowest concentration of 1.25 µg/mL.It is concluded that the synthesized bola-amphiphile based nano-vesicles can efficiently deliver curcumin to the tested cancer cells and needs to be tested for established anticancer drugs against different cancer cell lines for effective treatment of cancer.

Topics: Antineoplastic Agents; Cell Culture Techniques; Curcumin; Disaccharides; Micelles; Nanoparticles; Neoplasms

PD-1/PD-L1 immune checkpoint inhibitors are promising cancer immunotherapies however responses are still limited and the development of more effective combination immunotherapy is needed. We previously reported that STAT3 activation in cancer cells and immune cells was involved in immune-resistant mechanisms. In this study, we evaluated the effect of highly absorptive forms of curcumin extracts and synthetic curcumin on anti-tumor T cell responses. The curcumin po administration resulted in the significant augmentation of in vivo induction of tumor antigen-specific T cells through restoration of dendritic cells (DCs) by inhibiting directly STAT3 in DCs and indirectly via reduced IL-6 production from STAT3 activated cancer cells in 2 syngeneic MC38 and CT26 murine tumor models. Curcumin also showed direct DC enhancing activity and enhanced T cell induction for the immunized antigens in non-tumor-bearing mice and human hosts. Curcumin restored DC functions in xenogeneic nude mouse model implanted with high IL-6-producing human clear cell ovarian cancer cells. The combination of curcumin and PD-1/PD-L1 Abs demonstrated a synergistic anti-tumor activity in MC38 murine tumor models. These results indicated that curcumin augments the induction of tumor antigen-specific T cells by restoring the T cell stimulatory activity of DCs targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD-1/PD-L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers.

Topics: Animals; Antineoplastic Agents; Curcumin; Dendritic Cells; Drug Therapy, Combination; Female; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Interferon-gamma; Interleukin-6; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasms; NF-kappa B; Plant Extracts; STAT3 Transcription Factor; T-Lymphocytes

In this study, gum of Araucaria heterophylla was collected. The collected gum was subjected for extraction of polysaccharide using solvent extraction system. Thus, extracted polysaccharide was further purified using solvent method and was characterized using UV-Vis spectroscopy, Phenol sulfuric acid assay, FTIR, TGA, TLC and GC-MS. The gum derived polysaccharide was found to have the following sugars Rhamnose, Allose, Glucosinolate, Threose, Idosan, Galactose and Arabinose. The extracted polysaccharide was tested for various in-vitro bioactive studies such as antibacterial activity, antioxidant activity and anticancer activity. The polysaccharide was found to have antioxidant and anticancer activity. Further, the polysaccharide was subjected for carboxymethylation to favor the nanocarrier synthesis, where it was chelated using Sodium Tri Meta Phosphate (STMP) to form nanocarriers. The nanocarriers so formed were loaded with curcumin and were characterized using FTIR, SEM, EDX and AFM. Both the loaded and unloaded nanocarriers were studied for its in-vitro cytotoxic effect against the MCF7 human breast cancer cell lines. The nanocarriers were found to deliver the drug efficiently against the cancer cell line used in this study.

Topics: Antineoplastic Agents; Antioxidants; Arabinose; Araucaria; Curcumin; Drug Delivery Systems; Galactose; Glucose; Glucosinolates; Humans; MCF-7 Cells; Neoplasms; Polysaccharides; Rhamnose; Spectroscopy, Fourier Transform Infrared; Tetroses

Nowadays, two-dimensional (2D) nanomaterials with many fascinating physicochemical properties have drawn extensive attention as drug delivery platforms for cancer theranostics. Nevertheless, current existing 2D nanomaterial-based drug delivery systems normally undergo the bottlenecks of hash preparation process, low drug loading content and unsatisfactory therapeutic outcome. Herein, we developed a novel nanoparticles-induced assemble strategy to construct 2D nanosheets with ultra-high curcumin loading content of 59.6 % and excellent stability in water. Furthermore, a distinct photothermal effect and multimodal imaging property after polydopamine coating could be obtained, thereby leading to precise and efficient ablation of tumor in combination of curcumin-induced chemotherapy. More importantly, the design principle of our work offers novel facile strategy to assemble metal-binding drugs into 2D nanomedicine with high drug content and well-defined shapes.

Topics: Animals; Curcumin; Drug Delivery Systems; HeLa Cells; Humans; Hyperthermia, Induced; Indoles; MCF-7 Cells; Metals; Mice; Microscopy, Confocal; Multimodal Imaging; Nanomedicine; Nanoparticles; Neoplasm Transplantation; Neoplasms; Phototherapy; Polymers; Protein Binding; Theranostic Nanomedicine; Treatment Outcome; Water

Fluorinated graphene has recently gained much attention for cancer drug delivery, owing to its peculiar properties including high electronegativity difference, magnetic resonance imaging contrast agent, and the photothermal effect. However, the hydrophobic nature of fluorinated graphene greatly hinders its application as a biological material. Herein, a novel green method is reported for synthesis of a pH-sensitive charge-reversal and water-soluble fluorinated graphene oxide, modified with polyethyleneimine anchored to sericin-polypeptide (FPS). This nanocarrier was further loaded with curcumin (Cur), and characterized as a nanocarrier for anti-cancer drug delivery. The synthesized nanocarriers contain two different pH-sensitive amide linkages, which are negatively charged in blood pH (≈7.4) and can prolong circulation times. The amide linkages undergo hydrolysis once they reach the mildly acidic condition (pH≈6.5, corresponding to tumor extracellular matrix), and subsequently once reached the lower acidic condition (pH≈5.5, corresponded to endo/lysosomes microenvironment), the FPS charge can be switched to positive (≈+28 mV), which aids the nuclear release. This nanocarrier was designed to selectively enhance cell internalization and nuclear-targeted delivery of curcumin in HeLa, SkBr3 and PC-3 cancer cells. Moreover, FPS-Cur demonstrated high curcumin loading capacity, prolonged curcumin release and promotion of apoptosis in HeLa, SkBr3 and PC-3 cells. Therefore, with its pH-responsive charge-reversal properties, FPS-Cur would be a promising candidate for chemotherapy of cervical, breast and prostate cancers.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Curcumin; Drug Carriers; Drug Compounding; Drug Liberation; Female; Graphite; Halogenation; HeLa Cells; Humans; Hydrogen-Ion Concentration; Hydrolysis; Male; Mice; Nanoparticles; Nanotechnology; Neoplasms; PC-3 Cells; Sericins; Technology, Pharmaceutical

The limitations of anticancer drugs, including poor tumor targeting and weak uptake efficiency, are important factors affecting tumor therapy. According to characteristics of the tumor microenvironment, in this study, we aimed to synthesize matrix metalloproteinase (MMP)-responsive curcumin (Cur)-loaded nanoparticles (Cur-P-NPs) based on amphiphilic block copolymer (MePEG-peptide-PET-PCL) with MMP-cleavable peptide (GPLGIAGQ) and penetrating peptide (r9), modified to improve tumor targeting and cellular uptake. The average size of Cur-P-NPs was 176.9 nm, with a zeta potential of 8.1 mV, and they showed drug entrapment efficiency and a loading capacity of 87.07% ± 0.63% and 7.44% ± 0.16%, respectively. Furthermore, Cur release from Cur-P-NPs was sustained for 144 h at pH 7.4, and the release rate was accelerated under enzyme reaction condition. The MTT assay demonstrated that free P-NPs had favorable biosafety, and the anti-proliferative activity of Cur-P-NPs was positively correlated with Cur concentration in MCF-7 cells. Additionally, the results of cellular uptake, in vivo pharmacokinetics, and biodistribution showed that Cur-P-NPs had a good effect on cellular uptake and tumor targeting, resulting in the best bioavailability in tumor therapy. Therefore, Cur-P-NPs, as a promising drug delivery system, might lead to a new and efficient route for targeted therapy in clinical practice.

Topics: Animals; Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Female; Humans; Matrix Metalloproteinases; MCF-7 Cells; Mice, Nude; Nanoparticles; Neoplasms; Particle Size; Polyesters; Polyethylene Glycols; Polymers; Rats; Rats, Sprague-Dawley; Tissue Distribution; Tumor Microenvironment

In addition to oxidative stress, inflammation and apoptosis have an important role in the pathogenesis of cisplatin-induced kidney damage. This study aimed to investigate the molecular mechanisms of protective effects of curcumin against cisplatin-induced kidney inflammation and apoptosis in rats.. Eighteen rats were equally divided into three groups; normal (0.5% CMC-Na), cisplatin (CDPP) (7 mg/kg i.p.), and cisplatin+curcumin (CMN100) groups. Curcumin was given at a dose of 100 mg/kg orally for nine days, starts one week before giving a single dose of cisplatin. Kidney and plasma were taken for analysis.. Cisplatin challenged rats demonstrated kidney injury as shown by reduced creatinine clearance, increased of plasma BUN, plasma creatinine, and kidney MDA, decreased of kidney GSH levels, and kidney histopathology alterations. Also, cisplatin increased ERK1/2 phosphorylation and NF-κB expression, which subsequently increased mRNA expression of TNF-α, IL-6, KIM-1, NGAL, and Bax/Bcl-2 ratio as well as decreased mRNA expression of IL-10 in kidney tissues. Pre-treatment with curcumin significantly ameliorated inflammation and apoptosis induced by cisplatin. In addition, curcumin downregulated Ctr1 and OCT2 drug transporters as compared to cisplatin group. Histopathological examination furthers confirmed the kidney damage protection effect of curcumin.. These data indicate that curcumin has nephroprotective properties against cisplatin-induced kidney damage in rats and this effect is associated with its anti-inflammatory and anti-apoptosis profiles, in addition to its antioxidant. Hence, curcumin may be useful for preventing kidney damage against cisplatin administration.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Cisplatin; Curcumin; Disease Models, Animal; Humans; Kidney; Male; Neoplasms; Oxidative Stress; Rats; Rats, Sprague-Dawley; Treatment Outcome

Investigation of the impact of co-medication on the plasma levels of curcumin and tetrahydrocurcumin (THC) in cancer patients and a comparison of the pharmacokinetics of curcumin and plasma levels of THC between cancer patients and healthy individuals following intravenous infusion of Lipocurc™ (liposomal curcumin).. Correlation analysis was used to determine the impact of co-medication on infusion rate normalized plasma levels of curcumin and THC in cancer patients and to compare the plasma levels of curcumin and THC at different infusion rates between cancer patients and healthy individuals. In vitro hepatocyte and red blood cell distribution experiments were conducted with Lipocurc™ to support clinical findings. Plasma concentration time data were analyzed by the non-compartmental method to determine and compare the pharmacokinetic parameters of curcumin in cancer patients and healthy individuals.. Of 44 co-medications studied, three medications targeting the renin-angiotensin system, Lisinopril, Ramipril, and Valsartan elevated plasma levels of curcumin and THC in three cancer patients infused with Lipocurc™. Cell distribution experiments indicated that the disposition of curcumin in red blood cells may be a target for elevation of the plasma levels of curcumin. Plasma levels of curcumin in cancer patients increased to a greater extent with increased infusion rate compared to healthy individuals. Upon termination of infusion, the elimination phase for curcumin was shorter with a shorter terminal half-life and smaller volume of distribution for curcumin in cancer patients compared to healthy individuals.. Either co-medications or health status, or both, can impact the pharmacokinetics of curcumin infusion (as Lipocurc™) in cancer patients.

Topics: Animals; Case-Control Studies; Cells, Cultured; Curcumin; Dogs; Drug Therapy, Combination; Erythrocytes; Healthy Volunteers; Hepatocytes; Humans; Infusions, Intravenous; Liposomes; Male; Neoplasms; Tissue Distribution

Photodynamic therapy is amongst the most rapidly developing therapeutic strategies against cancer. However, most photosensitizers are administered intravenously with very few reports about pulmonary applications. To address this issue, an inhalable formulation consisting of nanoparticles loaded with photosensitizer (i.e. curcumin) was developed. The nanoparticles were prepared using nanoprecipitation method. Dynamic light scattering measurements of the curcumin loaded nanoparticles revealed a hydrodynamic diameter of 181.20 ± 11.52 nm. In vitro irradiation experiments with human lung epithelial carcinoma cells (A549) showed a selective cellular toxicity of the nanoparticles upon activation using LED irradiating device. Moreover, curcumin nanoparticles exhibited a dose-dependent photocytotoxicity and the IC

Topics: A549 Cells; Administration, Inhalation; Cell Culture Techniques; Cell Survival; Curcumin; Drug Carriers; Drug Compounding; Humans; Light; Nanoparticles; Neoplasms; Photochemotherapy; Photosensitizing Agents

In this work, a multifunctional magnetic Bio-Metal-Organic Framework (Fe

Topics: Animals; Biocompatible Materials; Cell Death; Cell Line, Tumor; Cell Survival; Chitosan; Curcumin; Drug Liberation; Erythrocytes; Ferric Compounds; Fluorouracil; Folic Acid; Hemolysis; Humans; Magnetic Resonance Imaging; Magnetics; Metal-Organic Frameworks; Mice; Mice, Inbred BALB C; Nanocomposites; Neoplasms; NIH 3T3 Cells; Phantoms, Imaging; Protein Corona; Theranostic Nanomedicine; X-Ray Diffraction

Topics: Antineoplastic Agents; Axl Receptor Tyrosine Kinase; Curcumin; Humans; Molecular Docking Simulation; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Quantitative Structure-Activity Relationship; Receptor Protein-Tyrosine Kinases

Liposomes are a popular formulation strategy for the delivery of anticancer drugs. While their benefits for formulating hydrophilic anticancer drugs have been clearly shown during the last decades, the suitability of liposomes for the delivery of hydrophobic drugs is questionable. Curcumin is a diphenolic plant compound that is extensively researched for its anticancer properties. It was chosen as a hydrophobic model drug in this study. Due to its low bioavailability, poor solubility and instability in aqueous media it is a highly problematic compound and requires particular formulation techniques. Curcumin liposomes with lipids of different rigidities were comprehensively investigated in respect to their physicochemical properties, their storage and serum stability. In vitro experiments were conducted with common 2D cell models and additionally with multicellular tumor spheroids (MCTS) as a more sophisticated tool to represent the physiology of avascular solid tumors. Our results indicate that liposomes containing the fluid phospholipid dioleoylphosphatidylcholine (DOPC) represent an excellent formulation to enhance the solubility and stability of curcumin. However, in presence of serum or cells, curcumin is rapidly released from the protecting and stabilizing lipid bilayer. Thus, improvement of the in vivo efficacy of curcumin is probably not achieved by using liposomes. Cytotoxicity and uptake experiments showed clearly a reduced effectivity of curcumin liposomes in the 3D cell model in comparison to the 2D model. This not only illustrates the limitations of monolayer cultures in predicting drug and nanocarrier interactions with solid tumors, but also further questions the use of liposomes as a formulation strategy in the treatment of solid tumors with curcumin.

Topics: Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Hydrophobic and Hydrophilic Interactions; Liposomes; Nanoparticles; Neoplasms; Phospholipids; Solubility; Spheroids, Cellular

Multifunctional nanodrugs with the integration of precise diagnostic and effective therapeutic functions have shown great promise in improving the efficacy of cancer therapy. We report herein a simple and effective approach to directly assemble an anticancer drug (curcumin), a photodynamic agent (Ce6) and tumor environment-sensitive molecules into cross-linked polyphosphazene and coat on superparamagnetic Fe3O4 nanoclusters to form discrete nanoparticles (termed as FHCPCe NPs). FHCPCe NPs have high physiological stability and good biocompatibility, and can enhance accumulation in tumor tissue via the enhanced permeability and retention effect. Meanwhile, the FHCPCe NPs exhibit an effective performance of dual-modality magnetic resonance imaging (MRI) due to the Fe3O4 cores and fluorescence imaging (FL) in the xenografted HeLa tumor because of the fluorescence of Ce6. Importantly, under the conditions of supernormal glutathione levels and acidic microenvironment in tumor tissue, curcumin and Ce6 can be effectively released by the degradation of FHCPCe NPs. Therefore, excellent anti-tumor effects both in vitro and in vivo have been achieved by synergistic chemotherapy/photodynamic therapy (CT/PDT) using multifunctional NPs. Our study highlights the promise of developing multifunctional nanomaterials for accurate multimodal imaging-guided highly sensitive therapy of cancer.

Topics: Animals; Chlorophyllides; Curcumin; Drug Carriers; Ferrosoferric Oxide; HeLa Cells; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Organophosphorus Compounds; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins; Reactive Oxygen Species; Transplantation, Heterologous; Whole Body Imaging

The combination of controlled release technology and targeted drug delivery has become a promising strategy for cancer therapy. In this study, cell-nanoparticle hybrid vector was constructed using mesenchymal stem cells as the targeting cellular carrier and biotinylated chitosan polymer nanoparticles as the drug depot. Drug-loaded nanoparticles (hydrodynamic size =377.0 ± 14.6 nm and zeta potential = 9.6 ± 1.9 mV) were prepared by encapsulating hydrophobic model drug curcumin into biotinylated chitosan polymer. The biotin-modified nanoparticles were anchored on biotinylated mesenchymal stem cells surface by biotin-avidin binding, achieving an upload of 54.73 ± 3.95 pg/cell. The anchorage of nanoparticles on mesenchymal stem cells had no effect on their viability and homing property. Biotin-avidin binding lasted over 48 h, which could be sufficient for cell-directed tumor-tropic delivery. The in vitro and in vivo anti-tumor results advocate that cell-nanoparticle hybrid vector could prove beneficial in pulmonary melanoma metastasis therapy.

Topics: Animals; Biotin; Cell Movement; Cell Survival; Chitosan; Curcumin; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Drug Liberation; Fluorescent Antibody Technique; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Nanoparticles; Neoplasms; Polymers; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Anti-Inflammatory Agents; Antioxidants; Apoptosis; Cell Proliferation; Curcumin; Humans; Neoplasms; Plants, Medicinal

In this study, we produced curcumin loaded gelatine microparticles, through spray-drying method, with dialdehyde carboxymethyl cellulose (DCMC) which is introduced as a new cross-linking agent for drug delivery systems and examined toxicities by comparison of traditional cross-linking agents. We employed various parameters in the production and tried to develop the most efficient drug delivery system through Taguchi method by examining efficiencies on gastric cancer under

Topics: Antineoplastic Agents; Carboxymethylcellulose Sodium; Cell Line; Cell Line, Tumor; Cross-Linking Reagents; Curcumin; Delayed-Action Preparations; Drug Liberation; Gelatin; Humans; Neoplasms

The efficacy of the plant-derived polyphenol curcumin, in various aspects of health and wellbeing, are a matter of public interest. An internet search of the term "Curcumin" displays about 12 million hits. Among the multitudinous information presented on partly doubtful websites, there are reports attracting the reader with promises ranging from eternal youth to cures for incurable diseases. Unfortunately, many of these reports are not based on scientific evidence, but they feed the desideratum of the reader for a "miracle cure". This circumstance makes it very difficult for researchers, whose work is scientifically sound and evidence is based on the therapeutic benefits (or side effects) of curcumin, to demarcate their results from sensational reports that circulate in the web and in other media. This is only one of many obstacles making it difficult to pave curcumin's way into clinical application; others are its nonpatentability and low economic usability. A further impediment comes from scientists who never worked with curcumin or any other natural plant-derived compound in their own labs. They have never tested these compounds in any scientific assay, neither in vitro nor in vivo; however, they claim, in a sometimes polemic manner, that everything that has so far been published on curcumin's molecular effects is based on artefacts. The here presented Special Issue comprises a collection of five scientifically sound articles and nine reviews reporting on the therapeutic benefits and the molecular mechanisms of curcumin or of chemically modified curcumin in various diseases ranging from malignant tumors to chronic diseases, microbial infection, and even neurodegenerative diseases. The excellent results of the scientific projects that underlie the five original papers give reason to hope that curcumin will be part of novel treatment strategies in the near future-either as monotherapy or in combination with other drugs or therapeutic applications.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Curcumin; Humans; Infections; Inflammation; Neoplasms; Neurodegenerative Diseases; Neuroprotective Agents

Curcumin exhibits potent anticancer activity via various mechanisms, but its in vivo efficacy has been hampered by poor solubility. Nanotechnology has been employed to deliver curcumin, but most of the reported systems suffered from low drug loading capacity and poor stability. Here, we report the development and optimization of a liposomal formulation for curcumin (Lipo-Cur) using an automated microfluidic technology. Lipo-Cur exhibited a mean diameter of 120 nm with a low polydispersity index (<0.2) and superior loading capacity (17 wt %) compared to other reported liposomal systems. Lipo-Cur increased the water solubility of curcumin by 700-fold, leading to 8-20-fold increased systemic exposure compared to the standard curcumin suspension formulation. When coadministered with cisplatin to tumor-bearing mice, Lipo-Cur augmented the antitumor efficacy of cisplatin in multiple mouse tumor models and decreased the nephrotoxicity. This is the first report demonstrating the dual effects of curcumin enabled by a nanoformulation in enhancing the efficacy and reducing the toxicity of a chemo-drug in animal models under a single and low dose administration.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Curcumin; Dimyristoylphosphatidylcholine; Disease Models, Animal; Drug Compounding; Drug Delivery Systems; Drug Liberation; Drug Therapy, Combination; Female; Liposomes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Nanotechnology; Neoplasms; Solubility; Tissue Distribution

Topics: Animals; Antineoplastic Agents; Carcinoma, Ehrlich Tumor; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Screening Assays, Antitumor; Female; Humans; Male; Mice; Microtubules; Neoplasms

Curcumin, a natural polyphenol, exhibits anti-oxidant, anti-inflammatory, anti-neoplastic and chemopreventive properties. In fact, targeting of this natural anticancer agent has received a great deal of attention during the recent years. In this study, we proposed that curcumin conjugation with lactoferrin molecules may lead to a potential drug delivery system targeted toward cancerous cells through both active and passive targeting. In this regard, curcumin conjugated lactoferrin was developed via a carbodiimide-based coupling reaction and the resulting conjugates were appraised for their molecular properties as a potential targeted drug delivery system. The mean diameter of the designed nanostructure was about 165 ± 26 nm with a PDI of 0.308 ± 0.045. The conjugated nanostructures showed a considerably improved cytotoxicity on HCT116 cells as illustrated by MTT assay along with a higher level of cellular uptake. Cellular uptake and targeting capability of conjugated samples were further investigated by confocal microscopy and the conjugated curcumin nanostructures showed an enhanced efficacy compared to curcumin. Furthermore, flow cytometry analysis proved that early apoptosis occurred in HCT116 cell line, after 24 h incubation with conjugated curcumin.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Humans; Lactoferrin; Nanoparticles; Neoplasms

Over the past fifty years, society has become aware of the importance of a healthy diet in terms of human fitness and longevity. More recently, the concept of the beneficial effects of certain components of our diet and other compounds, that are consumed often by different cultures in various parts of the world, has become apparent. These "healthy" components of our diet are often referred to as nutraceuticals and they can prevent/suppress: aging, bacterial, fungal and viral infections, diabetes, inflammation, metabolic disorders and cardiovascular diseases and have other health-enhancing effects. Moreover, they are now often being investigated because of their anti-cancer properties/potentials. Understanding the effects of various natural products on cancer cells may enhance their usage as anti-proliferative agents which may be beneficial for many health problems. In this manuscript, we discuss and demonstrate how certain nutraceuticals may enhance other anti-cancer drugs to suppress proliferation of cancer cells.

Topics: Animals; Antineoplastic Agents; Berberine; Cardiovascular Diseases; Curcumin; Dietary Supplements; Humans; Neoplasms; Resveratrol; Signal Transduction

A fluorescent 2,7-dimethoxy-substituted calix[4]carbazole (1) is facilely synthesized. The spectral behaviors of both the guest-induced switchable conformation of 1 and its abilities serving as the stabilizer and molecular carrier of curcumin are investigated. UV-vis, fluorescence and NMR spectral results show that upon binding to curcumin, the 1,3-alternate conformation of 1 is converted to be the cone one. The relative high association constant (6.4×10

Topics: Antineoplastic Agents; Calixarenes; Carbazoles; Cell Proliferation; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Stability; Fluorescent Dyes; Humans; Neoplasms; Tumor Cells, Cultured

Curcumin-conjugated gold clusters (CUR-AuNCs) were synthesized using a "green" procedure and utilized as an anticancer and a bioimaging agent. Curcumin is a well-known anticancer agent, which forms a cluster when reacting with a gold precursor under mild alkali condition. A fluorescence spectroscopy analysis showed that the CUR-AuNCs emitted red fluorescence (650 nm) upon visible light (550) irradiation. Fourier transform infrared spectroscopy analysis confirmed the stretching and bending nature between the gold atoms and curcumin. Meanwhile, transmission electron microscopy analysis showed a cluster of approximately 1-3 nm with a uniform size. Time-resolved fluorescence analysis demonstrated that the red fluorescence was highly stable. Moreover, laser confocal imaging and atomic force microscopy analysis illustrated that a cluster was well distributed in the cell. This cluster exhibited less toxicity in the mortal cell line (COS-7) and high toxicity in the cervical cancer cell line (HeLa). The results demonstrated the conjugation of curcumin into the fluorescent gold cluster as a potential material for anticancer therapy and bioimaging applications.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Survival; Chlorocebus aethiops; COS Cells; Curcumin; Fluorescent Dyes; Gold; HeLa Cells; Humans; Metal Nanoparticles; Neoplasms; Optical Imaging; Spectrometry, Fluorescence

Previous investigations in gene expression changes in blood after radiation exposure have highlighted its potential to provide biomarkers of exposure. Here, FDXR transcriptional changes in blood were investigated in humans undergoing a range of external radiation exposure procedures covering several orders of magnitude (cardiac fluoroscopy, diagnostic computed tomography (CT)) and treatments (total body and local radiotherapy). Moreover, a method was developed to assess the dose to the blood using physical exposure parameters. FDXR expression was significantly up-regulated 24 hr after radiotherapy in most patients and continuously during the fractionated treatment. Significance was reached even after diagnostic CT 2 hours post-exposure. We further showed that no significant differences in expression were found between ex vivo and in vivo samples from the same patients. Moreover, potential confounding factors such as gender, infection status and anti-oxidants only affect moderately FDXR transcription. Finally, we provided a first in vivo dose-response showing dose-dependency even for very low doses or partial body exposure showing good correlation between physically and biologically assessed doses. In conclusion, we report the remarkable responsiveness of FDXR to ionising radiation at the transcriptional level which, when measured in the right time window, provides accurate in vivo dose estimates.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Curcumin; Female; Ferredoxin-NADP Reductase; Humans; Lipopolysaccharides; Male; Middle Aged; Neoplasms; RNA; Tomography, X-Ray Computed; Up-Regulation; Whole-Body Irradiation; Young Adult

Three curcuminoids: bisdemethoxycurcumin, demethoxycurcumin, and curcumin from turmeric were successfully separated by a high capacity solvent system composed of heptane: chloroform: methanol: water mixture (5: 6: 3: 2 v/v/v/v) tailored for centrifugal partition chromatographs at K-values of 0.504, 1.057, 1.644, respectively. These three ferulic acid derivatives obtained at a purity rate exceeding 95% were analysed by an HPLC-MS spectrometer. Turmeric extract inhibited the proliferation/viability of A549 human lung cancer, HT29 colon cancer, and T98G glioblastoma cell lines in (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay (MTT). Single curcuminoids significantly decreased the viability/proliferation of lung cancer cells in a dose-dependent manner. However, total extract displayed the superior anticancer activity in the investigated cell lines. Crude extract in combination with cisplatin augmented the decrease in the viability of cancer cells compared with single compound treatment in A549 lung cancer cells. Total extract of Curcuma longa could be regarded as being more effective against lung cancer cells in vitro than its separated compounds.

Topics: A549 Cells; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chemical Fractionation; Chromatography, High Pressure Liquid; Coumaric Acids; Curcuma; Curcumin; Diarylheptanoids; HT29 Cells; Humans; Mass Spectrometry; Neoplasms; Phytotherapy; Plant Extracts; Solvents

In this work, we propose biofriendly in-situ preparation method of Au NPs (hexagonal and rod-shape structures) in the lumen as well as the surface cage of biocompatible halloysite nanotubes (HNTs) using curcumin (CUR) as anticancer drug and subsequently coating with bio-adhesive chitosan (CS) as a polysaccharide. The formation of Au NPs and their interactions with CUR and CS exist in the HNTs has been characterized by FTIR, XRD, XPS, STEM techniques. Interestingly, Au NPs showed longitudinal plasmon resonance bands at 760 and 980 nm that indicate the near-infrared (NIR) responsive property of hybrid nanoparticles. Rod shape and hexagonal structures of Au NPs were produced as confirmed by TEM images. The loading efficiency of CUR was found as much as 12%. Importantly, more CUR release was achieved under acidic conditions (pH 5.5) than basic conditions (pH 7.4). The anticancer potential of HNT hybrid nanoparticles on MCF-7 cancer cells was studied and showed efficient anticancer activity under intracellular tumor cell environment (pH 5.5) than extracellular conditions (pH 7.4). Moreover, the developed HNT hybrid nanoparticles consisting of Au NPs (NIR responsive property) and pH-responsive CUR release could make it suitable for cancer cell-targeted drug delivery platform with NIR-imaging.

Topics: Aluminum Silicates; Cell Line, Tumor; Cell Survival; Chitosan; Clay; Curcumin; Drug Delivery Systems; Drug Liberation; Gold; Humans; Hydrogen-Ion Concentration; Nanoparticles; Nanotubes; Neoplasms

p53 is an important tumor-suppressor protein that is mutated in more than 50% of cancers. Strategies for restoring normal p53 function are complicated by the oncogenic properties of mutant p53 and have not met with clinical success. To counteract mutant p53 activity, a variety of drugs with the potential to reconvert mutant p53 to an active wildtype form have been developed. However, these drugs are associated with various negative effects such as cellular toxicity, nonspecific binding to other proteins, and inability to induce a wildtype p53 response in cancer tissue. Here, we report on the effects of a curcumin analog, HO-3867, on p53 activity in cancer cells from different origins. We found that HO-3867 covalently binds to mutant p53, initiates a wildtype p53-like anticancer genetic response, is exclusively cytotoxic toward cancer cells, and exhibits high anticancer efficacy in tumor models. In conclusion, HO-3867 is a p53 mutant-reactivating drug with high clinical anticancer potential.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Female; Humans; Mice; Mice, Nude; Mutant Proteins; Mutation; Neoplasms; Piperidones; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Polyelectrolyte complex nanoparticles were fabricated via electrostatic complexation between Enteromorpha prolifera polysaccharide (EP) and chitosan (CS). The monodisperse EP/CS NPs with negatively charge were prepared at pH4.0 and mixing ratio of 3.0:1.0. Curcumin loaded nanoparticles (CUR-NPs) showed spherical morphology with negatively charge of -16.27±0.97mV and average diameter range of 230 to 330nm. The results of spectroscopic analysis, XRD and DSC confirmed that there were hydrogen-bonding interaction and hydrophobic interaction between curcumin and EP/CS NPs. The CUR-NPs improved storage, thermal and photo stability of curcumin and exhibited sustained release of curcumin in vitro. Moreover, the CUR-NPs showed higher cellular uptake than free CUR with incubation for 3h by CLSM visualization and fluorescence quantitative assay. Furthermore, MTT assay results demonstrated that the CUR-NPs possessed good anticancer activity against B16F10 cells. Therefore, the EP-based nanoparticles are promising candidates for carriers in controllable hydrophobic anti-tumor drug delivery.

Topics: Cell Line, Tumor; Chitosan; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Nanoparticles; Neoplasms; Polysaccharides

In this paper, a novel pH and redox dual-sensitive nanocarrier loaded with curcumin (Cur) and anticancer polypeptide (AP) was developed for dual targeting mitochondrial and CD44 receptor. The amphiphilic block copolymer was prepared by triphenylphosphonium (TPP)/oligomeric hyaluronic acid (oHA)/disulfide-menthone 1,2-glycerol ketal (SM), hereinafter referred to as TPP-oHSM. The TPP targeted the mitochondria, pH/redox dual-sensitive SM served as a hydrophobic part, and the CD44 receptor targeting oHA worked as a hydrophilic part. The chemical structure of the TPP-oHSM was identified using 1H NMR and FTIR technologies. Cur and AP were loaded into the TPP-oHSM micelles by self-assembly and denoted as C/A@TM. The C/A@TM prepared in this study exhibited an approximately spherical structure, with a mean diameter of 191.3 ± 3.1 nm and a negative zeta potential of -26.10 ± 0.45 mV. The in vitro release study and cellular uptake test revealed that the C/A@TM targeted the mitochondria and CD44 receptor, as well as it showed sensitivity towards pH and redox. In addition, the C/A@TM demonstrated satisfactory cytotoxic effects against MDA-MB-231 cells and MCF-7 cells. Finally, the in vivo application of the C/A@TM showed excellent therapeutic effects. The C/A@TM developed in this study exhibited promising multifunctional properties as a co-delivery carrier of polypeptide and chemical drug for an effective clinical therapy for cancer.

Topics: Antineoplastic Agents; Curcumin; Drug Delivery Systems; Humans; MCF-7 Cells; Micelles; Nanostructures; Neoplasms; Peptides

Transferrin receptor (TfR) is up-regulated in various malignant tumors not only to meet the iron requirement, but also to increase the cell survival via participation in various cellular signaling pathways. Here we explored transferrin as ligand for Poly(ethylene Glycol) (PEG)-ylated vitamin-E/lipid (PE) core micelles (VPM).. Transferrin modified polymer was synthesized and drug loaded micelles were evaluated in 2D Hela and HepG2 cancer cells for cellular uptake and cytotoxicity and in 3D Hela spheroids for growth inhibition, uptake and penetration studies.. Targeted (Tf-VPM) and non-targeted (VPM) micelles showed mean hydrodynamic diameter of 114.2 ± 0.64 nm and 117.4 ± 0.72 nm and zeta potential was -22.8 ± 0.62 and -14.8 ± 1.74 mV, respectively. Cellular uptake study indicated that the Tf-CVPM were taken up by cancer cells (Hela and HepG2) with higher efficiency. Enhanced cytotoxicity was demonstrated for Tf-VPM compared to CVPM. Marked spheroid growth inhibition following treatment with Tf-CVPM was observed compared to the treatment with non-targeted CVPM.. The developed transferrin-modified micelles have improved ability to solubilize the loaded drugs and could actively target solid tumors by its interaction with over-expressed transferrin receptors. Therefore, the nano-micelles could be further explored for its potential utilization in cancer therapy.

Topics: Antineoplastic Agents; Cell Survival; Curcumin; Drug Compounding; Drug Delivery Systems; Drug Screening Assays, Antitumor; HeLa Cells; Hep G2 Cells; Humans; Lipids; Molecular Targeted Therapy; Nanoparticles; Neoplasms; Polyethylene Glycols; Receptors, Transferrin; Spheroids, Cellular; Transferrin; Vitamin E

Nanotechnology plays an important role in the development of drug delivery, imaging, and diagnosis. In this study, nanocapsules containing protein-functionalized gold nanoclusters (AuNCs) as the shell and hydrophobic drug curcumin as the core were prepared as a tumor cell theranostic agent. After the nanocapsules were added into tumor cell media, they entered the cells with high efficiency and exhibited strong fluorescence within the cells. The results indicated that the nanocapsules were broken up in the cells and curcumin was released. Simultaneously, the nanocapsules exhibited significant inhibition effect against tumor cell proliferation in a concentration- and time-dependent manner, and the images of atomic force microscopy (AFM) showed that the cell morphology underwent obvious changes after the capsule treatment. Additionally, cell membrane appeared wrinkles after the cells treated with the nanocapsules, resulting in a rough cell surface, implying that the cytoskeleton would involve in the cell uptake of nanocapsules. Moreover, the AuNCs and curcumin in the system could exert synergistic effect on the inhibition of tumor cell growth and induction of cell apoptosis. The study highlights the potential of the system as a promising agent for drug delivery and tumor cell theranosis.

Topics: Animals; Cattle; Cell Line, Tumor; Curcumin; Humans; Metal Nanoparticles; Nanocapsules; Neoplasms; Serum Albumin, Bovine; Theranostic Nanomedicine

We designed acid-labile methotrexate (MTX) targeting prodrug self-assembling nanoparticles loaded with curcumin (CUR) drug for simultaneous delivery of multi-chemotherapeutic drugs and combination cancer therapy.. A dual-acting MTX, acting as both an anticancer drug and as a tumor-targeting ligand, was coupled to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethylene glycol)-2000] via Schiff's base reaction. The synthesized prodrug conjugate (DSPE-PEG-Imine-MTX) could be self-assembled into micellar nanoparticles (MTX-Imine-M) in aqueous solution, which encapsulated CUR into their core by hydrophobic interactions (MTX-Imine-M-CUR).. The prepared MTX-Imine-M-CUR nanoparticles were composed of an inner hydrophobic DSPE/CUR core and an outside hydrophilic bishydroxyl poly (ethyleneglycol) (PEG) shell with a self-targeting MTX prodrug corona. The imine linker between 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[aldehyde(polyethyleneglycol)-2000] and MTX, as a dynamic covalent bond, was strong enough to remain intact in physiological pH, even though it is rapidly cleaved in acidic pH. The MTX-Imine-M-CUR could codeliver MTX and CUR selectively and efficiently into the cancer cells via folate receptor-mediated endocytosis followed by the rapid intracellular release of CUR and the active form of MTX via the acidity of endosomes/lysosomes. Moreover, the MTX-Imine-M-CUR resulted in significantly higher in vitro and in vivo anticancer activity than pH-insensitive DSPE-PEGAmide-MTX assembling nanoparticles loaded with CUR (MTX-Amide-M-CUR), MTX unconjugated DSPE-PEG assembling micellar nanoparticles loaded with CUR (M-CUR), combination of both free drugs, and individual free drugs.. The smart system provided a simple, yet feasible, drug delivery strategy for targeted combination chemotherapy.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Death; Colloids; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Endocytosis; HeLa Cells; Humans; Hydrodynamics; Hydrogen-Ion Concentration; MCF-7 Cells; Methotrexate; Mice, Inbred BALB C; Mice, Nude; Micelles; Nanoparticles; Neoplasms; Particle Size; Phosphatidylethanolamines; Polyethylene Glycols; Prodrugs

Curcumin has a broad spectrum of pharmacological activities, one of them is anticancer activity that is mediated through multiple mechanisms. The major disadvantage associated with the use of curcumin is its low bioavailability due to its poor aqueous solubility. Nanoformulations of curcumin provide an effective solution for this problem. In this study, we have synthesized curcumin Ag nanoconjugates and evaluated their anticancer potential.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Curcumin; Drug Screening Assays, Antitumor; Humans; Metal Nanoparticles; Nanoconjugates; Neoplasms; Tyrosine

Ability to deliver drugs into the cell nuclei can significantly increase the efficacy of cancer therapies, in particular in the case of multidrug-resistant cancer Results: Polymer nanocarriers based on amphiphilic thiooctadecyl-terminated poly-N-vinyl-2-pyrrolidone were produced and loaded with a model hydrophobic drug, curcumin. Two commonly used loading approaches - emulsification and ultrasonic dispersion - were found to lead to two different size distributions with distinctively different biological effect. While nanocarriers produced via the emulsion method penetrated cells by dynamin-dependent endocytic mechanisms, sub-100 nm dispersion-produced nanocarriers were capable of crossing the membranes via biologically independent mechanisms.. This finding opens an intriguing possibility of intranuclear delivery by merely tailoring the size of polymeric carriers, thus promising a new approach for cancer therapies.

Topics: Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Hydrophobic and Hydrophilic Interactions; Neoplasms; Polymers; Pyrrolidinones

Curcumin (CUR) is a natural diketone with diverse bioactivities of inhibiting angiogenesis and tumor growth. However, its clinical application for cancer treatment was severely hindered by poor aqueous solubility and chemical instability. To overcome these drawbacks and achieve enhanced antitumor efficiency, low molecular weight heparin (LMWH) was conjugated to CUR via the one-step esterification reaction to yield LMWH-CUR (LCU) nanodrugs with the size of 180 nm, which exhibited enhanced accumulation within tumor site by EPR effect and long circulating capacity by LMWH hydrophilic shell. The solubility of conjugated CUR was increased to 0.12 mg/mL (equivalent of CUR) in comparison with 0.006 mg/mL of free CUR. The bioactivities of CUR were guaranteed because of the improved stability of LCU nanodrugs in low pH condition. Moreover, the stronger anti-angiogenesis efficacy of LCU nanodrugs than LMWH monotherapy was also verified. Notably, at a rather low dose of equivalent LMWH (5 mg/kg) and CUR (0.3 mg/kg), the tumor inhibition rate of LCU nanodrugs were much higher than that of LMWH (10 times) and LMWH plus CUR mixture (3.8 times) respectively, indicating its excellent in vivo antitumor efficacy. Overall, our study managed to obtain the novel nanodrugs with potent anti-angiogenesis and antitumor effects whereas avoiding tedious and complicated synthetic procedures. These results also suggested that LCU nanodrugs could be considered as a promising targeted delivery system for cancer treatment.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Blood Coagulation; Cell Survival; Curcumin; Drug Combinations; Drug Stability; Erythrocytes; Hemolysis; Hep G2 Cells; Humans; Mice; Nanoparticles; Neoplasms; Rabbits; Tumor Burden

Topics: Antineoplastic Agents; Curcumin; Doxorubicin; Drug Carriers; Drug Combinations; Drug Compounding; Drug Liberation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; MCF-7 Cells; Nanoparticles; Neoplasms; Porosity

For triage purposes following a nuclear accident, blood-based gene expression biomarkers can provide rapid dose estimates for a large number of individuals. Ionizing-radiation-responsive genes are regulated through the DNA damage-response pathway, which includes activation of multiple transcription factors. Modulators of this pathway could potentially affect the response of these biomarkers and consequently compromise accurate dose estimation calculations. In the present study, four potential confounding factors were selected: cancer condition, sex, simulated bacterial infection (lipopolysaccharide), and curcumin, an anti-inflammatory/antioxidant agent. Their potential influence on the transcriptional response to radiation of the genes CCNG1 and PHPT1, two biomarkers of radiation exposure ex vivo, was assessed. First, both CCNG1 and PHPT1 were detected in vivo in blood samples from radiotherapy patients and as such were validated as biomarkers of exposure. Importantly, their basal expression level was slightly but significantly affected in vivo by patients' cancer condition. Moreover, lipopolysaccharide stimulation of blood irradiated ex vivo led to a significant modification of CCNG1 and PHPT1 transcriptional response in a dose- and time-dependent manner with opposite regulatory effects. Curcumin also affected CCNG1 and PHPT1 transcriptional response counteracting some of the radiation induction. No differences were observed based on sex. Dose estimations calculated using linear regression were affected by lipopolysaccharide and curcumin. In conclusion, several confounding factors tested in this study can indeed modulate the transcriptional response of CCNG1 and PHPT1 and consequently can affect radiation exposure dose estimations but not to a level which should prevent the biomarkers' use for triage purposes.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Case-Control Studies; Curcumin; Cyclin G1; Female; Gene Expression Regulation, Neoplastic; Humans; Lipopolysaccharides; Male; Middle Aged; Neoplasms; Phosphoric Monoester Hydrolases; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated

Curcumin has been reported to inhibit inflammation, tumor growth, angiogenesis and metastasis by decreasing cell growth and by inducing apoptosis mainly through the inhibition of nuclear factor kappa-B (NFκB), a master regulator of inflammation. Recent reports also indicate potential metabolic effects of the polyphenol, therefore we analyzed whether and how it affects the energy metabolism of tumor cells. We show that curcumin (10 µM) inhibits the activity of ATP synthase in isolated mitochondrial membranes leading to a dramatic drop of ATP and a reduction of oxygen consumption in in vitro and in vivo tumor models. The effects of curcumin on ATP synthase are independent of the inhibition of NFκB since the IκB Kinase inhibitor, SC-514, does not affect ATP synthase. The activities of the glycolytic enzymes hexokinase, phosphofructokinase, pyruvate kinase and lactate dehydrogenase are only slightly affected in a cell type-specific manner. The energy impairment translates into decreased tumor cell viability. Moreover, curcumin induces apoptosis by promoting the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), a marker of lipid oxidation, and autophagy, at least in part due to the activation of the AMP-activated protein kinase (AMPK). According to the in vitro anti-tumor effect, curcumin (30 mg/kg body weight) significantly delayed in vivo cancer growth likely due to an energy impairment but also through the reduction of tumor angiogenesis. These results establish the ATP synthase, a central enzyme of the cellular energy metabolism, as a target of the antitumoral polyphenol leading to inhibition of cancer cell growth and a general reprogramming of tumor metabolism.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Energy Metabolism; Female; Hexokinase; I-kappa B Kinase; L-Lactate Dehydrogenase; Malondialdehyde; Mice; Mice, Nude; Mitochondrial Proton-Translocating ATPases; Neoplasms; Neovascularization, Pathologic; Oxygen Consumption; Phosphofructokinases; Pyruvate Kinase; Reactive Oxygen Species; Thiophenes

Topics: Antineoplastic Agents; Biocompatible Materials; Curcumin; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Liberation; HEK293 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Materials Testing; MCF-7 Cells; Methotrexate; Neoplasms; Polyesters; Polyethylene Glycols

The present study highlights the advantages of using an Analytical Quality by Design (AQbD) approach to the optimization of a high-performance liquid chromatography method for the simultaneous assay of curcumin (CUR), demetoxycurcumin (DMC), bisdemetoxycurcumin (BDMC) and doxorubicin (DOX) co-encapsulated in long circulating liposomes. Within the QbD paradigm, the present study aimed to establish the method operable design region (MODR) for the optimization of the high-performance liquid chromatography-fluorescence (HPLC-FLD) assay by means of Design of Experiments (DOE) and response surface methodology, in order to achieve a good separation and quantification of all analyzed compounds along to an acceptable analysis time. A deep understanding of the quality target product profile (QTPP) and of the analytical target profile (ATP), followed by a risk assessment for variables that affect the efficiency of the method led to the development of a precise, accurate and cost-effective method. The assay was linear over the range of 2-20 μg/ml for all investigated compounds. The intra-and inter-day precision were less than 2%, with accuracies between 97-104% of the true values. The method was successfully applied to the quantification of curcuminoids and DOX from long-circulating liposomes.

Topics: Antineoplastic Agents; Chemical Fractionation; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Curcumin; Doxorubicin; Humans; Limit of Detection; Liposomes; Neoplasms; Quality Control; Sensitivity and Specificity

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; CRISPR-Cas Systems; Crystallography, X-Ray; Curcumin; Drug Synergism; Dyrk Kinases; Female; Gene Editing; Gene Knockout Techniques; HEK293 Cells; Humans; Inhibitory Concentration 50; Mice; Neoplasms; Oligopeptides; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO-Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO-Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC-R). GO-Y078 inhibited the growth and mobility of HUVEC-R at 0.75 μmol/L concentration. Expression analyses by microarray and RT-PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO-Y078. In a knockdown experiment using Si-oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO-Y078. Knockdown of FN1 resulted in the suppression of HUVEC-R growth at 24 hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO-Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO-Y078.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Drug Resistance, Neoplasm; Fibronectins; Gene Knockdown Techniques; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Neovascularization, Pathologic; RNA, Small Interfering; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays; Xenopus laevis

In this study, twenty curcumin analogue hybrids as potential anticancer agents through regulation protein of TrxR were designed and synthesized. Results of anticancer activity showed that 5,7-dimethoxy-3-(3-(2-((1E, 4E)-3-oxo-5-(pyridin-2-yl)penta-1,4-dien-1- yl)phenoxy)propoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (compound 7d) could induce gastric cancer cells apoptosis by arresting cell cycle, break mitochondria function and inhibit TrxR activity. Meanwhile, western blot revealed that this compound could dramatically up expression of Bax/Bcl-2 ratio and high expression of TrxR oxidation. These results preliminarily show that the important role of ROS mediated activation of ASK1/MAPK signaling pathways by this title compound.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Membrane Potential, Mitochondrial; Mitochondria; Neoplasms; Reactive Oxygen Species; Signal Transduction; Stomach Neoplasms; Thioredoxin Reductase 1

Due to the drug resistance of cancer stem cells (CSCs), CSC-targeted delivery of multiple drugs in nanoparticle-based drug delivery system holds great potential for the destruction of the CSCs and Tumor. In this chapter, we describe the preparation of multi-layered pH-responsive polymeric nanoparticles (NPs) by multiple emulsifications to encapsulate multiple hydrophilic and hydrophobic theranostic agents for controlled and sequenced release. Hyaluronic acid (HA) is used for not only actively targeting the CSCs to reduce their drug resistance due to dormancy (i.e., slow metabolism), but also replacing the commonly used poly (vinyl alcohol) (PVA) as a stabilizing agent to synthesize the nanoparticles.

Topics: Chitosan; Curcumin; Doxorubicin; Drug Delivery Systems; Drug Liberation; Emulsions; Humans; Hyaluronic Acid; Nanoparticles; Neoplasms; Neoplastic Stem Cells; Polyvinyl Alcohol

Curcumin has well-established anti-cancer properties in vitro, however, its therapeutic potential has been hindered by its poor bioavailability. Lipocurc is a proprietary liposome-encapsulated curcumin formulation that enables intravenous delivery and has been shown to reach its highest concentration within lung tissue. The goal of this study was to characterize the anti-cancer and anti-angiogenic activity of Lipocurc in vitro, in addition to evaluating Lipocurc infusions in dogs with naturally occurring cancer. We therefore evaluated the effect of Lipocurc, relative to free curcumin, on the viability of canine osteosarcoma, melanoma and mammary carcinoma cell lines, as well as the ability of Lipocurc to inhibit endothelial cell viability, migration and tube formation. We also undertook a pilot clinical trial consisting of four weekly 8-hour Lipocurc infusions in 10 cancer-bearing dogs. Tumour cell proliferation was inhibited by curcumin at concentrations exceeding those achievable in the lung tissue of dogs. Similarly, equivalent high concentrations of Lipocurc and curcumin also inhibited endothelial cell viability, migration and tube formation. Four out of six dogs completing planned infusions of Lipocurc experienced stable disease; however, no radiographic responses were detected.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Curcumin; Dog Diseases; Dogs; Female; Inhibitory Concentration 50; Liposomes; Male; Neoplasms; Neovascularization, Pathologic

Dose-dependent irreversible cardiac toxicity of doxorubicin (DOX) becomes a major obstacle for the clinical use. Nowadays much attention is being paid to combination therapy with DOX and antioxidant agents, which would improve the clinical efficacy by protecting from cardiotoxicity along with the maintained performance as an antitumor drug. With the assistance of nanoscience and polymer engineering, herein a complex polymeric micellar system was developed for co-loading DOX and a premium natural antioxidant curcumin (CUR), and we investigated whether this new formulation for DOX delivery could achieve such a goal.. The dually loaded micelles co-encapsulating DOX and CUR (CPMDC) were prepared through thin-film rehydration by using the amphiphilic diblock copolymer monomethoxy poly(ethylene glycol) (mPEG)-poly(ε-caprolactone) (PCL)-N-t-butoxycarbonyl-phenylalanine (BP) synthesized by end-group modification of mPEG-PCL with BP. Quantitative analysis was conducted by HPLC methods for drugs in micelles or biosamples. Molecular dynamics simulation was performed using HyperChem software to illustrate interactions among copolymer and active pharmaceutical ingredients. The safety and antitumor efficacy were evaluated by in vitro viability of H9C2 cells, and tumor growth inhibition in tumor-bearing mice respectively. The protection effects against DOX-induced cardiotoxicity were investigated according to several physiological, histopathological and biochemical markers concerning systemic and cardiac toxicity.. CPMDC were obtained with favorable physicochemical properties meeting the clinical demand, including uniform particle size, fairly high encapsulation efficiency and drug loadings, as well as good drug release profiles and colloidal stability. The result from molecular dynamics simulation indicated a great impact of the interactions among copolymer and small molecules on the ratiometrical co-encapsulation of both drugs. MTT assay of in vitro H9C2 cells viability demonstrated good safety of the CPMDC formulation, which also showed definite signs of decrease in xenograft tumor growth. The studies on pharmacokinetics and tissue distribution further revealed that DOX delivered by CPMDC could result in prolonged systemic circulation and increased DOX accumulation in tumor but decreased level of the toxic metabolite doxorubicinol in heart tissue compared to free DOX alone or the cocktail combination.. The findings from present study substantiated that such a complex micellar system codelivering DOX with CUR does produce the effect of killing two birds with one stone via distinctive nanocarrier-modified drug-drug interactions.

Topics: Animals; Antineoplastic Agents; Cardiotoxicity; Cell Line; Cell Proliferation; Cell Survival; Curcumin; Doxorubicin; Drug Liberation; Female; Humans; Mice, Inbred C57BL; Micelles; Neoplasms; Particle Size; Polyesters; Polyethylene Glycols; Polymers; Rats; Tissue Distribution; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Chitosan; Curcumin; Drug Delivery Systems; Humans; MCF-7 Cells; Nanoparticles; Neoplasms; Polyelectrolytes; Polyesters; Receptors, Transferrin

Curcumin was employed to prepare anticancer nanoparticles (size 175 ± 15 nm) using anti-inflammatory enzyme serratiopeptidase by desolvation method. Here serratiopeptidase acted as a carrier as well as bioactive molecule in the nanoformulations. The Cur-SPD NPs (curcumin loaded serratiopeptidase nanoparticles) were characterized using DLS, FESEM and FTIR. The in vitro release behavior depicted biphasic pattern at 37 °C (pH 7.4) and release of 95% of both molecules occurred in 24 h. Serratiopeptidase not only provided stability to curcumin but also increased its effectiveness against cancer cells. These nanoparticles had anti-cancer activity in MCF-7 and HeLa cell lines as shown by cytotoxicity assay, DAPI nuclear staining, ROS production and DNA damage. The immunomodulatory tests showed that Cur-SPD NPs reduce level of IL-6 but increase TNFα level in THP1 cell lines. Structural similarity of serratiopeptidase to matrix metallo proteases (MMPs), particularly MMP8, have been found (based on low RMSD values) to induce TNFα production and play tumour suppressive role in certain cancers. Thus anti-cancer properties of Cur-SPD NPs may be attributed to synergistic effect of curcumin and serratiopeptidase. Thus results in present investigation provide an insight on role of serratiopeptidase in development of co-delivery of multifunctional nanoparticles with anti-cancer properties introduction.

Topics: Antineoplastic Agents; Curcumin; Drug Delivery Systems; HeLa Cells; Humans; MCF-7 Cells; Nanoparticles; Neoplasms; Peptide Hydrolases

Coumarin and curcumin have a wide spectrum of biological and pharmacological activities including antioxidant, anti-inflammatory, antimicrobial and anticancer but hindered therapeutic applications due to low stability and poor solubility in water. The main objective of the current study was to overcome these drawbacks via improved bioavailability by nanoencapsulated emulsions. Pickering emulsion (PE) via oil-in-water approach were stabilized by aminated nanocellulose (ANC) particles through application of a full factorial optimization design for nanoemulsions containing different composition of oil phase with medium chain triglyceride (MCT) and Tween 80. The fabricated nanoemulsions and PEs with average particle sizes (≤150 nm) were obtained. Influencing factors such as ANC concentration, storage time and pH on the stability of emulsions were examined alongside zeta potentials. Encapsulation efficiency (EE) of coumarin and curcumin were determined as >90%. Release kinetic profiles for encapsulated PEs displayed sustained release with supposed increase bioavailability. Higher release percent were detected for curcumin encapsulated PE in contrast to coumarin. In vitro cytotoxicity evaluation for coumarin and curcumin loaded PEs were further investigated for anticancer and antimicrobial activities using human cell lines (L929 and MCF-7) and different microorganisms (Gram (+), Gram (-) and fungi), respectively. The results clearly demonstrated PE coumarin and curcumin as promising candidates to inhibit microbial growth and to prevent preferential killing of cancer cells compared to normal cells.

Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Candida albicans; Cellulose; Coumarins; Curcumin; Emulsions; Gram-Negative Anaerobic Bacteria; Gram-Positive Bacteria; Humans; MCF-7 Cells; Mice; Nanocapsules; Neoplasms

Curcumin diglutaric acid (CG) is a prodrug of curcumin that shows better solubility and antinociceptive activity compared to curcumin. To improve its properties further, CG was encapsulated into polysaccharide-based nanoparticles in this study. A chitosan/alginate nanoparticulate system was chosen for encapsulation of CG due to its biocompatibility, biodegradability, non-toxicity, mucoadhisiveness and good film formation. CG-loaded chitosan/alginate nanoparticles were prepared by o/w emulsification and ionotropic gelification, with the conditions optimized using response surface methodology. A chitosan/alginate mass ratio of 0.04:1, CG concentration of 3 mg/mL and Pluronic®F127 concentration of 0.50% (w/v) were determined to be optimal for the nanoparticle preparation. FTIR and XRD confirmed encapsulation of CG into the chitosan/alginate nanoparticles. The CG-loaded chitosan/alginate nanoparticles showed better stability under UV radiation and in a simulated gastrointestinal environment, compared to a CG dispersion in water. The nanoparticles showed slow cumulative release of CG in simulated gastrointestinal fluids without enzymes and in body fluid. A Weibull model of the best fit for all conditions suggested that the release pattern of CG from CG-loaded chitosan/alginate nanoparticles was mainly controlled by Fickian diffusion and erosion of polymer materials. Finally, CG-loaded chitosan/alginate nanoparticles showed higher in vitro cellular uptake in human epithelial colorectal adenocarcinoma (Caco-2 cells) and better anticancer activity against Caco-2, human hepatocellular carcinoma (HepG2) and human breast cancer (MDA-MB-231) cells. Therefore, the CG-loaded chitosan/alginate nanoparticles are a promising approach for oral administration of CG for cancer treatment.

Topics: Alginates; Antineoplastic Agents; Caco-2 Cells; Chitosan; Curcumin; Hep G2 Cells; Humans; Nanoparticles; Neoplasms; Prodrugs

Here, we have reported the influence of MMT and genipin in releasing curcumin from the Genipin crosslinked Chitosan/MMT nanoparticles, prepared by ionic gelation method. The nanoparticles were characterised using Fourier Transform Infrared Spectroscopy (FTIR), X-Ray Diffractometry (XRD), Scanning Electron Microscopy (SEM), and Transmission Electron Microscopy (TEM). Zeta potential and average diameter of the nanoparticles were found in the range 32-47 mV and 430-560 nm. Swelling and release of curcumin from the nanoparticles increased with the decrease in pH of the medium, MMT, and genipin content. Curcumin released from the nanoparticles reduced the viability of MCF-7 and Hep G2 cells as compared to untreated cells. The nanoparticles increased the level of reduced glutathione (GSH), superoxide dismutase (SOD), and catalase level in human PBMCs and decreased the level of Lipid peroxidation suggesting an enhanced protection against cellular damage. Lower pH and higher MMT concentration in the nanoparticles improved the mucoadhesive properties.

Topics: Antineoplastic Agents; Bentonite; Cell Survival; Chitosan; Cross-Linking Reagents; Curcumin; Delayed-Action Preparations; Drug Liberation; Hep G2 Cells; Humans; Iridoids; MCF-7 Cells; Neoplasms

Dichloroacetate (DCA) and curcumin have been shown to be potent drug candidates in cancer therapy. Our study aimed to investigate the combined effects of DCA and essential oil-blended curcumin (ECUR) using the hepatoma Huh-7 cell model.. Muse™ Cell Cycle assay, Muse™ Annexin V & Dead Cell assay, Muse™ Oxidative Stress assay, and western blot analysis were applied to explore the underlying mechanisms.. DCA combined with ECUR dramatically augmented inhibition of cell survival and enhanced apoptotic induction. The enhanced apoptosis was accompanied by mitochondria-dependent apoptotic signaling activation and corroborated with significant cellular morphological alternations.. Apoptosis was the major event contributing to the synergistically boosted antiproliferative effect. Coupling DCA treatment with curcumin may rationally be expected to lower the DCA dose needed and relatively reduce accompanying toxicity and oxidative damage while enhancing anticancer potential. This novel 'add-on' approach is, thus, of enormous value to the current DCA therapy.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dichloroacetic Acid; Drug Synergism; Humans; Mitochondria; Neoplasms; Oxidative Stress

Curcumin is widely considered beneficial to human health, but insolubility and instability greatly hamper reproducible exploitation of the advantageous traits. Here we report on the development, characterization and evaluation of a curcumin-loaded nanoemulsion (CUR-NEM) that is highly effective in preventing post-surgery tumor reincidence and metastasis. The method of fabrication utilized safe excipients and generated particles of 200 nm (PDI ≤ 0.2) with negative zeta potential (-30 mV) and a high yield of curcumin (95%), which can be converted by lyophilization to a dry powder. In vitro assays showed that CUR-NEM is safe in non-cancerous human cells (HEK-293T) and preferentially cytotoxic in gastric (AGS), colon (HT29-ATCC, HT29-US), breast (MDA-MB-231) and melanoma (B16F10) cells. In addition, in melanoma cells the nanoformulation increases intracellular curcumin accumulation and reactive oxygen species (ROS) formation, while preventing cell-migration and invasion. In vivo studies in C57BL/6 mice demonstrated that a single dose, applied topically to the wounded area after surgical excision of primary tumors formed upon subcutaneous injection of syngeneic B16F10 cells, was sufficient to completely prevent reincident tumor growth and spontaneous lung metastasis, while in untreated animals 70% reincidence and metastasis were observed. In vivo experiments also showed that the fluorescence signal due to curcumin was maintained at least 15 days after topical application of CUR-NEM, while when administered in DMSO the curcumin signal disappeared within 4 days. Importantly, the administration of a dose 22 times larger than that applied topically to animals after tumor surgery did not alter biochemical parameters. Due to the safety and efficacy of the formulation, we envisage it as ideal for topical application in cancer patients following surgery, to prevent tumor reincidence and metastasis. In addition, other routes of administration/protocols could also be proposed to treat/prevent malignant tumors in patients.

Topics: A549 Cells; Adenocarcinoma; Animals; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Drug Carriers; Emulsions; HEK293 Cells; Humans; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasm Metastasis; Neoplasms; Reactive Oxygen Species; Solvents

Natural polyphenols are organic chemicals which contain phenol units in their structures. They show antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Still, definitively demonstrating the human benefits of isolated polyphenolic compounds (alone or in combination) using modern scientific methodology has proved challenging. The most common discrepancy between experimental and clinical observations is the use of nonphysiologically relevant concentrations of polyphenols in mechanistic studies. Thus, it remains highly controversial how applicable underlying mechanisms are with bioavailable concentrations and biological half-life. The present Perspective analyses proposed antitumor mechanisms, in vivo reported antitumor effects, and possible mechanisms that may explain discrepancies between bioavailability and bioefficacy. Polyphenol metabolism and possible toxic side effects are also considered. Our main conclusion emphasizes that these natural molecules (and their chemical derivatives) indeed can be very useful, not only as cancer chemopreventive agents but also in oncotherapy.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Biological Availability; Drug Delivery Systems; Humans; Neoplasms; Phytochemicals; Polyphenols

Low water solubility, extensive metabolism, and drug resistance are the existing unavoidable disadvantages of the insoluble drug curcumin in biomedical applications. Herein, we employed d-α-tocopherol polyethylene glycol 1000 succinate (TPGS)-functionalized near-infrared (NIR)-triggered photothermal mesoporous nanocarriers with bamboo charcoal nanoparticles (TPGS-BCNPs) to load and deliver curcumin for improving its bioavailability. This system could considerably increase the accumulation of curcumin in cancer cells for enhanced curcumin bioavailability via simultaneously promoting the cellular internalization of the as-synthesized composite (TPGS-BCNPs@curcumin) by the size effect of NPs and considerably triggering controlled curcumin release from TPGS-BCNPs@curcumin by NIR stimulation and reducing efflux of curcumin by the P-glycoprotein (P-gp) inhibition of TPGS, so as to enhance the therapeutic effect of curcumin and realize a better chemo-photothermal synergetic therapy in vitro and in vivo. Besides cancer therapy, studies indicated that curcumin and some carbon materials could be used as radical scavengers that play an important role in the radioprotection of normal cells. Hence, we also investigated the free-radical-scavenging ability of the TPGS-BCNPs@curcumin composite in vitro to preliminarily evaluate its radioprotection ability for healthy tissues. Therefore, our work provides a multifunctional delivery system for curcumin bioavailability enhancement, chemo-photothermal synergetic therapy of cancer, and radioprotection of healthy tissues.

Topics: Biological Availability; Cell Line, Tumor; Charcoal; Curcumin; Humans; Nanoparticles; Neoplasms

Tumour-activation of prodrugs has the potential to improve the efficacy of anticancer agents while minimising systemic toxicity. Cobalt complexes are of interest in this respect as chaperones to deliver and release anticancer agents in the low oxygen, reducing environment of solid tumours. In addition to being able to release a cytotoxic ligand under the conditions of the tumour microenvironment, it is fundamental that the chaperone complex must also be able to penetrate through multiple cell layers to deliver the cytotoxin to all regions of the tumour. Herein, we report an investigation of the distribution and metabolism of two chaperone complexes of the anticancer agent curcumin within monolayer tumour cells and multicellular tumour spheroids. Using a combination of X-ray fluorescence microscopy, confocal fluorescence microscopy, and X-ray absorption spectroscopy, we demonstrate how the nature of the chaperone complex can profoundly influence the cellular uptake, distribution, and release mechanism of curcumin, providing key insights into the design of this class of prodrug.

Topics: Antineoplastic Agents; Cobalt; Coordination Complexes; Curcumin; Drug Delivery Systems; Humans; Ligands; Microscopy, Confocal; Neoplasms; Spectrometry, X-Ray Emission; Spheroids, Cellular; Tumor Cells, Cultured; Tumor Microenvironment

Most chemotherapeutic drugs commonly suffer from several shortcomings, including the lack of aqueous solubility, limited stability and adverse side effects. Although caging strategy has recently been employed as an effective approach to conceal and stabilize these drugs to achieve light-activated cancer therapy, it is plagued by the sophisticated drug modification process and deleterious solvent usage. In addition, using UV or Visible light to remove photocaged group is restricted to its limited tissue penetration ability in and phototoxicity. In this paper, by anchoring photochromic spiropyran on the mesoporous silica coated upconversion nanoparticles (UCNP-SP), we design a NIR-controlled cage mimicking system. Our results indicate that hydrophobic drug can be concealed inside the channels of the nanocarrier with high stability and "uncaged" via NIR irradiation-triggered hydrophobicity-hydrophilicity switch of the spiropyran molecules, finally inducing drug release and recovering their bioactivity. Moreover, under NIR illumination, the UV/Visible emissions from UCNP can also efficaciously initiate the generation of reactive oxygen species (ROS) by Curcumin, further improving the therapeutic efficiency. Both in vitro and in vivo experimental results validate that NIR irradiated nanosystem can produce remarkably enhanced antitumor efficiency.

Topics: Animals; Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Cell Survival; Curcumin; Drug Liberation; Hydrophobic and Hydrophilic Interactions; Indoles; Light; Luminescent Agents; Mice; Nanoparticles; Neoplasms; Nitro Compounds; Photosensitizing Agents; Reactive Oxygen Species; Silicon Dioxide

Primary Effusion Lymphoma (PEL) is an HHV-8-related non Hodgkin lymphoma localized in body cavities (as pleural, peritoneal and pericardial) presenting lymphomatous effusion that, until now, lack of an effective therapy. Curcumin was reported to display pro-apoptotic effect via the inhibition of the JAK/STAT pathway, that is overexpressed in PEL cells, as consequence of virus infection. The administration of curcumin is severely restricted by its physicochemical properties, mainly its low solubility in biological fluid and consequently low bioavailability. Encapsulation into biocompatible and biodegradable PLGA nanoparticles (NPs) could be a strategy to overcome biological limits of curcumin, offering a valuable step forward for its clinical application. In this study we described single-emulsion process for curcumin loading into NPs (encapsulation efficiency about 35%). We applied a post-formulation strategy (NHS/EDC reaction) to decorate the surface of the curcumin-loaded NPs with quantum dots (QDs) as imaging agents (QDs-NPs-Cur, 24pmol of QDs per 100mg of NPs) obtaining tools useful for possible application in theranostic approach. Bifunctionalized NPs were tested in vitro on two PEL's cell line (BCBL-1 and HBL-6). The efficacy of the treatment was evaluated by cytofluorimetric assay by measuring both cell viability and cell density. We found that the NPs significantly improve the cellular effect of curcumin (respect to free drug). Moreover, by means of confocal microscopy, both the localization of bifunctional NPs and of the released drug were easily detectable. Thus, we conclude that the delivery of curcumin using bifunctional traceable NPs is a promising future approach for the diagnosis and the treatment of PEL.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Drug Liberation; Humans; Lactic Acid; Neoplasms; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Quantum Dots

Peptide nanostructure has been widely explored for drug-delivery systems in recent studies. Peptides possess comparatively lower cytotoxicity and are more efficient than polymeric carriers. Here, we propose a peptide nanorod system, composed of an amphiphilic oligo-peptide RH

Topics: Animals; Antineoplastic Agents; Apoptosis; Biocompatible Materials; Cell Line, Tumor; Curcumin; Drug Carriers; HeLa Cells; Hemolysis; Humans; Nanotubes; Neoplasms; Oligopeptides; Phenylalanine; Surface-Active Agents; Zebrafish

Curcumin is an effective and safe anticancer agent, and also known to induce vasodilation, but its hydrophobicity limits its clinical application. In this study, a simple emulsion method was developed to prepare biodegradable poly (ethylene glycol)-poly (lactic acid) (PEG-PLA) nanospheres to encapsulate curcumin to improve its solubility and stability. The nanoparticle size was around 150 nm with a narrow size distribution. Fluorescence microscopy showed that curcumin encapsulated PEG-PLA nanospheres were taken up rapidly by Hela and MDA-MB-231 cancer cells. This novel nanoparticulate carrier may improve the bioavailability of curcumin without affecting its anticancer properties.

Topics: Curcumin; Drug Delivery Systems; HeLa Cells; Humans; Nanospheres; Neoplasms; Polyesters; Polyethylene Glycols

This study aimed to investigate the particle size effect on bioactivity, cellular internalization and bioavailability of curcumin (CUR) nanosuspension (CUR-NS). CUR-NSs of different particle sizes were prepared by two different anti-solvent precipitation methods. CUR-NS with the smallest size showed similar in vitro anticancer activity and bioavailability to the CUR solution, whereas nanosuspensions of larger particle sizes displayed higher in vitro cellular internalization and cytotoxicity, as well as higher in vivo AUC and slower clearance rate after i.v. administration in rats. CUR solution and different sized CUR-NSs reached the highest concentrations in the lung, followed by liver and spleen while the lowest concentration was observed in the brain after i.v. administration in mice. Specifically, CUR-NS of 70nm accumulated more in the brain, whereas CUR-NS of 200nm accrued more in liver and spleen. CUR-NS of 20nm displayed no significant biodistribution difference compared with CUR solution in all tissues.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Male; Mice, Inbred C57BL; Nanoparticles; Neoplasms; Particle Size; Rats, Sprague-Dawley; Tissue Distribution

Curcumin (CUR) is a promising drug candidate based on its broad bioactivities and good antitumor effect, but the application of CUR is potentially restricted because of its poor solubility and bioavailability.. This study aims at developing a simple and effective drug delivery system for CUR to enhance its solubility and bioavailability thus to improve its antitumor efficacy.. Curcumin nanosuspensions (CUR-NSps) were prepared by precipitation-ultrasonication method using mPEG2000-DSPE and soybean lecithin as a combined stabilizer.. CUR-NSps with a high drug payload of 67.07% were successfully prepared. The resultant CUR-NSps had a mean particle size of 186.33 ± 2.73 nm with a zeta potential of -19.00 ± 1.31 mV. In vitro cytotoxicity assay showed that CUR-NSps exhibited enhanced cytotoxicity compared to CUR solution. The pharmacokinetics results demonstrated that CUR-NSps exhibited a significantly greater AUC. These results suggest that CUR-NSps might represent a promising drug formulation for intravenous administration of CUR for the treatment of cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Area Under Curve; Biological Availability; Calorimetry, Differential Scanning; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Stability; Glycine max; HeLa Cells; Hep G2 Cells; Humans; Inhibitory Concentration 50; Injections, Intravenous; Lecithins; Male; Mice, Inbred ICR; Nanomedicine; Nanoparticles; Neoplasms; Particle Size; Phosphatidylethanolamines; Polyethylene Glycols; Rats, Sprague-Dawley; Solubility; Surface Properties; Technology, Pharmaceutical; Tissue Distribution; Tumor Burden; X-Ray Diffraction; Xenograft Model Antitumor Assays

Topics: Coated Materials, Biocompatible; Curcumin; Cytotoxins; Diarylheptanoids; Drug Carriers; Hep G2 Cells; Humans; Lactic Acid; Nanoparticles; Neoplasms; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

Curcumin (Cur), a phenolic anti-oxidant compound obtained from Curcuma longa plant, possesses a variety of therapeutic properties. However, it is suffered from its low water solubility and low bioavailability property, which seriously restricts its clinical application. In this study, we developed a glycyrrhetinic acid (GA) modified curcumin supramolecular pro-gelator (GA-Cur) and a control compound Nap-Cur by replacing GA with the naphthylacetic acid (Nap). Both compounds showed good water solubility and could form supramolecular gels by disulfide bond reduction triggered by glutathione (GSH) in vitro. Both formed gels could sustainedly release Cur in buffer solutions. We also investigated the cytotoxicity of pro-gelators to HepG2 cells by a MTT assay and determined the cellular uptake behaviours of them by fluorescence microscopy and LC-MS. Due to the over expression of GA receptor in liver cancer cells, our pro-gelator of GA-Cur showed an enhanced cellular uptake and better inhibition capacity to liver tumor cells than Nap-Cur. Therefore, the GA-Cur could significantly inhibit HepG2 cell growth. Our study provides a novel nanomaterial for liver tumor chemotherapy.

Topics: Curcumin; Drug Delivery Systems; Glycyrrhetinic Acid; Hep G2 Cells; Humans; Hydrogels; Neoplasms

Germacrone is one of the major bioactive components in the Curcuma zedoaria oil product, which is extracted from Curcuma zedoaria Roscoe, known as zedoary. The present study designed some novel germacrone derivatives based on combination principles, synthesized these compounds, and investigated their inhibitions on Bel-7402, HepG2, A549 and HeLa cells. Meanwhile, the study evaluated inhibitions of these derivatives on c-Met kinase, which has been detected in a number of cancers. The results suggested that the majority of the compounds showed stronger inhibitory effect on cancers and c-Met kinase than germacrone. Furthermore, our docking experiments analyzed the results and explained the molecular mechanism. Molecular dynamics simulations were then applied to perform further evaluation of the binding stabilities between compounds and their receptors.

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcuma; HeLa Cells; Hep G2 Cells; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Plant Extracts; Proto-Oncogene Proteins c-met; Sesquiterpenes, Germacrane

Thirty (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones, featuring a central linear trienone linker and two identical nitrogen-containing heteroaromatic rings, were designed and synthesized as curcumin-based anticancer agents on the basis of their structural similarity to the enol-tautomer of curcumin, in addition to taking advantage of the possibly enhanced pharmacokinetic profiles contributed by the basic nitrogen-containing heteroaromatic rings. Their cytotoxicity and antiproliferative activity were evaluated towards both androgen-dependent and androgen-independent prostate cancer cell lines, as well as HeLa human cervical cancer cells. Among them, the ten most potent analogues are 5- to 36-fold more potent than curcumin in inhibiting cancer cell proliferation. The acquired structure-activity relationship data indicate (i) that (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones represent a potential scaffold for development of curcumin-based agents with substantially improved cytotoxicity and anti-proliferative effect; and (ii) 1-alkyl-1H-imidazol-2-yl and 1-alkyl-1H-benzo[d]imidazole-2-yl serve as optimal heteroaromatic rings for increased in vitro potency of this scaffold. Two of most potent compounds displayed no apparent cytotoxicity toward MCF-10A normal mammary epithelial cells at 1 μM concentration. Treatment of PC-3 prostate cancer cells with the most potent compound led to appreciable cell cycle arrest at a G1/G0 phase and cell apoptosis induction.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Design; Drug Screening Assays, Antitumor; Female; HeLa Cells; Humans; Male; Neoplasms; Prostatic Neoplasms; Structure-Activity Relationship; Trientine; Uterine Cervical Neoplasms

Curcumin, a natural compound extracted from the rhizomes of Curcuma Longa, is known to display pronounced anticancer activity but lacks good pharmacokinetic properties. In that respect, augmenting the water solubility by structural modification of the curcumin scaffold may result in improved bioavailability and pharmacokinetics. A possible scaffold modification, especially important for this study, concerns the imination of the labile β-diketone moiety in curcumin. Previous work revealed that novel N-alkyl β-enaminones showed a similar water solubility as compared to curcumin, accompanied by a stronger anti-proliferative activity. To extend this β-enaminone compound library, new analogues were prepared in this work using more polar amines (hydroxyalkylamines and methoxyalkylamines instead of alkylamines) with the main purpose to improve the water solubility without compromising the biological activity of the resulting curcuminoids. Compared to their respective parent compounds, i.e. curcumin and bisdemethoxycurcumin, the bisdemethoxycurcumin N-(hydroxy/methoxy)alkyl enaminone analogues showed better water solubility, antioxidant and anti-proliferative activities. In addition, the curcumin enaminones displayed activities comparable to or better than curcumin, and the water solubility was improved significantly. The constructed new analogues may thus be of interest for further exploration concerning their impact on oxidative stress related diseases such as cancer.

Topics: Amines; Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Cell Proliferation; Curcuma; Curcumin; Diarylheptanoids; Humans; Neoplasms; Solubility; Water

Six acetophenone derivatives, acronyculatins I (1), J (2), K (3), L (4), N (5), and O (6), were recently isolated from Acronychia trifoliolata, and the structure of the known acronyculatin B (7) was revised. Because of the limited quantities of isolated products as well as their structure similarity, racemic acronyculatins I-L, N, O, and B (1-7) were synthesized to confirm their structures and to obtain sufficient material for biological evaluation. Trihydroxyacetophenone was converted to the target compounds by various sequences of hydroxy group protection, allylation or prenylation, and epoxidation followed by cyclization. C-Prenylations were carried out by direct addition of a prenyl group or through 1,3- or 3,3-sigmatropic rearrangement. The synthesized racemic compounds were evaluated in an anti-tumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. All tested compounds significantly inhibited EBV-EA activation. Especially, racemic acronyculatin I (1) displayed the most potent inhibitory effects, with an IC

Topics: Acetophenones; Antigens, Viral; Carcinogens; Herpesvirus 4, Human; Humans; Molecular Structure; Neoplasms; Rutaceae; Stereoisomerism; Structure-Activity Relationship; Tetradecanoylphorbol Acetate

The objective of this study is to develop a new-type biodegradable, biocompatible curcumin-loaded nanoerythrosomes (Cur-RBC-NPs) by means of the sonication method. The size of Cur-RBC-NPs was optimized by varying drug loading parameters. The morphology, size distribution, stability, in vitro release pattern, cellular uptake of nanoparticles and in vitro anti-tumor effects were evaluated, respectively. The results showed the prepared Cur-RBC-NPs were nearly uniform spheres, with an average diameter of (245.7 ± 1.3) nm. Encapsulation efficiency (EE) and load efficiency (LE) of Cur-RBC-NPs were 50.65% ± 1.36% and 6.27% ± 0.29%. And the nanoparticles had a good sustained release property. According to the in vitro experiment, Cur-RBC-NPs were effectively taken in by tumor cells, and exhibited a significant anti-tumor effect. In conclusion, the method for preparing Cur-RBC-NPs is convenient, with a good sustained release behavior and anti-tumor efficacy, and so expected to be a new-type nano-drug delivery system in clinical practice.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Carriers; Humans; Nanoparticles; Neoplasms; Particle Size

Curcumin-based structural modification for developing more effective curcumin analogues has been drawning increasing attention. As alternative approach, using LC/MS guided purification, we previously obtained a series of novel natural terpene-conjugated curcuminoids from turmeric, and some of them exhibited even more potent anti-cancer activity against multiple types of cancer cells than curcumin. The purpose of this follow-up study was designed to decipher the mechanisms involved in anti-cancer activity of these novel curcumin analogues. Apoptosis was evaluated using sub-G1 analysis by flow cytometry and Cell Death ELISA Kit. Changes of protein expression were analyzed by western blotting. RNA interference was employed to inhibit expression of specific protein. We found that bisabolocurcumin ether (T1) and demethoxybisabolocurcumin ether (T2) were able to trigger much stronger apoptosis induction in multiple types of cancer cells than curcumin, which was attributed to persistent and stronger ROS generation. ROS induction by T1 resulted in activation of p38/H2AX axis and p53. Inhibition of p38/H2AX led to a significant reduction of apoptosis, whereas inactivation of p53 caused a dramatically enhanced H2AX phosphorylation and apoptosis induction, suggesting activation of p38/H2AX contributed to apoptosis induction by T1, whereas p53 activation protected novel curcumins-induced apoptosis via suppression of H2AX activation. Our findings provide mechanistic support for the potential use of terpene-conjugated curcuminoids as a novel class of cancer chemopreventive agents. © 2015 Wiley Periodicals, Inc.

Topics: Antineoplastic Agents; Apoptosis; Breast; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Histones; Humans; Neoplasms; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Terpenes

In this study, curcumin and/or docosahexaenoic acid (DHA) were encapsulated in Thai silk fibroin/gelatin (SF/G) sponges, prepared at different blending ratios, aimed to be applied as a controlled release system for localized cancer therapy. The SF/G sponges were fabricated by freeze-drying and glutaraldehyde cross-linking techniques. Physicochemical properties of the SF/G sponges were characterized. Then, curcumin and/or DHA were loaded in the sponges by physical adsorption. The encapsulation efficiency and the in vitro release of curcumin and/or DHA from the sponges were evaluated. SF/G sponges could encapsulate curcumin and/or DHA at high encapsulation efficiency. The highly cross-linked and slowly degrading SF/G (50/50) sponge released curcumin and/or DHA at the slowest rate. The in vitro cytotoxicity of the sponges against noncancer cells (L929 mouse fibroblast) and anticancer of curcumin and/or DHA released from the sponges against cervical cancer cells (CaSki) were tested. All sponges were not toxic to L929 mouse fibroblast. The mixed curcumin–DHA at the ratio of 1:4 had the highest inhibiting effect on the growth of CaSki, comparing with the release of curcumin or DHA alone. SF/G sponges could be a potential carrier for dual release of curcumin and DHA for anticancer effect.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biodegradable Plastics; Cell Line, Tumor; Cell Survival; Cross-Linking Reagents; Curcumin; Delayed-Action Preparations; Docosahexaenoic Acids; Fibroblasts; Fibroins; Freeze Drying; Gelatin; Glutaral; Mice; Neoplasms; Porosity; Silk; Thailand

A better understanding of how curcumin influences cancer cell biology could help devise new strategies to enhance its antitumor effect. Many curcumin actions are proposed to occur by targeting mitochondrial function, among which glucose metabolism and reactive oxygen species (ROS) production are pivotal. However, little is known of how curcumin influences cancer cell glucose metabolism. We thus evaluated the effect of curcumin on cancer cell glucose metabolism and mitochondrial function, and further investigated whether these responses could be modified to enhance the anticancer potency of the compound. MCF-7 breast cancer cells treated with curcumin were measured for 18F-fluorodeoxyglucose (18F‑FDG) uptake, lactate production, hexokinase activity, oxygen consumption rate (OCR), ROS production and mitochondrial membrane potential (MMP). Activation of signaling pathways was evaluated by western blots, and cell survival was assessed with sulforhodamine B assays. Curcumin stimulated a 3.6-fold increase of 18F-FDG uptake in MCF-7 cells, along with augmented hexokinase activity and lactate efflux. This was accompanied by significantly suppressed cellular OCR, consistent with a metabolic shift to glycolytic flux. Inhibiting this metabolic response with 2-deoxyglucose (2-DG) blocked curcumin-induced mTOR activation and resulted in a greater anti-proliferative effect. Curcumin-induced MMP depolarization led to reduced ROS production, which may hinder the anticancer effect of the compound. Intracellular ROS was completely restored by adding Cu2+, which can bind and modify the curcumin's physico-chemical property, and this resulted in a marked potentiation of its anti-proliferative effect. Thus, curcumin suppresses cancer cell MMP and ROS generation, and this response is accompanied by stimulated 18F-FDG uptake via shifting of metabolism from mitochondrial respiration to glycolytic flux. These mitochondrial and metabolic responses may provide potential targets that can help enhance the anticancer action of curcumin.

Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Curcumin; Fluorodeoxyglucose F18; Humans; Membrane Potential, Mitochondrial; Mitochondria; Neoplasms; Positron-Emission Tomography; Radiopharmaceuticals; Reactive Oxygen Species; Signal Transduction

Ample attention has focused on cancer drug delivery via prodrug nanoparticles due to their high drug loading property and comparatively lower side effects. In this study, we designed a PEG-DOX-Cur prodrug nanoparticle for simultaneous delivery of doxorubicin (DOX) and curcumin (Cur) as a combination therapy to treat cancer. DOX was conjugated to PEG by Schiff's base reaction. The obtained prodrug conjugate could self-assemble in water at pH 7.4 into nanoparticles (PEG-DOX NPs) and encapsulate Cur into the core through hydrophobic interaction (PEG-DOX-Cur NPs). When the PEG-DOX-Cur NPs are internalized by tumor cells, the Schiff's base linker between PEG and DOX would break in the acidic environment that is often observed in tumors, causing disassembling of the PEG-DOX-Cur NPs and releasing both DOX and Cur into the nuclei and cytoplasma of the tumor cells, respectively. Compared with free DOX, free Cur, free DOX-Cur combination, or PEG-DOX NPs, PEG-DOX-Cur NPs exhibited higher anti-tumor activity in vitro. In addition, the PEG-DOX-Cur NPs also showed prolonged blood circulation time, elevated local drug accumulation and increased tumor penetration. Enhanced anti-tumor activity was also observed from the PEG-DOX-Cur-treated animals, demonstrating better tumor inhibitory property of the NPs. Thus, the PEG-DOX-Cur prodrug nanoparticle system provides a simple yet efficient approach of drug delivery for chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Delivery Systems; Humans; Hydrogen-Ion Concentration; Nanoparticles; Neoplasms; Prodrugs

Intracellular drug delivery by nanoparticles is often hampered by their endosomal entrapment followed by their degradation in the lysosomal compartment and/or exocytosis. Here, we show that internalization and endosomal escape of cargoes in a cationized natural nanocarrier, high-density lipoprotein (HDL), can be controlled in a pH-dependent manner through stable complexation with a membranolytic anionic block polymer. A genetically and chemically cationized form of HDL (catHDL) is prepared for the first time by both genetic fusion with YGRKKRRQRRR peptide and incorporation of 1,2-dioleoyloxy-3-(trimethylammonium)propane. Upon addition of poly(ethylene glycol)-block-poly(propyl methacrylate-co-methacrylic acid) (PA), catHDL yields inhibition of internalization at neutral pH and its subsequent recovery at mildly acidic pH. catHDL forms a stable discoidal-shape complex with PA (catHDL/PA) (ca. 50 nm in diameter), even in the presence of serum. Significant enhancement of endosomal escape of a catHDL component is observed after a 1-h treatment of human cancer cells with catHDL/PA. Doxorubicin and curcumin, fluorescent anti-cancer drugs, encapsulated into catHDL/PA are also translocated outside of endosomes, compared with that into catHDL, and their cytotoxicities are enhanced inside the cells. These data suggest that catHDL/PA may have a potential benefit to improve the cellular delivery and endosomal escape of therapeutics under mildly acidic conditions such as in tumor tissues.

Topics: Amino Acid Sequence; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Delayed-Action Preparations; Doxorubicin; Endosomes; Fatty Acids, Monounsaturated; Humans; Hydrogen-Ion Concentration; Lipoproteins, HDL; Neoplasms; Polyethylene Glycols; Polymethacrylic Acids; Quaternary Ammonium Compounds; Recombinant Fusion Proteins

We have synthesized a curcumin derivative, 4-{5-(4-hydroxy-3-methoxy-phenyl)-2-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-3-oxo-penta-1,4-dienyl}-piperidine-1-carboxylic acid tert-butyl ester (C1) that displays much stronger antiproliferative activity against various types of cancer cells including multidrug resistance cells than curcumin. C1 depolymerized both interphase and mitotic microtubules in MCF-7 cells and also inhibited the reassembly of microtubules in these cells. C1 inhibited the polymerization of purified tubulin, disrupted the lattice structure of microtubules and suppressed their GTPase activity in vitro The compound bound to tubulin with a dissociation constant of 2.8±1 μM and perturbed the secondary structures of tubulin. Further, C1 treatment reduced the expression of Bcl2, increased the expression of Bax and down regulated the level of a key regulator of p53, murine double minute 2 (Mdm2) (S166), in MCF-7 cells. C1 appeared to induce p53 mediated apoptosis in MCF-7 cells. Interestingly, C1 showed more stability in aqueous buffer than curcumin. The results together showed that C1 perturbed microtubule network and inhibited cancer cells proliferation more efficiently than curcumin. The strong antiproliferative activity and improved stability of C1 indicated that the compound may have a potential as an anticancer agent.

Topics: Animals; Antineoplastic Agents; Curcumin; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; MCF-7 Cells; Mice; Microtubules; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-mdm2; Tubulin; Tumor Suppressor Protein p53

Many hydrophobic drugs encounter severe bioavailability issues owing to their low aqueous solubility and limited cellular uptake. We have designed a series of amphiphilic polyaspartamide polyelectrolytes (PEs) that solubilize such hydrophobic drugs in aqueous medium and enhance their cellular uptake. These PEs were synthesized through controlled (∼20 mol %) derivatization of polysuccinimide (PSI) precursor polymer with hydrophobic amines (of varying alkyl chain lengths, viz. hexyl, octyl, dodecyl, and oleyl), while the remaining succinimide residues of PSI were opened using a protonable and hydrophilic amine, 2-(2-amino-ethyl amino) ethanol (AE). Curcumin (Cur) was employed as a representative hydrophobic drug to explore the drug-delivery potential of the resulting PEs. Unprecedented enhancement in the aqueous solubility of Cur was achieved by employing these PEs through a rather simple protocol. In the case of PEs containing oleyl/dodecyl residues, up to >65000× increment in the solubility of Cur in aqueous medium could be achieved without requiring any organic solvent at all. The resulting suspensions were physically and chemically stable for at least 2 weeks. Stable nanosized polyelectrolyte complexes (PECs) with average hydrodynamic diameters (DH) of 150-170 nm (without Cur) and 220-270 nm (after Cur loading) were obtained by using submolar sodium polyaspartate (SPA) counter polyelectrolyte. The zeta potential of these PECs ranged from +36 to +43 mV. The PEC-formation significantly improved the cytocompatibility of the PEs while affording reconstitutable nanoformulations having up to 40 wt % drug-loading. The Cur-loaded PECs were readily internalized by mammalian cells (HEK-293T, MDA-MB-231, and U2OS), majorly through clathrin-mediated endocytosis (CME). Cellular uptake of Cur was directly correlated with the length of the alkyl chain present in the PECs. Further, the PECs significantly improved nuclear transport of Cur in cancer cells, resulting in their death by apoptosis. Noncancerous cells were completely unaffected under this treatment.

Topics: Antineoplastic Agents; Cell Membrane Permeability; Cell Survival; Curcumin; Drug Carriers; Drug Delivery Systems; Hemolysis; Humans; Hydrophobic and Hydrophilic Interactions; Nanocomposites; Neoplasms; Polyelectrolytes; Solubility

A novel mechanism of DNA damage induced by photosensitized curcumin (Cur) was explored using laser flash photolysis, pulse radiolysis and gel electrophoresis. Cur neutral radical (Cur) was confirmed as an identical product in photo-sensitization of Cur by laser flash photolysis and pulse radiolysis. A series of reaction rate constants between Cur and nucleic acid bases/nucleotides were determined by pulse radiolysis. Gel electrophoresis was carried out to investigate damage induced by photosensitized Cur to biologically active DNA. The results indicate that the damage to DNA may be caused by Cur produced from the photosensitization of Cur.

Topics: Antineoplastic Agents; Curcumin; DNA Damage; Free Radicals; Humans; Neoplasms; Photolysis; Photosensitizing Agents; Pulse Radiolysis

As with human beings, dogs suffer from the consequences of cancer. We investigated the potential of a formulation comprised of resveratrol, ellagic acid, genistein, curcumin and quercetin to modulate biomarkers indicative of disease prevention. Dog biscuits were evaluated for palatability and ability to deliver the chemopreventive agents. The extent of endogenous DNA damage in peripheral blood lymphocytes from dogs given the dietary supplement or placebo showed no change. However, H2O2-inducible DNA damage was significantly decreased after consumption of the supplement. The expression of 11 of 84 genes related to oxidative stress was altered. Hematological parameters remained in the reference range. The concept of chemoprevention for the explicit benefit of the canine is compelling since dogs are an important part of our culture. Our results establish a proof-of-principle and provide a framework for improving the health and well-being of "man's best friend".

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemoprevention; Curcumin; DNA Damage; Dog Diseases; Dogs; Ellagic Acid; Food, Formulated; Genistein; Hydrogen Peroxide; Neoplasms; Oxidative Stress; Quercetin; Resveratrol; Stilbenes; Treatment Outcome

We report herein an in vitro anticancer evaluation of a series of seven curcumin analogues (3a-g). The National Cancer Institute (NCI US) Protocol was followed and all the compounds were evaluated for their anticancer activity on nine different panels (leukemia, non small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer) represented by 60 NCI human cancer cell lines. All the compounds showed significant anticancer activity in one dose assay (drug concentration 10 μM) and hence were evaluated further in five dose assays (0.01, 0.1, 1, 10 and 100 μM) and three dose related parameters GI50, TGI and LC50 were calculated for each (3a-g) in micro molar drug concentrations (μM). The compound 3d (NSC 757927) showed maximum mean percent growth inhibition (PGI) of 112.2%, while compound 3g (NSC 763374) showed less mean PGI of 40.1% in the one dose assay. The maximum anticancer activity was observed with the SR (leukemia) cell line with a GI50 of 0.03 μM. The calculated average sensitivity of all cell lines of a particular subpanel toward the test agent showed that all the curcumin analogues showed maximum activity on leukemia cell lines with GI50 values between 0.23 and 2.67 μM.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Flow Cytometry; Humans; Neoplasms; Tumor Cells, Cultured

A glycyrrhetinic acid-modified chitosan-cystamine-poly(ε-caprolactone) copolymer (PCL-SS-CTS-GA) micelle was developed for the co-delivery of doxorubicin (DOX) and curcumin (CCM) to hepatoma cells. Glycyrrhetinic acid (GA) was used as a targeting unit to ensure specific delivery. Co-encapsulation of DOX and CCM was facilitated by the incorporation of poly(ε-caprolactone) (PCL) groups. The highest drug loading content was 19.8% and 8.9% (w/w) for DOX and CCM, respectively. The PCL-SS-CTS-GA micelle presented a spherical or ellipsoidal geometry with a mean diameter of approximately 110nm. The surface charge of the micelle changed from negative to positive, when the pH value of the solution decreased from 7.4 to 6.8. Meanwhile, it also exhibited a character of redox-responsive drug release and GA/pH-mediated endocytosis in vitro. In simulated body fluid with 10mM glutathione, the release rate in 12h was 80.6% and 67.2% for DOX and CCM, respectively. The cell uptake of micelles was significantly higher at pH 6.8 than pH 7.4. The combined administration of DOX and CCM was facilitated by PCL-SS-CTS-GA micelle. Results showed that there was strong synergic effect between the two drugs. The PCL-SS-CTS-GA micelle might turn into a promising and effective carrier for improved combination chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Chitosan; Curcumin; Cystamine; Doxorubicin; Drug Liberation; Endocytosis; Flow Cytometry; Glycyrrhetinic Acid; Hep G2 Cells; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen-Ion Concentration; Intracellular Space; Micelles; Neoplasms; Polyesters; Spectroscopy, Fourier Transform Infrared

Poly(lactide-co-glycolide)-cholesterol (PLGA-C)-based nanoparticles (NPs) were developed for the tumor-targeted delivery of curcumin (CUR). PLGA-C/CUR NPs with ∼200nm mean diameter, narrow size distribution, and neutral zeta potential were fabricated by a modified emulsification-solvent evaporation method. The existence of cholesterol moiety in PLGA-C copolymer was confirmed by proton nuclear magnetic resonance ((1)H NMR) analysis. In vitro stability of developed NPs after 24h incubation was confirmed in phosphate buffered saline (PBS) and serum media. Sustained (∼6days) and pH-responsive drug release profiles from PLGA-C NPs were presented. Blank PLGA and PLGA-C NPs exhibited a negligible cytotoxicity in Hep-2 (human laryngeal carcinoma) cells in the tested concentration range. According to the results of flow cytometry and confocal laser scanning microscopy (CLSM) studies, PLGA-C NPs presented an improved cellular accumulation efficiency, compared to PLGA NPs, in Hep-2 cells. Enhanced in vivo tumor targetability of PLGA-C NPs, compared to PLGA NPs, in Hep-2 tumor-xenografted mouse model was also verified by a real-time near-infrared fluorescence (NIRF) imaging study. Developed PLGA-C NPs may be a candidate of efficient and biocompatible nanosystems for tumor-targeted drug delivery and cancer imaging.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cholesterol; Curcumin; Drug Delivery Systems; Humans; Mice; Nanoparticles; Neoplasms; Particle Size; Polyglactin 910

In recent years, gold nanoparticles (AuNPs) have received immense interest in various biomedical applications including drug delivery, photothermal ablation of cancer and imaging agent for cancer diagnosis. However, the synthesis of AuNPs poses challenges due to the poor reproducibility and stability of the colloidal system. In the present work, we developed a one step, facile procedure for the synthesis of AuNPs from hydrogen tetrachloroaurate (III) hydrate (HAuCl4. 3H2O) by using ascorbic acid and xanthan gum (XG) as reducing agent and stabilizer, respectively. The effect of concentrations of HAuCl4, 3H2O, ascorbic acid and methoxy polyethylene glycol-thiol (mPEG800-SH) were optimized and it was observed that stable AuNPs were formed at concentrations of 0.25 mM, 50 μM and 1 mM for HAuCl4.3H2O, ascorbic acid, and mPEG800-SH, respectively. The XG stabilized, deep red wine colored AuNPs (XG-AuNPs) were obtained by drop-wise addition of aqueous solution of ascorbic acid (50 mM) and XG (1.5 mg ml(-1)). Synthesized XG-AuNPs showed λmax at 540 nm and a mean hydrodynamic diameter of 80 ± 3 nm. PEGylation was performed with mPEG800-SH to obtain PEGylated XG-AuNPs (PX-AuNPs) and confirmed by Ellman's assay. No significant shift observed in λmax and hydrodynamic diameter between XG-AuNPs and PX-AuNPs. Colloidal stability of PX-AuNPs was studied in normal saline, buffers within a pH range of 1.2-7.4, DMEM complete medium and in normal storage condition at 4 ˚C. Further, water soluble curcumin was prepared using PVP-K30 as solid dispersion and loaded on to PX-AuNPs (CPX-AuNPs), and evaluated for cellular uptake and cytotoxicity in Murine melanoma (B16F10) cells. Time and concentration dependent studies using CPX-AuNPs showed efficient uptake and decreased cell viability compared to free curcumin.

Topics: Animals; Curcumin; Gold; Metal Nanoparticles; Mice; Neoplasms; Polysaccharides, Bacterial; Reproducibility of Results

Curcumin, a natural polyphenol exhibits chemopreventive and chemotherapeutic activities towards cancer. In order to improve the bioavailability and therapeutic efficacy, curcumin is encapsulated in alginate aldehyde-gelatin (Alg Ald-Gel) nanogels. Alginate aldehyde-gelatin nanogels are prepared by inverse miniemulsion technique. Physicochemical properties of the curcumin loaded nanogels are evaluated by, Dynamic light scattering (DLS), NMR spectroscopy and Scanning electron microscopy (SEM). Curcumin loaded nanogels show hydrodynamic diameter of 431±8nm and a zeta potential of -36±4mV. The prepared nanogels exhibit an encapsulation efficiency of 72±2%. In vitro drug release studies show a controlled release of curcumin from nanogels over a period of 48h. Hemocompatibility and cytocompatibility of the nanogels are evaluated. Bare nanogels are cytocompatible and curcumin loaded nanogels induce anticancer activity towards MCF-7 cells. In vitro cellular uptake of the curcumin loaded nanogels using confocal laser scanning microscopy (CLSM) confirms the uptake of nanogels in MCF-7 cells. Hence, the developed nanogel system can be a suitable candidate for curcumin delivery to cancer cells.

Topics: Alginates; Curcumin; Delayed-Action Preparations; Gels; Humans; MCF-7 Cells; Nanoparticles; Neoplasms

NF-κB is strongly associated with poor prognosis of different cancer types and an important factor responsible for the malignant phenotype of glioblastoma. Overcoming chemotherapy-induced resistance caused by activation of PI3K/Akt and NF-κB pathways is crucial for successful glioblastoma therapy. We developed an all-in-one nanomedicine formulation for co-delivery of a chemotherapeutic agent (topoisomerase II inhibitor, doxorubicin) and a multidrug resistance modulator (NF-κB inhibitor, curcumin) for treatment of glioblastoma due to their synergism. Both agents were incorporated into PEG-PE-based polymeric micelles. The glucose transporter-1 (GLUT1) is overexpressed in many tumors including glioblastoma. The micellar system was decorated with GLUT1 antibody single chain fragment variable (scFv) as the ligand to promote blood brain barrier transport and glioblastoma targeting. The combination treatment was synergistic (combination index, CI of 0.73) against U87MG glioblastoma cells. This synergism was improved by micellar encapsulation (CI: 0.63) and further so with GLUT1 targeting (CI: 0.46). Compared to non-targeted micelles, GLUT1 scFv surface modification increased the association of micelles (>20%, P<0.01) and the nuclear localization of doxorubicin (∼3-fold) in U87MGcells, which also translated into enhanced cytotoxicity. The increased caspase 3/7 activation by targeted micelles indicates successful apoptosis enhancement by combinatory treatment. Moreover, GLUT1 targeted micelles resulted in deeper penetration into the 3D spheroid model. The increased efficacy of combination nanoformulations on the spheroids compared to a single agent loaded, or to non-targeted formulations, reinforces the rationale for selection of this combination and successful utilization of GLUT1 scFv as a targeting agent for glioblastoma treatment.

Topics: Antineoplastic Agents; Biotinylation; Blood-Brain Barrier; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Flow Cytometry; Glioblastoma; Glucose Transporter Type 1; Humans; Ligands; Micelles; Nanomedicine; Neoplasms; NF-kappa B; Phenotype; Polymers; Prognosis; Single-Chain Antibodies; Spheroids, Cellular

Curcumin has shown promise as a safe and specific anticancer agent. The COP9 signalosome (CSN) component CSN5, a known specific target for curcumin, can control p53 stability by increasing its degradation through ubiquitin system. But the correlation of CSN5-controlled p53 to anticancer therapeutic effect of curcumin is currently unknown. Here we showed that CSN5-controlled p53 was transcriptional inactive and responsible for autophagy in human normal BJ cells and cancer HepG2 cells under curcumin treatment. Of note, CSN5-initiated cellular autophagy by curcumin treatment was abolished in p53-null HCT116p53-/- cancer cells, which could be rescued by reconstitution with wild-type p53 or transcription inactive p53 mutant p53R273H. Furthermore, CSN5-controlled p53 conferred a pro-survival autophagy in diverse cancer cells response to curcumin. Genetic p53 deletion, as well as autophagy pharmacological inhibition by chloroquine, significantly enhanced the therapeutic effect of curcumin on cancer cells in vitro and in vivo, but not normal cells. This study identifies a novel CSN5-controlled p53 in autophagy of human cells. The p53 expression state is a useful biomarker for predicting the anticancer therapeutic effect of curcumin. Therefore, the pharmacologic autophagy manipulation may benefit the ongoing anticancer clinical trials of curcumin.

Topics: Antineoplastic Agents; Autophagy; Cell Survival; COP9 Signalosome Complex; Curcumin; HeLa Cells; Hep G2 Cells; Humans; Intracellular Signaling Peptides and Proteins; Neoplasms; Peptide Hydrolases; RNA, Small Interfering; Transcription, Genetic; Tumor Suppressor Protein p53

Topics: Antineoplastic Agents; Curcumin; Humans; Inflammation; Neoplasms

Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.

Topics: Animals; B7-H1 Antigen; Cell Line, Tumor; COP9 Signalosome Complex; Curcumin; Female; Humans; Intracellular Signaling Peptides and Proteins; Mice; Neoplasm Transplantation; Neoplasms; NF-kappa B; Peptide Hydrolases; Protein Stability; Tumor Necrosis Factor-alpha; Ubiquitination

The authors assessed the use of herbal medicine by Middle Eastern patients with cancer, as reported by their oncology health care professionals (HCPs). Herbal products identified by the study HCPs were evaluated for potential negative effects.. Oncology HCPs from 16 Middle Eastern countries received a 17-item questionnaire asking them to list 5 herbal products in use by their patients with cancer. A literature search (PubMed, Micromedex, AltMedDex, and the Natural Medicine Comprehensive Database) was conducted to identify safety-related concerns associated with the products listed.. A total of 339 HCPs completed the study questionnaire (response rate of 80.3%), identifying 44 herbal and 3 nonherbal nutritional supplements. Safety-related concerns were associated with 29 products, including herb-drug interactions with altered pharmacodynamics (15 herbs), direct toxic effects (18 herbs), and increased in vitro response of cancer cells to chemotherapy (7 herbs).. Herbal medicine use, which is prevalent in Middle Eastern countries, has several potentially negative effects that include direct toxic effects, negative interactions with anticancer drugs, and increased chemosensitivity of cancer cells, requiring a reduction in dose-density. Oncology HCPs working in countries in which herbal medicine use is prevalent need to better understand the implications of this practice. The presence of integrative physicians with training in complementary and traditional medicine can help patients and their HCPs reach an informed decision regarding the safety and effective use of these products.

Topics: Adult; Allied Health Personnel; Animals; Antineoplastic Agents; Arum; Camelus; Curcuma; Daucus carota; Female; Garlic; Herb-Drug Interactions; Herbal Medicine; Honey; Humans; Male; Medical Oncology; Middle Aged; Middle East; Milk; Neoplasms; Nigella sativa; Physicians; Phytotherapy; Plant Preparations; Research Personnel; Surveys and Questionnaires; Urtica dioica

A number of new curcumin-quinolone hybrids were synthesised from differently substituted 3-formyl-2-quinolones and vanillin and their in vitro cytotoxicity was determined on a panel of representative cell lines (A549, MCF7, SKOV3 and H460) using MTT assay. The most potent compound 14, was analysed for its mode of action using various cell biology experiments. SKOV3 cells treated with compound 14 showed distorted cell morphology under phase contrast imaging and induction of apoptosis was confirmed by Annexin V/PE assay. Further experiments on generation of reactive oxygen species (ROS) and cell cycle analysis revealed that these hybrids induce apoptosis by ROS generation and arrest cell cycle progression in S and G2/M phase.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Curcumin; Humans; Neoplasms; Quinolones; Reactive Oxygen Species

Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis by stimulating endothelial cells. Increase in cyclic AMP (cAMP) level inhibits VEGF-induced endothelial cell proliferation and migration. Cyclic nucleotide phosphodiesterases (PDEs), which specifically hydrolyse cyclic nucleotides, are critical in the regulation of this signal transduction. We have previously reported that PDE2 and PDE4 up-regulations in human umbilical vein endothelial cells (HUVECs) are implicated in VEGF-induced angiogenesis and that inhibition of PDE2 and PDE4 activities prevents the development of the in vitro angiogenesis by increasing cAMP level, as well as the in vivo chicken embryo angiogenesis. We have also shown that polyphenols are able to inhibit PDEs. The curcumin having anti-cancer properties, the present study investigated whether PDE2 and PDE4 inhibitors and curcumin could have similar in vivo anti-tumour properties and whether the anti-angiogenic effects of curcumin are mediated by PDEs. Both PDE2/PDE4 inhibitor association and curcumin significantly inhibited in vivo tumour growth in C57BL/6N mice. In vitro, curcumin inhibited basal and VEGF-stimulated HUVEC proliferation and migration and delayed cell cycle progression at G0/G1, similarly to the combination of selective PDE2 and PDE4 inhibitors. cAMP levels in HUVECs were significantly increased by curcumin, similarly to rolipram (PDE4 inhibitor) and BAY-60-550 (PDE2 inhibitor) association, indicating cAMP-PDE inhibitions. Moreover, curcumin was able to inhibit VEGF-induced cAMP-PDE activity without acting on cGMP-PDE activity and to modulate PDE2 and PDE4 expressions in HUVECs. The present results suggest that curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition.

Topics: Angiogenesis Inhibitors; Animals; Cell Cycle; Cell Movement; Cell Proliferation; Curcumin; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles; Male; Melanoma; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Rolipram; Triazines; Vascular Endothelial Growth Factor A; Wound Healing

A multibranched Cu(II) complex CuL2 curcumin-based was synthesized and characterized by single-crystal X-ray diffraction analysis. The photophysical properties of the complex have been investigated both experimentally and theoretically. The results show that the target complex exhibits higher quantum yield and larger two-photon absorption (TPA) cross-section in the near infrared (NIR) region compared with its free ligand. The cell imaging studies in vitro and in vivo reveal that the complex shows good photostability and excellent tumor targeting capability to tested cancerous cells, which can be potentially used for early tumor detection.

Topics: Animals; Curcumin; Early Diagnosis; Humans; MCF-7 Cells; Mice; Microscopy, Electron, Scanning; Neoplasms; Spectroscopy, Near-Infrared

The curcumin-encapsulated chitosan-graft-poly(N-vinyl caprolactam) nanoparticles containing gold nanoparticles (Au-CRC-TRC-NPs) were developed by ionic cross-linking method. After "optimum RF exposure" at 40 W for 5 min, Au-CRC-TRC-NPs dissipated heat energy in the range of ∼42°C, the lower critical solution temperature (LCST) of chitosan-graft-poly(N-vinyl caprolactam), causing controlled curcumin release and apoptosis to cancer cells. Further, in vivo PK/PD studies on swiss albino mice revealed that Au-CRC-TRC-NPs could be sustained in circulation for a week with no harm to internal organs. The colon tumor localization studies revealed that Au-CRC-TRC-NPs were retained in tumor for a week. These results throw light on their feasibility as multi-responsive nanomedicine for RF-assisted cancer treatment modalities.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Caprolactam; Cell Line, Tumor; Chitosan; Curcumin; Disease Models, Animal; Drug Delivery Systems; Gold; Humans; Hydrogen-Ion Concentration; Mice; Nanoparticles; Neoplasms; Particle Size; Pulsed Radiofrequency Treatment; Thermodynamics; Tissue Distribution; Tumor Burden

Curcumin is a major component of the plant Curcuma longa L. It is traditionally used as a spice and coloring in foods and is an important ingredient in curry. Curcuminoids have anti-oxidant and anti-inflammatory properties and gained increasing attention as potential neuroprotective and cancer preventive compounds. In the present study, we report that curcumin is a potent tight-binding inhibitor of human carbonyl reductase 1 (CBR1, Ki=223 nM). Curcumin acts as a non-competitive inhibitor with respect to the substrate 2,3-hexandione as revealed by plotting IC50-values against various substrate concentrations and most likely as a competitive inhibitor with respect to NADPH. Molecular modeling supports the finding that curcumin occupies the cofactor binding site of CBR1. Interestingly, CBR1 is one of the most effective human reductases in converting the anthracycline anti-tumor drug daunorubicin to daunorubicinol. The secondary alcohol metabolite daunorubicinol has significantly reduced anti-tumor activity and shows increased cardiotoxicity, thereby limiting the clinical use of daunorubicin. Thus, inhibition of CBR1 may increase the efficacy of daunorubicin in cancer tissue and simultaneously decrease its cardiotoxicity. Western-blots demonstrated basal expression of CBR1 in several cell lines. Significantly less daunorubicin reduction was detected after incubating A549 cell lysates with increasing concentrations of curcumin (up to 60% less with 50 μM curcumin), suggesting a beneficial effect in the co-treatment of anthracycline anti-tumor drugs together with curcumin.

Topics: Alcohol Oxidoreductases; Aldehyde Reductase; Aldo-Keto Reductases; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Curcumin; Daunorubicin; Humans; NADP; Neoplasms

Multidrug resistance (MDR) is a condition that makes cells simultaneously unresponsive to different drugs, unrelated to their chemical structure and mechanism of action. MDR caused by the presence and overexpression of ABC transporters makes obstacles in cancer treatment and lower the effectiveness of chemotherapy. Natural products are investigated by many researchers as MDR modulators for their low toxicity and potent, selective behavior. When coadministered, MDR modulators compete with cytotoxic agents for binding to the active site of the membrane transporters and reduce drug efflux. Natural product-based drugs are important in struggling against drug resistance during cancer therapy. This review is focused on the potential mechanisms against drug resistance, the development of inhibitors for ABC drug transporters, natural product modulators, and nanoparticle drug delivery.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Products; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Genistein; Humans; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors

In our ongoing search for new anti-invasive chemotypes, we have made an excursion from previously reported potent 1,3-diarylpropenones (chalcones) to congeners bearing longer linkers between the aromatic moieties. Nine 1,ω-diarylalkenones, including curcumin and bisdemethoxycurcumin, were evaluated in the chick heart invasion assay. Unfortunately, these compounds proved less potent and more toxic than earlier evaluated chemotypes. In the 1,3-diarylpenta-2,4-dien-1-one series, fluoro and/or trimethoxy substitution caused an increase in potency. This agrees with observations made earlier for the chalcone class.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chalcones; Chickens; Curcumin; Halogenation; Heart; Humans; Neoplasm Invasiveness; Neoplasms; Structure-Activity Relationship

An insight into the complex cancer pathophysiology reveals that a dependable amelioration of the disease could only be envisaged with a multipronged treatment approach. It is highly evident that singular chemotherapeutic agents used in clinical practice have shown limitations like severe side effects, MDR and are often associated with poor QOL while combinations of drugs have yielded better therapeutic outcomes. The current hypothesis takes it a step forward wherein a chemotherapeutic agent is combined with a natural chemosensitizer, both loaded into a nanopotentiated particulate system, which would eventually deliver the drug cargo at the target site with certitude. The encapsulated natural bioactive would then favorably act on the tumor milieu through multiple portals and chemosensibilize the cells towards cytotoxic action of the synthetic drug moiety. This 2C (chemotherapeutic and chemosensitizer) approach along with nanosystem's attributes like high payload, prolonged action and diminished side effects would proffer a more dependable treatment modality. In conclusion, the proposed system would be a value addition to the currently available armamentarium of cancer treatment tools.

Topics: Antineoplastic Agents, Phytogenic; Curcumin; Drug Delivery Systems; Drug Therapy, Combination; Flavonoids; Fluorouracil; Humans; Models, Biological; Nanoparticles; Neoplasms; Resveratrol; Stilbenes

Histone deacetylases (HDACs) are representative targets for the natural and synthetic chemicals used to transform cells to confer antitumor properties. In the current study, curcumin and hydroxamate-derivative PCI-34058-bound HDAC1 were subjected to atomistic simulation. The results support the view that fitting of curcumin and PCI-34058 within the HDAC1 pocket depends on extensive interactions between the aromatic moieties of the inhibitors and the extensive network of aromatic amino acid side chains lining the pocket of HDAC1. The interaction forces a local perturbation of the coiled structures connecting the pocket residues resulting in ligand-induced tightening of the pocket. In addition to the competitive occupancy of the histone-acetyl-lysine binding pocket by the inhibitors, interference with the in-pocket aspartate-histidine (ASP-HIS) charge relay system was also observed in inhibitor-bound HDAC1 systems. In conclusion, curcumin and PCI-34058-mediated ligand-dependent HDAC1 tunnel closure interferes negatively with the ASP-HIS charge relay system in HDAC1. Future design of HDAC inhibitors may benefit from optimizing competitive interaction with the ligand site and interference with the charge relay system.

Topics: Amino Acid Sequence; Catalytic Domain; Curcumin; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indoles; Ligands; Models, Molecular; Neoplasms

The electrical current exclusion (ECE) principle provides an alternative to common methods of cell diameter measurement and especially in atrophy and cancer associated cachexia research. C2C12 myoblasts were differentiated into myotubes and treated with 100 μM dexamethasone to induce atrophy in vitro. Subsequently, they were incubated for 24 h with media containing different concentrations of curcumin and/or branched-chain amino acids (BCAAs) in order to counteract atrophy. After treatment with curcumin, an increase in cell diameter was detectable; the highest increase with 13.9 ± 0.4% was seen with 10 μM curcumin. The combination of curcumin and BCAAs showed an increase of 13.4 ± 1.2 %. Cell diameter measurement via the ECE showed that curcumin, and curcumin in combination with BCAAs, were able to restore atrophic C2C12 myotubes. Therefore, the application of ECE in muscle atrophy and also cancer-associated cachexia research allows rapid screening of novel compounds in order to test their efficacy in vitro.

Topics: Cachexia; Cell Differentiation; Cell Line; Curcumin; Dexamethasone; Humans; Muscle Fibers, Skeletal; Muscle Proteins; Muscular Atrophy; Myoblasts; Neoplasms

Epidermal Growth Factor Receptor (EGFR) is an important target of anticancer therapy. Nowadays, the search for new molecules inhibiting this receptor is turning toward natural substances. One of the most promising natural compounds that have shown an anti-EGFR activity is curcumin, a polyphenol found in turmeric. Its effect on the receptor kinase activity and on the receptor autophosphorylation has been already described, but the mechanism of how curcumin interacts with EGFR is not fully elucidated. We demonstrate that the mode of action of curcumin is dual. This polyphenol is able to inhibit directly but partially the enzymatic activity of the EGFR intracellular domain. The present work shows that curcumin also influences the cell membrane environment of EGFR. Using biomimetic membrane models, we show that curcumin insertion into the lipid bilayer leads to its rigidification. Single particle tracking analyses performed in the membrane of A431 cancer cells confirmed that this effect of curcumin on the membrane slows down the receptor diffusion. This is likely to affect the receptor dimerization and, in turn, its activation.

Topics: Cell Line, Tumor; Cell Membrane; Curcumin; ErbB Receptors; Humans; Lipid Bilayers; Neoplasms

P-gp mediated drug efflux has been recognized as a major obstacle limiting the success of cancer chemotherapy. To overcome this issue, doxorubicin (DOX) and curcumin (Cur; P-gp inhibitor and apoptosis inhibitor) co-encapsulated pegylated polymeric micelles ((DOX+Cur)-PMs) were designed, prepared and characterized to simultaneously deliver chemotherapeutic drug and multidrug resistance (MDR) modulator to tumor sites. The (DOX+Cur)-PMs were spherical nano-size particle, with a loading content of 6.83%, and high colloidal stability. Co-delivery micelles exhibited excellent cytotoxicity by reversing MDR, promoting cellular uptake and enhancing cellular apoptosis in MCF7/Adr cells. The tumor growth inhibitory effect of (DOX+Cur)-PMs in 4T1-bearing mice was more effective compared with the combination solution of DOX and Cur and even DOX-PMs. In conclusion, simultaneous delivery of DOX and Cur by (DOX+Cur)-PMs has been demonstrated to be a promising approach for overcoming MDR and improving antitumor efficacy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Carriers; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Male; Mice; Micelles; Nanoparticles; Neoplasms; Polymers; Rats

Intracellularly degradable, self-assembled amphiphilic biotin-poly(ethylene glycol)-b-poly(curcumin-dithiodipropionic acid) nanoparticles are developed. They display excellent in vivo anticancer efficacy, benefitted from their high tumor-targeted accumulation and stimuli-triggered intracellular drug release. They can be loaded with other anticancer drugs (e.g., doxorubicin) to exploit the synergy of combinational dual-drug therapy to further enhance in vivo anticancer efficacy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Carriers; HeLa Cells; Humans; Mice; Nanoparticles; Neoplasms; Polyethylene Glycols; Polymers; Tissue Distribution; Transplantation, Heterologous

The excited triplet state of tanshinone I (Tan I) extracted from the traditional Chinese medicine Salvia miltiorrhiza Bunge was characterized by laser flash photolysis. The synergic effect of Tan I on the phototherapy of cancer cells with curcumin (Cur) was also investigated by MTT assay because the excited energy transfer from the triplet state of Tan I ((3)Tan I(∗)) to Cur occurred. At the same time, the characteristic absorption spectra of (3)Tan I(∗) were recorded, and its molar absorption coefficient and rate constants for several excited energy transfers were obtained. The photo-therapeutic effect of Cur is enhanced by combination with Tan I.

Topics: Abietanes; Antineoplastic Agents; Curcumin; Drug Synergism; Drugs, Chinese Herbal; Energy Transfer; Humans; Lasers; Molecular Structure; Neoplasms; Photolysis; Phototherapy; Salvia miltiorrhiza; Tumor Cells, Cultured

The use of different nanocarriers for delivering hydrophobic pharmaceutical agents to tumor sites has garnered major attention. Despite the merits of these nanocarriers, further studies are needed to improve their drug loading capacities (which are typically <10%) and reduce their potential systemic toxicity. Therefore, the development of alternative self-carried nanodrug delivery strategies without using inert carriers is highly desirable. In this study, we developed a self-carried curcumin (Cur) nanodrug for highly effective cancer therapy in vitro and in vivo with real-time monitoring of drug release. With a biocompatible C18PMH-PEG functionalization, the Cur nanoparticles (NPs) showed excellent dispersibility and outstanding stability in physiological environments with drug loading capacities >78 wt%. Both confocal microscopy and flow cytometry confirmed the cellular fluorescence "OFF-ON" activation and real-time monitoring of the Cur molecule release. In vitro and in vivo experiments clearly show that the therapeutic efficacy of the PEGylated Cur NPs is considerably better than that of free Cur. This self-carried strategy with real-time monitoring of drug release may open a new way for simultaneous cancer therapy and monitoring.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Carriers; Female; Humans; Mice; Mice, Nude; Nanoparticles; Neoplasms; Tissue Distribution; Xenograft Model Antitumor Assays

In this study, we have examined the encapsulation and release of hydrophilic and hydrophobic drugs in self-degrading niosomes as a unique method for anticancer therapy. Niosomes were prepared by amphiphilic self-assembly of Tween 80 and cholesterol through film hydration method. Encapsulation studies with two active molecules curcumin and doxorubicin hydrochloride (Dox) showed that curcumin is supposed to accumulate in the shell whereas Dox accumulates in the inner aqueous core of the niosome. Confocal studies indicated that nile red adsorbs preferentially to the head group of the Tween 80 and forms two separate layers in the shell. It was also seen that the niosomes undergo self-degradation in PBS through a sequential process, forming interconnected pores followed by complete collapse after 1week. The release profile shows two phases: i) initial Dox release in the first two days, followed by ii) curcumin release over 7days. Enhanced (synergistic) cytotoxicity was observed for dual-drug loaded niosomes against HeLa cell lines. Thus these niosomes are shown to offer a promising delivery system for hydrophobic and hydrophilic drugs collectively.

Topics: Cholesterol; Curcumin; Doxorubicin; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Liposomes; Neoplasms; Polysorbates

Topics: Alphapapillomavirus; Antineoplastic Agents; Antiviral Agents; Curcumin; Humans; Neoplasms; Papillomavirus Infections

Although curcumin is effective in killing cancer cells, its low water solubility and inadequate bioavailability remain major limitations to its therapeutic application. Formulating curcumin micellar nanoparticles (Cur-NPs) encapsulated with a biodegradable polymer can significantly improve curcumin's solubility, stability, and bioavailability in vitro. In this study, differently sized Cur-NPs coated with polyvinyl alcohol (PVA) were engineered. The particle size, encapsulation efficiency, in vitro release, stability, cytotoxicity, and cellular uptake of these Cur-NPs were characterized in several cancer cell lines. The results showed that, relative to solubilized curcumin, Cur-NPs demonstrated higher cytotoxicity against cancer cells. To our knowledge, this study is the first to demonstrate that the extent of the anti-cancer potency and cellular uptake of Cur-NPs is directly correlated to particle size, where Cur-NPs with the smallest size (28 nm) were the most potent. Confocal microscopy revealed the subcellular localization of the smaller Cur-NPs (28 nm) to be in both the nucleus and cytoplasm, while the larger particles (200 nm) were only localized in the cytoplasm.

Topics: Antineoplastic Agents; Biological Availability; Curcumin; Drug Carriers; Drug Compounding; Drug Stability; Humans; MCF-7 Cells; Micelles; Microtechnology; Nanoparticles; Neoplasms; Particle Size; Solubility; Tumor Cells, Cultured

Theranostic nanomedicine is capable of diagnosis, therapy, and monitoring the delivery and distribution of drug molecules and has received growing interest. Herein, a self-monitored and self-delivered photosensitizer-doped FRET nanoparticle (NP) drug delivery system (DDS) is designed for this purpose. During preparation, a donor/acceptor pair of perylene and 5,10,15,20-tetro (4-pyridyl) porphyrin (H2TPyP) is co-doped into a chemotherapeutic anticancer drug curcumin (Cur) matrix. In the system, Cur works as a chemotherapeutic agent. In the meantime, the green fluorescence of Cur molecules is quenched (OFF) in the form of NPs and can be subsequently recovered (ON) upon release in tumor cells, which enables additional imaging and real-time self-monitoring capabilities. H2TPyP is employed as a photodynamic therapeutic drug, but it also emits efficient NIR fluorescence for diagnosis via FRET from perylene. By exploiting the emission characteristics of these two emitters, the combinatorial drugs provide a real-time dual-fluorescent imaging/tracking system in vitro and in vivo, and this has not been reported before in self-delivered DDS which simultaneously shows a high drug loading capacity (77.6%Cur). Overall, our carrier-free DDS is able to achieve chemotherapy (Cur), photodynamic therapy (H2TPyP), and real-time self-monitoring of the release and distribution of the nanomedicine (Cur and H2TPyP). More importantly, the as-prepared NPs show high cancer therapeutic efficiency both in vitro and in vivo. We expect that the present real-time self-monitored and self-delivered DDS with multiple-therapeutic and multiple-fluorescent ability will have broad applications in future cancer therapy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Fluorescence Resonance Energy Transfer; Humans; Male; Mice, Nude; Nanoparticles; Neoplasms; Photosensitizing Agents; Theranostic Nanomedicine; Zebrafish

Many curcuminoid derivatives have been reported to have multiple biological activities. The aim of this study was to improve the biological activity of curcuminoids by synthesizing 16 new derivatives which combined cinnamic acids with curcuminoids, and we also analyzed the structure-activity relationship of the new compounds. Almost all the new compounds showed encouraging activity, especially compound 7g. It had much better antioxidant activity than curcuminoids and Vitamin C (VC), and also had the most significant antibacterial activity, which was 5-folder better than ampicillin (one of the best marketed antibiotics) with a minimum inhibitory concentration (MIC) of 0.5 µg/mL against Gram-positive cocci (Staphylococcus aureus and Streptococcus viridans) as well as Escherichia coli and 0.6 µg/mL against Enterobacter cloacae. Compound 7g also showed the greatest anticancer activity with a much lower IC50, which was 0.51 µM against MCF-7, 0.58 µM against HepG-2, 0.63 µM against LX-2, and 0.79 µM against 3T3. The results suggest that these compounds have promising potential as candidates for the treatment of cancer and thus further studies are warranted.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Cinnamates; Curcumin; Escherichia coli; Escherichia coli Infections; Humans; Neoplasms; Staphylococcus aureus; Streptococcal Infections; Structure-Activity Relationship; Viridans Streptococci

Novel functionalized quaternary ammonium curcuminoids have been synthesized from piperazinyl curcuminoids and Baylis-Hillman reaction derived allyl bromides. These molecules are found to be highly water soluble with increased cytotoxicity compared to native curcumin against three cancer cell lines MIAPaCa-2, MDA-MB-231, and 4T1. Preliminary in vivo toxicity evaluation of a representative curcuminoid 5a in healthy mice indicates that this molecule is well tolerated based on normal body weight gains compared to control group. Furthermore, the efficacy of 5a has been tested in a pancreatic cancer xenograft model of MIAPaCa-2 and has been found to exhibit good tumor growth inhibition as a single agent and also in combination with clinical pancreatic cancer drug gemcitabine.

Topics: Animals; Antineoplastic Agents; Body Weight; Cell Line, Tumor; Cell Movement; Curcumin; Female; Humans; Mice; Mice, Nude; Neoplasms; Quaternary Ammonium Compounds; Transplantation, Heterologous

Human chorionic gonadotropin (hCG) has essential roles in pregnancy. Reports linking hCG in non-trophoblastic tumors with poor patient prognosis has spurred interest in patho-physiological roles the hormone might play.. The ability of hCG to prevent tumor cell death and sustain viability in the presence of chemotherapeutic drugs was assessed and potential synergies with TLR ligands explored. hCG-induced up-modulation of genes involved in chemoresistance was documented and targets validated by siRNA knock-down. Whether hCG could drive collaboration between tumor cells and macrophages in the production of IL-6 and consequent chemoresistance was assessed. The effects of concurrent anti-hCG immunization and chemotherapy on the growth of syngeneic murine tumors were evaluated.. hCG maintained basal levels of cytokine secretion by tumor cells exposed to chemotherapeutic drugs, and enhanced viability and proliferation; pre-treatment with hCG also decreased apoptosis, as assessed by Annexin-V binding and the cleavage of caspase 3. While co-incubation with hCG along with several TLR ligands mediated heightened chemo-resistance, TLR-2/6 and TLR-9 ligands increased the phosphorylation of JNK, and TLR-2 and TLR-8 ligands the phosphorylation of ERK in presence of hCG and curcumin, providing evidence of tri-molecular synergy. The hormone increased the transcription and/or expression of molecular intermediates (SURVIVIN, HIF-1α, PARP-1, Bcl-2, c-FLIP, KLK-10, XIAP, c-IAP-1) associated with chemo-resistance and increased levels of stress modulators (PON2, HO-1, HSP27 and NRF-2). siRNAs to SURVIVIN, NRF-2, HO-1 and HIF-1α attenuated hCG-mediated chemo-resistance. hCG-conditioned tumor cell supernatants induced heightened secretion of IL-6 and TNF-α from peripheral blood adherent cells and secreted IL-6 imparted chemo-resistance to naïve tumor cells. Co-administration of curcumin along with an anti-hCG vaccine (hCGβ conjugated to Tetanus Toxoid (TT)) to mice carrying syngeneic tumors resulted in significantly enhanced benefits on animal survival; synergy was demonstrated between anti-hCG antibodies and curcumin in the reduction of tumor cell viability.. The data suggest that hCG, via direct as well as collaborative effects with TLR ligands and accessory cell-secreted cytokines, mediates chemo-resistance in gonadotropin-sensitive tumors and outlines the potential benefits of combination therapy.

Topics: Animals; Cancer Vaccines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chorionic Gonadotropin; Coculture Techniques; Curcumin; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Macrophages; Mice; Neoplasm Transplantation; Neoplasms; Signal Transduction; Toll-Like Receptors

This paper is to prepare curcumin (Cur) loaded mesoporous silica nanoparticle (Cur-MSN), evaluate its release behavior and anti-cancer activity in vitro. Mesoporous silica nanoparticle (MSN) was prepared by polymerization method and Cur-MSN was obtained using solvent evaporation method and impregnation centrifugation method. The preparation method was optimized using entrapment efficiency (EE) and loading efficiency (LE) as indexes. Cur-MSN was characterized with scanning electron microscope and its particle size and zeta potential were determined. Finally, in vitro release behavior in 0.2% SDS solution and its cell-killing effect on HeLa cells were also evaluated. The Cur-MSN prepared with process optimization method was round and uniform and exhibited typical mesoporous characterization. The mean particle size and Zeta potential of Cur-MSN were 75.8 nm and -30.1 mV, respectively. EE and LE of three batches of Cur-MSN were (72.55 ± 2.01)% and (16.21 ± 1.12)%, respectively. In vitro release behavior of Cur-MSN showed a sustained release profile with 83.5% cumulative release within 96 h. The killing effect of Cur-MSN on HeLa cells was dose-dependent with IC50 of 19.40 mg x L(-1), which was similar to that of Cur.

Topics: Antineoplastic Agents, Phytogenic; Curcumin; Drug Carriers; Drugs, Chinese Herbal; Humans; Nanoparticles; Neoplasms; Particle Size; Porosity; Silicon Dioxide

Anorexia is a common symptom for patients with advanced cancer. Gentian, ginger, and turmeric have traditionally been used to stimulate appetite. We tested these agents in combination, in a pilot study to assess tolerability in patients indicating 4/10 or worse anorexia on the Edmonton Symptom Assessment System, and who were not currently on chemotherapy. We collected exploratory data on the patient's appetite using a visual analogue scale.. Between 2009 and 2012, 17 patients were enrolled in arm 1 (turmeric 1 g and ginger 1 g orally twice daily, and gentiana lutea tincture 1 mL three times a day, for 14 days). The three patients enrolled in arm 2 received the same doses of ginger and turmeric but no gentian. All patients completed a daily appetite diary and a weekly symptom assessment.. In arm 1, seven patients (41%) completed treatment. Seven patients (41%) stopped early because of unacceptable toxicity or patient-initiated discontinuation, and 3 stopped because of other reasons. All patients in arm 2 stopped taking the study medication within few days of starting the treatment, leading the study committee to recommend stopping the trial. The most common adverse effects attributed to study drugs were nausea (6 patients), vomiting (3), fatigue (3), diarrhea (2) and bloating (2). There was no statistically significant effect seen on appetite.. At the doses used in this study, the combination of ginger, turmeric, and gentian is not tolerated well in cancer patients. Future studies should use fewer agents or lower doses.

Topics: Aged; Aged, 80 and over; Anorexia; Curcuma; Fatigue; Female; Gastrointestinal Diseases; Gentiana; Humans; Male; Middle Aged; Neoplasms; Phytotherapy; Pilot Projects; Plant Extracts; Zingiber officinale

Biodegradable polyanhydrides possess unique features like those that they can predominantly undergo surface erosion, and the payloads can be released by a steady speed. However, there is little work that has been published to describe the polyanhydride micelles with redox-responsiveness as a nanocarrier for drug delivery. In this study, we develop one type of new amphiphilic polyanhydride copolymer containing disulfide bonds between the hydrophilic and hydrophobic segments. The copolymer can self-assemble into stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 69 nm. The disassembly behaviors of the micelles triggered by glutathione are evaluated from the changes of the micellar size, morphology and molecular weight. An approximate zero-order in vitro drug release mode with a fast speed can be achieved in a reducing and acid environment similar with that of tumor cells. In vitro cytotoxicity analysis demonstrate that the Cur-loaded micelles are of great efficiency in inhibiting the growth of cancer cells due to the rapidly intracellular delivery of therapeutic agent. Both the qualitative and quantitative results of the antitumor activity in 4T1 tumor-bearing BALB/c mice reveal that the redox-responsive micelles have a more significant therapeutic effect to artificial solid tumor compared to the redox-insensitive micelles. This study provides a new insight into the biomedical application of polyanhydrides in drug delivery.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biocompatible Materials; Cell Cycle; Curcumin; Decanoic Acids; Dicarboxylic Acids; Flow Cytometry; Glutathione; HeLa Cells; Humans; Hydroxybenzoate Ethers; In Situ Nick-End Labeling; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred BALB C; Micelles; Neoplasms; Oxidation-Reduction; Polyanhydrides; Polyethylene Glycols; Tissue Distribution

Various types of cancer accounts for 10% of total death worldwide which necessitates better therapeutic strategies. Curcumin, a curcuminoid present in Curcuma longa, shown to exhibit antioxidant, anti-inflammatory and anticarcinogenic properties. Present study, we aimed to analyze inhibitory properties of curcumin towards virulent proteins for various cancers by computer aided virtual screening. Based on literature studies, twenty two receptors were selected which have critical virulent functions in various cancer. The binding efficiencies of curcumin towards selected targets were studied by molecular docking. Out of all, curcumin showed best results towards epidermal growth factor (EGF), virulent protein of gastric cancer; glutathione-S-transferase Pi gene (GST-PI), virulent protein for prostate cancer; platelet-derived growth factor alpha (PDGFA), virulent protein for mesothelioma and glioma compared with their natural ligands. The calculated binding energies of their docked conformations with curcumin found to be -7.59 kcal/mol, -7.98 kcal/mol and -7.93 kcal/mol respectively. Further, a comparative study was performed to screen binding efficiency of curcumin with two conventional antitumor agents, litreol and triterpene. Docking studies revealed that calculated binding energies of docked complex of litreol and EGF, GST-PI and PDGFA were found to be -5.08 kcal/mol, -3.69 kcal/mol and -1.86 kcal/mol respectively. The calculated binding energies of triterpene with EGF and PDGFA were found to be -4.02 kcal/mol and -3.11 kcal/mol respectively, whereas GST-PI showed +6.07 kcal/mol, indicate poor binding. The predicted pharmacological features of curcumin found to be better than litreol and triterpene. Our study concluded that curcumin has better interacting properties towards these cancer targets than their normal ligands and conventional antitumor agents. Our data pave insight for designing of curcumin as novel inhibitors against various types of cancer.

Topics: Administration, Oral; Algorithms; Animals; Antineoplastic Agents; Antioxidants; Caco-2 Cells; Catechols; Curcumin; Dogs; Drug Screening Assays, Antitumor; Epidermal Growth Factor; Glutathione S-Transferase pi; Humans; Ligands; Madin Darby Canine Kidney Cells; Molecular Conformation; Molecular Docking Simulation; Neoplasms; Platelet-Derived Growth Factor; Protein Binding; Triterpenes

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is an attractive target for cancer therapy. Despite a number of effective EGFR inhibitors that are constantly expanding and different methods being employed to obtain novel compounds, the search for newer EGFR inhibitors is still a major scientific challenge. In the present study, a molecular docking and molecular dynamics investigation has been carried out with an ensemble of EGFR-TK structures against a synthetically feasible library of curcumin analogs to discover potent EGFR inhibitors. To resolve protein flexibility issue we have utilized 5 EGFR wild type crystal structures during docking as this gives improved possibility of identifying an active compound as compared to using a single crystal structure. We then identified five curcumin analogs representing different scaffolds that can serve as lead molecules. Finally, the 5 ns molecular dynamics simulation shows that knoevenagel condensate of curcumin specifically C29 and C30 can be used as starting blocks for developing effective leads capable of inhibiting EGFR.

Topics: Antineoplastic Agents; Catalytic Domain; Crystallography, X-Ray; Curcumin; Drug Discovery; ErbB Receptors; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Structure-Activity Relationship

In this study, thermally responsive polymeric nanoparticle-encapsulated curcumin (nCCM) was prepared and characterized. The nCCM is ≈ 22 and 300 nm in diameter at 37 and 22 °C, respectively. The smaller size of the nCCM at 37 °C was found to significantly facilitate its uptake in vitro by human prostate adenocarcinoma PC-3 cancer cells. However, the intracellular nCCM decreases rapidly (rather than plateaus) after reaching its peak at ≈ 1.5 h during a 3-day incubation of the PC-3 cells with nCCM. Moreover, a mild hyperthermia (with negligible cytotoxicity alone) at 43 °C applied between 1 and 1.5 h during the 3-day incubation not only increases the peak uptake but also alters intracellular distribution of nCCM (facilitating its delivery into cell nuclei), which helps to retain a significantly much higher level of intracellular curcumin. These effects of mild hyperthermia could be due in part to the thermal responsiveness of the nCCM: they are more positively charged at 43 °C and can be more easily attracted to the negatively charged nuclear membrane to enter nuclei as a result of electrostatic interaction. Ultimately, a combination of the thermally responsive nCCM and mild hyperthermia significantly enhances the anticancer capability of nCCM, resulting in a more than 7-fold decrease in its inhibitory concentration to reduce cell viability to 50% (IC50). Further mechanistic studies suggest injury pathways associated with heat shock proteins 27 and 70 should contribute to the enhanced cancer cell destruction by inducing cell apoptosis and necrosis. Overall, this study demonstrates the potential of combining mild hyperthermia and thermally responsive nanodrugs such as nCCM for augmented cancer therapy.

Topics: Cell Line, Tumor; Chitosan; Combined Modality Therapy; Curcumin; Humans; Hyperthermia, Induced; Intracellular Space; Magnetic Resonance Spectroscopy; Nanoparticles; Neoplasms; Particle Size; Poloxamer; Temperature

To improve the potential of curcumin to treat advanced hormone-refractory prostate cancer, three series (A-C) of heteroaromatic analogs (thirty two compounds) with different monoketone linkers have been synthesized and evaluated for cytotoxicity against two human androgen-independent prostate cancer cell lines (PC-3 and DU-145). Among them, thirty analogs are more potent than curcumin against PC-3 cells, and twenty one analogs are more cytotoxic towards DU-145 cells relative to curcumin. The most potent compounds (44, 45, 51, and 52) also showed impressive cytotoxicity against three other metastatic cancer cell lines (MDA-MB-231, HeLa, and A549), with IC50 values ranging from 50 nM to 390 nM. All four most potent analogs exhibited no apparent cytotoxicity towards the MCF-10A normal mammary epithelial cells. Taken together, selective enhancement of cell death in prostate cancer cell lines and other aggressive cancer cell lines suggests that nitrogen-containing heteroaromatic rings are promising bioisosteres of the substituted phenyl ring in curcumin.

Topics: Antineoplastic Agents; Cell Death; Cell Line, Tumor; Curcumin; Drug Design; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Male; Neoplasms; Prostate; Prostatic Neoplasms

The efficient targeting and therapeutic efficacy of a combination of drugs (curcumin and 5-Fluorouracil [5FU]) and magnetic nanoparticles encapsulated poly(D,L-lactic-co-glycolic acid) nanoparticles, functionalized with two cancer-specific ligands are discussed in our work. This multifunctional, highly specific nanoconjugate resulted in the superior uptake of nanoparticles by cancer cells. Upon magnetic hyperthermia, we could harness the advantages of incorporating magnetic nanoparticles that synergistically acted with the drugs to destroy cancer cells within a very short period of time. The remarkable multimodal efficacy attained by this therapeutic nanoformulation offers the potential for targeting, imaging, and treatment of cancer within a short period of time (120 minutes) by initiating early and late apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line; Combined Modality Therapy; Curcumin; Drug Carriers; Fluorouracil; Folic Acid; Humans; Hyperthermia, Induced; Lactic Acid; Magnetite Nanoparticles; MCF-7 Cells; Mice; Nanoconjugates; Nanomedicine; Nanotechnology; Neoplasms; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Transferrin

A hallmark of cancer is resistance to apoptosis, with both the loss of proapoptotic signals and the gain of anti-apoptotic mechanisms contributing to tumorigenesis. As inducing apoptosis in malignant cells is one of the most challenging tasks regarding cancer, researchers increasingly focus on natural products to regulate apoptotic signaling pathways. Curcumin, a polyphenolic derivative of turmeric, is a natural compound derived from Curcuma longa, has attracted great interest in the research of cancer during the last half century. Extensive studies revealed that curcumin has chemopreventive properties, which are mainly due to its ability to arrest cell cycle and to induce apoptosis in cancer cells either alone or in combination with chemotherapeutic agents or radiation. The underlying action mechanisms of curcumin are diverse and has not been elucidated so far. By regulating multiple important cellular signalling pathways including NF-κB, TRAIL, PI3 K/Akt, JAK/STAT, Notch-1, JNK, etc., curcumin are known to activate cell death signals and induce apoptosis in pre-cancerous or cancer cells without affecting normal cells, thereby inhibiting tumor progression. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy. This article reviews the main effects of curcumin on the different apoptotic signaling pathways involved in curcumin induced apoptosis in cancer cells via cellular transduction pathways and provides an in depth assessment of its pharmacological activity in the management of tumor progression.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Clinical Trials as Topic; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; NF-kappa B; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT Transcription Factors; TNF-Related Apoptosis-Inducing Ligand

Combined therapy with drugs of different therapeutic effects is an effective way in the treatment of diseases and damaged tissues or organs. However, how to precisely control the release order, dose, and time of the drugs using vehicles is still a challenging task. In this work, for the first time, a study to develop a nanoscale multi-drug delivery system based on polymer micelle-enriched electrospun nanofibers is presented. The multi-drug delivery system is achieved, first, by the fabrication of hydrophobic curcumin encapsulated micelles assembled from biodegradable mPEG-PCL copolymer and, second, by the blending of the micelle powder with hydrophilic doxorubicin in polyvinyl alcohol solution, followed by simply electrospinning this combination. Due to the different domains of the two drugs within the nanofibers, the release behaviors show a time-programmed release, and can be temporally and spatially regulated. In vitro tumor cell inhibition assay indicates that the delivery system possesses great potential in cancer chemotherapy.

Topics: Animals; Animals, Newborn; Cell Survival; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; HeLa Cells; Humans; Micelles; Microscopy, Atomic Force; Nanofibers; Neoplasms; Polyvinyl Alcohol; Rats; Time Factors

Poly (DL-lactic-co-glycolic) acid [PLGA] copolymers with different ratios (78/22, 68/32 and 61/39) and molecular weight (15,400, 11,000 and 10,000 Da) were synthesized and characterized by (1)H NMR, FTIR, GPC and TGA-DTA studies. Curcumin loaded PLGA with the size of 100-300 nm were obtained by electrospinning in which no visible aggregation observed on the surface. The diameter of CPNF (61/39) nanofiber obtained from the topographical imaging by AFM is 160±10 nm. The water contact angle measurements indicate that an increase in GA content results in increase in the hydrophilicity of the PLGA copolymer. The in vitro release profile and release kinetics from the CPNF demonstrated a sustained release of curcumin from CPNF. The release profile follows Korsmeyer-Peppas model suggesting a combination of surface drug dissolution and non-Fickian diffusion as a major drug release mechanism. The effect of CPNF on cell viability was assessed by the MTT (3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide) assay to examine the cytotoxic effect of released curcumin on A431 cells in vitro.

Topics: Cell Death; Cell Line, Tumor; Curcumin; Humans; Lactic Acid; Microscopy, Atomic Force; Molecular Weight; Nanofibers; Neoplasms; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Spectroscopy, Fourier Transform Infrared; Viscosity; Water

Recently, a new class of multifunctional nanodroplets that combine the properties of polymeric drug carriers, ultrasound imaging contrast agents, and enhancers of ultrasound-mediated drug delivery has been developed. We studied the formation mechanism of nanodroplets of a drug and its application in chemotherapy. Curcumin was loaded in polymeric micelles as a anti-cancer drug using polyethylene glycol block-poly(caprolactone) with encapsulation efficiency of 95.60%. At room temperature, the developed systems comprised perfluorocarbon nanodroplets stabilized by walls comprising biodegradable block copolymers. Upon heating to 37°C, the nanodroplets were converted to nano/microbubbles. Under ultrasound, nanobubbles cavitated and collapsed, resulting in release of the encapsulated drug. The percentage release of curcumin-loaded nanodroplets by insonation was 90.95%, showing enhancement compared with the non-ultrasound group. Nanodroplets strongly retained the loaded drugs in vivo yet, under ultrasound-mediated vaporization, they released the drugs, thereby implementing effective targeting into the tumor. The tumor inhibition of the group in which curcumin-loaded nanodroplets were combined with ultrasound was 71.30%, more than that of the group of curcumin-loaded nanodroplets (53.00%). Nanodroplets showed high enhancement of anti-cancer effects under ultrasound. Upon intravenous injection, a long-lasting, strong and selective ultrasound contrast was observed, suggesting their coalescence into larger, highly echogenic microbubbles. These multifunctional nanodroplets, which manifest excellent therapeutic and ultrasound properties, could be promising anti-cancer drug delivery systems.

Topics: Animals; Antineoplastic Agents; Contrast Media; Curcumin; Drug Carriers; Drug Compounding; Female; Liver; Mice; Micelles; Microscopy, Electron, Transmission; Nanostructures; Neoplasms; Polyesters; Polyethylene Glycols; Sonication; Tumor Burden; Ultrasonography

We report herein the development of a novel aqueous formulation and improved antitumor activity for curcumin by encapsulating it into a biocompatible and biodegradable poly(L-lactic acid) based poly(anhydride-ester)-b-poly(ethylene glycol) (PAE-b-PEG) micelle. The resulting curcumin loaded micelles were completely water-dispersible, overcoming the problem of poor water solubility that limited its efficacy and bioavailability. In vitro cellular studies revealed that the curcumin-loaded micelles were taken up mainly via endocytosis route and exhibited higher cytotoxicities toward model cancer cell lines (HeLa and EMT6) than free curcumin. An in vivo biodistribution study revealed that the curcumin-loaded micelles displayed significantly enhanced accumulation inside the tumor of EMT6 breast tumor-bearing mice. More impressively, the curcumin-loaded micelles showed stronger antitumor activity, higher anti-angiogenesis effects and induced apoptosis on the EMT6 breast tumor model bearing mice than free curcumin. Furthermore, the curcumin-loaded micelles showed no significant toxicity towards hemotological system, major organs or tissues in mice. Combined with a high antitumor activity and low toxic side-effects, the curcumin-loaded micelles developed here thus appear to be a highly attractive nanomedicine for effective, targeted cancer therapy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Death; Cell Proliferation; Curcumin; Endocytosis; Female; Fluorescence; HeLa Cells; Humans; Hydrodynamics; Inhibitory Concentration 50; Mice; Micelles; Microscopy, Electron, Transmission; Neoplasms; Particle Size; Polyesters; Polyethylene Glycols; Polymers; Tissue Distribution; Treatment Outcome

Curcumin (CUR) and curcuminoids complexes labeled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer's disease. Gallium-68 is a positron-emitting, generator-produced radionuclide, and its properties can be exploited in situ in medical facilities without a cyclotron. Moreover, CUR showed a higher uptake in tumor cells compared to normal cells, suggesting potential diagnostic applications in this field. In spite of this, no studies using labeled CUR have been performed in this direction, so far. Herein, (68)Ga-labeled complexes with CUR and two curcuminoids, namely diacetyl-curcumin (DAC) and bis(dehydroxy)curcumin (bDHC), were synthesized and characterized by means of experimental and theoretical approaches. Moreover, a first evaluation of their affinity to synthetic β-amyloid fibrils and uptake by A549 lung cancer cells was performed to show the potential application of these new labeled curcuminoids in these diagnostic fields. The radiotracers were prepared by reacting (68)Ga(3+) obtained from a (68)Ge/(68)Ga generator with 1 mg/mL curcuminoids solutions. Reaction parameters (precursor amount, reaction temperature, and pH) were optimized to obtain high and reproducible radiochemical yield and purity. Stoichiometry and formation of the curcuminoid complexes were investigated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, NMR, ultraviolet-visible, and fluorescence spectroscopy on the equivalent (nat)Ga-curcuminoids (nat = natural) complexes, and their structure was computed by theoretical density functional theory calculations. The analyses evidenced that CUR, DAC, and bDHC were predominantly in the keto-enol form and attested to Ga(L)2(+) species formation. Identity of the (68)Ga(L)2(+) complexes was confirmed by coelution with the equivalent (nat)Ga(L)2(+) complexes in ultrahigh-performance liquid chromatography analyses.(68)Ga(CUR)2(+), (68)Ga(DAC)2(+), and (68)Ga(bDHC)2(+) were highly (87 ± 4, 90 ± 1%) and moderately (48 ± 2%), respectively, retained by synthetic β-amyloid fibrils in vitro. All the Ga-curcuminoid complexes showed an uptake in A549 lung cancer cells, at least equivalent to the respective free curcuminoids, confirming potential applications as cancer-detecting radiotracers.

Topics: Alzheimer Disease; Cell Line, Tumor; Curcumin; Gallium Radioisotopes; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Neoplasms; Organometallic Compounds; Quantum Theory; Radiopharmaceuticals; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet

Targeted drug delivery system for tumor cells is an appealing platform on enhancing the therapeutic effects and reducing the side effects of the drug. In this study, we developed folate-modified curcumin (Cur) loaded micelles (Cur-FPPs) for cancer chemotherapy. The targeting material, Folate-PEG3000-PLA2000, was synthesized by the amide bond formation reaction. And the Cur loaded micelles were prepared by thin-film hydration method with mPEG2000-PLA2000 (Cur-PPs) or mPEG2000-PLA2000 and Folate-PEG3000-PLA2000 (Cur-FPPs) as carrier. A central composite design (CCD) was used to optimize the formulation, and the optimized Cur-FPPs was prepared with the weight ratio of Folate-PEG3000-PLA2000 and mPEG2000-PLA2000 at 1:9. The average size of the mixed micelles was 70nm, the encapsulating efficiency and drug-loading were 80.73±0.16% and 4.84±0.01%, respectively. Compared with the Cur propylene glycol solution, the in vitro release of Cur from Cur-FPPs showed a sustained manner. Furthermore, the in vitro cytotoxicity and cellular uptake of Cur-FPPs were significantly enhanced towards MCF-7 and HepG2 cells. The pharmacokinetic studies in rats indicated that a 3-fold increase in the half-life was achieved for Cur loaded micelle formulations relative to solubilized Cur. All the results demonstrated that folate-modified Cur micelles could serve as a potential nanocarrier to improve the solubility and anti-cancer activity of Cur.

Topics: Animals; Cell Death; Cell Survival; Curcumin; Drug Delivery Systems; Endocytosis; Folic Acid; Hemolysis; Hep G2 Cells; Humans; Irritants; Lactic Acid; Male; MCF-7 Cells; Micelles; Microscopy, Fluorescence; Neoplasms; Particle Size; Polyesters; Polyethylene Glycols; Polymers; Rabbits; Rats; Static Electricity; Surface-Active Agents

Here we report on the first supramolecular hydrogelator of curcumin and the evaluation of its inhibition capacity towards cancer cells and tumor growth.

Topics: Cell Division; Cell Line, Tumor; Curcumin; Drug Screening Assays, Antitumor; Humans; Hydrogels; Microscopy, Electron, Scanning; Microscopy, Fluorescence; Neoplasms

The field of recombinant protein therapeutics has been evolving rapidly, making significant impact on clinical applications for several diseases, including cancer. However, the functional aspects of proteins rely exclusively on their structural integrity, in which nanoparticle mediated delivery offers unique advantages over free proteins. In the present work, a novel strategy has been developed where the nanoparticles (NPs) used for the delivery of the recombinant protein could contribute to enhancing the therapeutic efficacy of the recombinant protein. The transcription factor, NFκB, involved in cell growth and its inhibitor, IκBα, regulates its proliferation. Another similar naturally available molecule, which inhibits the function of NFκB, is curcumin. Hence, we have developed a 'green synthesis' method for preparing water-soluble curcumin nanoparticles to stabilize recombinant IκBα protein. The NPs were characterized by UV-vis and fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering before administration into human cervical carcinoma (HeLa) and glioblastoma (U87MG) cells. Experimental results demonstrated that this combined module had enhanced therapeutic efficacy, causing apoptotic cell death, which was confirmed by cytotoxicity assay and flowcytometry analyses. The expression of apoptotic genes studied by semi-quantitative reverse transcription PCR delineated the molecular pathways involved in cell death. Thus, our study revealed that the functional delivery of recombinant IκBα-loaded curcumin NPs has promise as a natural-product-based protein therapeutics against cancer cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Curcumin; Drug Delivery Systems; HeLa Cells; Humans; I-kappa B Proteins; Nanoparticles; Neoplasms; NF-KappaB Inhibitor alpha; Recombinant Proteins

DNA topoisomerase I (topo I) and II (topo II) are essential enzymes that solve the topological problems of DNA by allowing DNA strands or double helices to pass through each other during cellular processes such as replication, transcription, recombination, and chromatin remodeling. Their critical roles make topoisomerases an attractive drug target against cancer. The present molecular docking study provides insights into the inhibition of topo I and II by curcumin natural derivatives. The binding modes suggested that curcumin natural derivatives docked at the site of DNA cleavage parallel to the axis of DNA base pairing. Cyclocurcumin and curcumin sulphate were predicted to be the most potent inhibitors amongst all the curcumin natural derivatives docked. The binding modes of cyclocurcumin and curcumin sulphate were similar to known inhibitors of topo I and II. Residues like Arg364, Asn722 and base A113 (when docked to topo I-DNA complex) and residues Asp479, Gln778 and base T9 (when docked to topo II-DNA complex) seem to play important role in the binding of curcumin natural derivatives at the site of DNA cleavage.

Topics: Amino Acids; Antigens, Neoplasm; Binding Sites; Curcuma; Curcumin; DNA; DNA Cleavage; DNA Replication; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; DNA-Binding Proteins; Humans; Molecular Docking Simulation; Neoplasms; Plant Extracts; Structure-Activity Relationship

This study aimed to demonstrate that curcumin (Cur)-containing graphene composites have high anticancer activity. Specifically, graphene-derivatives were used as nanovectors for the delivery of the hydrophobic anticancer drug Cur based on pH dependence. Different Cur-graphene composites were prepared based on polar interactions between Cur and the number of oxygen-containing functional groups of respective starting materials. The degree of drug-loading was found to be increased by increasing the number of oxygen-containing functional groups in graphene-derivatives. We demonstrated a synergistic effect of Cur-graphene composites on cancer cell death (HCT 116) both in vitro and in vivo. As-prepared graphene quantum dot (GQD)-Cur composites contained the highest amount of Cur nano-particles and exhibited the best anticancer activity compared to the other composites including Cur alone at the same dose. This is the first example of synergistic chemotherapy using GQD-Cur composites simultaneous with superficial bioprobes for tumor imaging.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Female; Graphite; HCT116 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Mice; Mice, Inbred BALB C; Microscopy, Electrochemical, Scanning; Nanocomposites; Neoplasm Transplantation; Neoplasms; Quantum Dots; Transplantation, Heterologous

Curcumin, a specific secondary metabolite of Curcuma species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC0-540 of EVL by 70.6% and 71.5%, respectively, and both dosages reduced the Cmax of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4.

Topics: Administration, Oral; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cell Line, Tumor; Curcumin; Cytochrome P-450 CYP3A; Drug Interactions; Everolimus; Humans; Neoplasms; Rats; Sirolimus

A novel series of chalcone derivatives containing pyrimidinyl group were synthesized and evaluated for their cytotoxic activities in vitro against various human cancer cell lines. Most of the prepared compounds showed potential cytotoxicity against several human cancer cell lines. The compound 5g displayed more potent cytotoxic activities against human cancer cell lines in comparison with Curcumin.

Topics: Antineoplastic Agents; Cell Line, Tumor; Chalcone; Curcumin; Drug Screening Assays, Antitumor; Humans; K562 Cells; MCF-7 Cells; Neoplasms; Structure-Activity Relationship

Current cancer therapies are challenged by weakly soluble drugs and by drug combinations that exhibit non-uniform biodistribution and poor bioavailability. In this study, we have presented a new platform of advanced healthcare materials based on albumin nanoparticles (ANPs) engineered as tumor penetrating, delivery vehicles of combinatorially applied factors to solid tumors. These materials were designed to overcome three sequential key barriers: tissue level transport across solid tumor matrix; uptake kinetics into individual cancer cells; therapeutic resistance to single chemotherapeutic drugs. The ANPs were designed to penetrate deeper into solid tumor matrices using collagenase decoration and evaluated using a three-dimensional multicellular melanoma tumor spheroid model. Collagenase modified ANPs exhibited 1-2 orders of magnitude greater tumor penetration than unmodified ANPs into the spheroid mass after 96 hours, and showed preferential uptake into individual cancer cells for smaller sized ANPs (<100 nm). For enhanced efficacy, collagenase coated ANPs were modified with two therapeutic agents, curcumin and riluzole, with complementary mechanisms of action for combined cell cycle arrest and apoptosis in melanoma. The collagenase coated, drug loaded nanoparticles induced significantly more cell death within 3-D tumor models than the unmodified, dual drug loaded ANP particles and the kinetics of cytotoxicity was further influenced by the ANP size. Thus, multifunctional nanoparticles can be imbued with complementary size and protease activity features that allow them to penetrate solid tumors and deliver combinatorial therapeutic payload with enhanced cancer cytotoxicity but minimal collateral damage to healthy primary cells.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Collagenases; Curcumin; Drug Carriers; Humans; Nanoparticles; Neoplasms; Particle Size; Recombinant Proteins; Riluzole; Serum Albumin

Pyrazolealdehydes (4a-d), Knoevenagel's condensates (5a-d) and Schiff's bases (6a-d) of curcumin-I were synthesized, purified and characterized. Hemolysis assays, cell line activities, DNA bindings and docking studies were carried out. These compounds were lesser hemolytic than standard drug doxorubicin. Minimum cell viability (MCF-7; wild) observed was 59% (1.0 μg/mL) whereas the DNA binding constants ranged from 1.4×10(3) to 8.1×10(5) M(-1). The docking energies varied from -7.30 to -13.4 kcal/mol. It has been observed that DNA-compound adducts were stabilized by three governing forces (Van der Wall's, H-bonding and electrostatic attractions). It has also been observed that compounds 4a-d preferred to enter minor groove while 5a-d and 6a-d interacted with major grooves of DNA. The anticancer activities of the reported compounds might be due to their interactions with DNA. These results indicated the bright future of the reported compounds as anticancer agents.

Topics: Antineoplastic Agents; Cell Survival; Curcumin; DNA; Hemolysis; Humans; MCF-7 Cells; Molecular Docking Simulation; Neoplasms; Pyrazoles; Schiff Bases

Curcumin has anti-proliferative and pro-apototic properties against a variety of cancer cells in vitro. Unfortunately, the water-insolubility and instability leads to its low bioavailability in vivo tests. Here, we report a general approach to using poly(amidoamine) dendrimer with acetyl terminal groups to encapsulate curcumin(G₅-Ac/Cur) for drug delivery to cancer cells. The solubility, release kinetics, anticancer activity, and apoptotic-related protein expression (Bax and Bcl-2) were investigated in detail. Comparing with curcumin, the water-solubility value of G₅-Ac/Cur increased 200-fold, and the release of curcumin from the complexes was in a sustained manner. G₅-Ac/Cur showed higher anti-proliferative activity against A549 cell lines and had the better effect on the generation of intracellular reactive oxygen species, the mitochondrial membrane potential and cell apoptosis. Furthermore, the ratio of Bax/Bcl-2 was higher in samples treated with G₅-Ac/Cur. The results indicated that the G₅-Ac drug delivery system could improve the solubility and anti-cancer effect of curcumin.

Topics: Antineoplastic Agents; Cell Line, Tumor; Chemistry, Pharmaceutical; Curcumin; Dendrimers; Drug Carriers; Humans; Neoplasms

Inhibitors of poly(ADP-ribose) polymerase (PARP) are promising anticancer drugs, particularly for the treatment of tumors deficient in the DNA damage response (DDR). However, it is challenging to design effective therapeutic strategies for use of these compounds against cancers without DDR deficiencies. In this context, combination therapies in which PARP inhibitors are used alongside DDR inhibitors have elicited a great deal of interest. Curcumin, a component of turmeric (Curcuma longa), has been tested in clinical studies for its chemosensitizing potential; however, the mechanisms of chemosensitization by curcumin have not been fully elucidated. This study demonstrates that curcumin suppresses three major DDR pathways: non-homologous end joining (NHEJ), homologous recombination (HR) and the DNA damage checkpoint. Curcumin suppresses the histone acetylation at DNA double-strand break (DSB) sites by inhibiting histone acetyltransferase activity, thereby reducing recruitment of the key NHEJ factor KU70/KU80 to DSB sites. Curcumin also suppresses HR by reducing expression of the BRCA1 gene, which regulates HR, by impairing histone acetylation at the BRCA1 promoter. Curcumin also inhibits ataxia telangiectasia and Rad3-related protein (ATR) kinase (IC50 in vitro = 493 nM), resulting in impaired activation of ATR-CHK1 signaling, which is necessary for HR and the DNA damage checkpoint pathway. Thus, curcumin suppresses three DDR pathways by inhibiting histone acetyltransferases and ATR. Concordantly, curcumin sensitizes cancer cells to PARP inhibitors by enhancing apoptosis and mitotic catastrophe via inhibition of both the DNA damage checkpoint and DSB repair. Our results indicate that curcumin is a promising sensitizer for PARP inhibitor-based therapy.

Topics: Acetylation; Animals; Antineoplastic Agents; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Blotting, Western; BRCA1 Protein; Cell Cycle Checkpoints; Cell Proliferation; Checkpoint Kinase 1; Cobalt Radioisotopes; Curcumin; DNA Damage; DNA Repair; Enzyme Inhibitors; Gamma Rays; Histone Acetyltransferases; Histones; Homologous Recombination; Humans; Mice; Neoplasms; p300-CBP Transcription Factors; Peptide Fragments; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Promoter Regions, Genetic; Protein Kinases; Sialoglycoproteins; Signal Transduction; Tumor Cells, Cultured

Increasing number of Phase I/II clinical studies have demonstrated clinical potential of curcumin for treatment of various types of human cancers. Despite significant anti-tumor efficacies and bio-safety profiles of curcumin, poor systemic bioavailability is retarding its clinical success. Efforts are now being directed toward developing stable formulations of curcumin using various drug delivery systems. To this end, herein we report on the development of a new tumor vasculature targeting liposomal formulation of curcumin containing a lipopeptide with RGDK-head group and two stearyl tails, di-oleyolphosphatidylcholine (DOPC) and cholesterol. We show that essentially water insoluble curcumin can be solubilized in fairly high concentrations (~500 μg/mL) in such formulation. Findings in the Annexin V/Propidium iodide (PI) binding based flow cytometric assays showed significant apoptosis inducing properties of the present curcumin formulation in both endothelial (HUVEC) and tumor (B16F10) cells. Using syngeneic mouse tumor model, we show that growth of solid melanoma tumor can be inhibited by targeting such liposomal formulation of curcumin to tumor vasculature. Results in immunohistochemical staining of the tumor cryosections are consistent with tumor growth inhibition being mediated by apoptosis of tumor endothelial cells. Findings in both in vitro and in vivo mechanistic studies are consistent with the supposition that the presently described liposomal formulation of curcumin inhibits tumor growth by blocking VEGF-induced STAT3 phosphorylation in tumor endothelium. To the best of our knowledge, this is the first report on inhibiting tumor growth through targeting liposomal formulation of curcumin to tumor vasculatures.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Female; Human Umbilical Vein Endothelial Cells; Humans; Liposomes; Mice; Mice, Inbred C57BL; Neoplasms; Neovascularization, Pathologic; Oligopeptides

Combination therapy has been a norm in clinical practice to effectively treat cancer. Besides polytherapy, nowadays, smart and nanobased drug carriers are extensively being explored to deliver drugs according to pathophysiological environment of diseases. In this regard, herein we designed intelligent mesoporous architecture, incorporating both combinational therapy with smart nanotechnology, to simultaneously deliver two highly hydrophobic chemotherapeutic drugs in response to extracellular and/or intracellular acidic environ of tumor. Novelty of the system lies in the employment of acid responsive ZnO QDs to clog not only the nanochannels of mesoporous silica, encapsulating one hydrophobic drug, but also exploitation of chelate forming propensity of another hydrophobic drug (curcumin) to load a significant quantity onto the surface of ZnO nanolids. Cell viability results revealed an extraordinarily high cytotoxic efficiency of that lethal drug cocktail even at a concentration as low as 3 μg/mL nanocarrier. We envision that this sophisticated nanocarrier, which utilizes both interior pore and exterior surface of nanolids for loading different hydrophobic guest molecules and their subsequent acid responsive release, will undoubtedly, illustrates its remarkable potential in targeted chemotherapy.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Cytotoxins; Delayed-Action Preparations; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Nanostructures; Neoplasms; Porosity; Silicon Dioxide; Zinc Oxide

Cancer is the second leading cause of death in the United States. Conventional therapies cause widespread systemic toxicity and lead to serious side effects which prohibit their long term use. Additionally, in many circumstances tumor resistance and recurrence is commonly observed. Therefore, there is an urgent need to identify suitable anticancer therapies that are highly precise with minimal side effects. Curcumin is a natural polyphenol molecule derived from the Curcuma longa plant which exhibits anticancer, chemopreventive, chemo- and radio-sensitization properties. Curcumin's widespread availability, safety, low cost and multiple cancer fighting functions justify its development as a drug for cancer treatment. However, various basic and clinical studies elucidate curcumin's limited efficacy due to its low solubility, high rate of metabolism, poor bioavailability and pharmacokinetics. A growing list of nanomedicine(s) using first line therapeutic drugs have been approved or are under consideration by the Food and Drug Administration (FDA) to improve human health. These nanotechnology strategies may help to overcome challenges and ease the translation of curcumin from bench to clinical application. Prominent research is reviewed which shows that advanced drug delivery of curcumin (curcumin nanoformulations or curcumin nanomedicine) is able to leverage therapeutic benefits by improving bioavailability and pharmacokinetics which in turn improves binding, internalization and targeting of tumor(s). Outcomes using these novel drug delivery systems have been discussed in detail. This review also describes the tumor-specific drug delivery system(s) that can be highly effective in destroying tumors. Such new approaches are expected to lead to clinical trials and to improve cancer therapeutics.

Topics: Animals; Antineoplastic Agents, Phytogenic; Biological Availability; Chemistry, Pharmaceutical; Curcumin; Drug Carriers; Humans; Nanomedicine; Neoplasms; Technology, Pharmaceutical

In this paper, a facile strategy to develop graphene-based delivery nanosystems for effective drug loading and sustained drug release was proposed and validated. Specifically, biocompatible naphthalene-terminated PEG (NP) and anticancer drugs (curcumin or doxorubicin (DOX)) were simultaneously integrated onto oxidized graphene (GO), leading to self-assembled, nanosized complexes. It was found that the oxidation degree of GO had a significant impact on the drug-loading efficiency and the structural stability of nanosystems. Interestingly, the nanoassemblies resulted in more effective cellular entry of DOX in comparison with free DOX or DOX-loaded PEG-polyester micelles at equivalent DOX dose, as demonstrated by confocal microscopy studies. Moreover, the nanoassemblies not only exhibited a sustained drug release pattern without an initial burst release, but also significantly improved the stability of formulations which were resistant to drug leaking even in the presence of strong surfactants such as aromatic sodium benzenesulfonate (SBen) and aliphatic sodium dodecylsulfonate (SDS). In addition, the nanoassemblies without DOX loading showed negligible in vitro cytotoxicity, whereas DOX-loaded counterparts led to considerable toxicity against HeLa cells. The DOX-mediated cytotoxicity of the graphene-based formulation was around 20 folds lower than that of free DOX, most likely due to the slow DOX release from complexes. A zebrafish model was established to assess the in vivo safety profile of curcumin-loaded nanosystems. The results showed they were able to excrete from the zebrafish body rapidly and had nearly no influence on the zebrafish upgrowth. Those encouraging results may prompt the advance of graphene-based nanotherapeutics for biomedical applications.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Delayed-Action Preparations; Doxorubicin; Drug Carriers; Drug Delivery Systems; Graphite; HeLa Cells; Humans; Micelles; Nanostructures; Neoplasms; Zebrafish

Curcuma spp. (Zingiberaceae) is one of the significant ingredients in food and traditional medicines. The current study was to investigate health-benefits of the rhizomes of endemic Curcuma caesia, Curcuma zedoaria and Curcuma aeruginosa using in vitro antioxidant, antiinflammatory and human tumor cell proliferation inhibitory activities. Among these, C. caesia (black turmeric) showed the best overall biological activities based on [3-(4, 5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) and lipid peroxidation (LPO), cyclooxygenase (COX-1 and -2) enzymes, and tumor cell growth inhibitory assays. The hexane and methanolic extracts of C. caesia (CCH and CCM) showed LPO inhibition by 31 and 43 %, and COX-2 enzyme by 29 and 38 %, respectively, at 100 μg/ml. Eleven terpenoids were isolated and identified. The MTT antioxidant assay revealed that the extracts of three Curcuma spp. at 250 μg/ml and isolates at 5 μg/ml demonstrated activity comparable to positive controls vitamin C and t-butyl hydroquinone (TBHQ) at 25 μg/ml. The extracts inhibited LPO by 40 % at 250 μg/ml whereas pure isolates 1-11 by about 20 %. The extracts and isolates inhibited COX-1 and -2 enzymes between the ranges of 3-56 and 5-30 %, respectively. The in vitro biological activity exhibited by the extracts and isolates of C. caesia rhizome further supported its use in traditional medicine.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Cell Line, Tumor; Curcuma; Cyclooxygenase Inhibitors; Diet; Functional Food; Humans; India; Lipid Peroxidation; Neoplasms; Phytotherapy; Plant Extracts; Rhizome; Species Specificity; Terpenes

To investigate the anticancer effect of curcumin Solid Dispersions (SDs).. Curcumin SDs were prepared by patent technology. The anticancer effect of curcumin SDs were investigated by vivo and vitro tests of SCG-7901, BEL-7402, S-180 and Ehrlich ascites tumor models.. The results showed that Curcumin SDs had markedly anticancer effect and could improve the anticancer effect of cisplatin.. Curcumin SDs could be developed into one kind of adjuvant drug for anticancer, as it has markedly anticancer effect, and could improve the anticancer effects of cisplatin.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemistry Techniques, Synthetic; Cisplatin; Curcuma; Curcumin; Drug Synergism; Drug Therapy, Combination; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms; Solubility

In the present paper, cationic nanoparticles of curcumin, chitosan and poly(ɛ-caprolactone) were developed by a simple nano-precipitation method. The developed curcumin loaded chitosan/poly(ɛ-caprolactone) (chitosan/PCL) nanoparticle showed almost spherical shape and its diameter was varied between 220 nm and 360 nm and zeta potential was varied between +30 mV and 0 mV as a function with pH value. The encapsulation of curcumin into nanoparticles was confirmed by fluorescence spectral analysis. In vitro release study showed the sustained release behavior of curcumin from nanoparticles during the period of 5 days study. In vitro cytotoxicity test revealed the drug concentration dependent on the cell viability against Hela cells and OCM-1 cells after 48 h co-incubation. Furthermore, in vitro cell uptake study revealed that the cell uptake of curcumin was greatly enhanced by encapsulated curcumin into cationic chitosan/PCL nanoparticles. Therefore, the developed cationic chitosan/PCL nanoparticles might be a promising candidate for curcumin delivery to cancer cells.

Topics: Antineoplastic Agents; Cations; Cell Survival; Chitosan; Curcumin; Delayed-Action Preparations; HeLa Cells; Humans; Nanoparticles; Neoplasms; Polyesters

Claisen-Schmidt condensation of 3-(1,2,3,6-tetrahydro-1-methylpyridin-4-yl)-2,4,5- trimethoxybenzaldehyde 3 and various aromatic, heterocyclic and alicyclic amides of 3- aminoacetophenone 6(a-s) afforded novel curcumin mimics. All the synthesized compounds were characterized by IR, (1)H NMR, Mass spectroscopy and evaluated for antioxidant, cytotoxicity and antimicrobial activity. Out of the 20 compounds screened, compounds 7i, 7l, 7q, and 7n have shown excellent radical scavenging activity, compounds 7o, 7t, 7f, and 7r have shown significant xanthine oxidase inhibition, and compounds 7a, 7k and 7l were found to be potent inhibitors of selected cancer cell lines. Compounds 7h, 7t, 7l, 7i, and 7e have shown good antibacterial activity, whereas compounds 7j, 7f, 7o, 7h, and 7t exhibited significant antifungal activity.

Topics: Anti-Infective Agents; Antineoplastic Agents; Antioxidants; Bacteria; Biomimetics; Cell Proliferation; Curcumin; Enzyme Inhibitors; Fungi; Humans; Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured; Xanthine Oxidase

Curcumin, the main compound of spice turmeric, is one of the natural products that has been shown to possess effective anti-cancer properties. However, the absorption efficacy of curcumin is too low to make dramatic results in therapy. Therefore, we based the main aim of this study on improving the bioavailability of curcumin taking advantage of dendrosome nanoparticles; and subsequently evaluating in vitro and in vivo anti-tumor properties of dendrosomal curcumin. In vitro studies were carried out utilizing A431 and WEHI-164 cell lines and mouse embryonic normal fibroblasts. Our data revealed that dendrosomal curcumin not only exhibits a much higher bioavailability than void curcumin (P<0.05) but also inhibits the proliferation of cancer cells (P<0.01) in a time- and dose-dependent manner that could be ascribed to the induction of apoptosis. However, dendrosome did not indicate any toxic effect on different types of cell lines. For in vivo studies, BALB/c tumor-bearing mice were treated with dendrosomal curcumin, void curcumin, dendrosome and PBS. The results indicated that dendrosomal curcumin reduces significantly the tumor size in comparison with void curcumin and control samples (P<0.05). Furthermore, in animals treated with dendrosomal curcumin a longer survival was observed (P<0.01). We also found that the mice treated with dendrosomal curcumin, showed a significant increase in splenocyte proliferation and IFN-γ production as well as a significant decrease in IL-4 production. This can be a proof of anti-tumor immunity caused by dendrosomal curcumin. The findings demonstrate that dendrosomal curcumin offers a great potential to be a promising anti-cancer therapeutic agent.

Topics: Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Drug Carriers; Female; Humans; Interferon-gamma; Interleukin-4; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasm Transplantation; Neoplasms; Spleen; Tumor Burden

Twenty-nine phenolic compounds were isolated from the root bark of fresh (Yunnan) ginger and their structures fully characterized. Selected compounds were divided into structural categories and twelve compounds subjected to in-vitro assays including DPPH radical scavenging, xanthine-oxidase inhibition, monoamine oxidase inhibition, rat-brain homogenate lipid peroxidation, and rat pheochromocytoma PC12 cell and primary liver cell viability to determine their antioxidant and cytoprotective properties. Isolated compounds were also tested against nine human tumor cell lines to characterize anticancer potency. Several diarylheptanoids and epoxidic diarylheptanoids were effective DPPH radical scavengers and moderately effective at inhibiting xanthine oxidase. An enone-dione analog of 6-shogaol (compound 2) was isolated and identified to be most effective at protecting PC12 cells from H₂O₂-induced damage. Almost all tested compounds inhibited lipid peroxidation. Three compounds, 6-shogaol, 10-gingerol and an enone-diarylheptanoid analog of curcumin (compound 6) were identified to be cytotoxic in cell lines tested, with KB and HL60 cells most susceptible to 6-shogaol and the curcumin analog with IC₅₀<10 μM. QSAR analysis revealed cytotoxicity was related to compound lipophilicity and chemical reactivity. In conclusion, we observed distinct compounds in fresh ginger to have biological activities relevant in diseases associated with reactive oxygen species.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Biphenyl Compounds; Catechols; Curcumin; Cytoprotection; Fatty Alcohols; HL-60 Cells; Humans; Hydrogen Peroxide; Hydrophobic and Hydrophilic Interactions; KB Cells; Lipid Peroxidation; Neoplasms; PC12 Cells; Phenols; Phytotherapy; Picrates; Plant Bark; Plant Extracts; Plant Roots; Rats; Xanthine Oxidase; Zingiber officinale

The natural product curcumin has gained considerable attention in recent years for its multiple pharmacological activities, but more efforts are needed to understand how curcumin can have these pharmacological effects considering its low bioavailability. In addition, it is unclear how curcumin exerts inhibitory effects against numerous enzymes, especially those that cannot accommodate curcumin within recognized binding pockets. By analyzing the similarities between the biological activities of curcumin and its degradation products against diseases such as Alzheimer's disease and cancer, as well as the preferential inhibition of some enzymes by degradation products, it appears that the bioactive degradation products may contribute to the pharmacological effects of curcumin. This possibility should be given full attention when elucidating the pharmacology of this promising natural product for various diseases.

Topics: Alzheimer Disease; Animals; Curcumin; Humans; Neoplasms; Proteolysis

3,4-Dihydropyrimidinones of curcumin were synthesized in excellent yield by multi-component one-pot condensation of curcumin, substituted aromatic aldehydes and urea/thiourea under solvent free conditions using SnCl(2)·2H(2)O catalyst. All the synthesized compounds have been characterized by IR, (1)H NMR, (13)C NMR, Mass spectra as well as elemental analyses. The synthesized compounds 4a-n were evaluated for their synergistic antimicrobial (antibacterial and antifungal) activity against bacteria and fungi. Zone of inhibition was measured by adopting disc diffusion method. In vitro minimum inhibitory concentrations were measured using broth microdilution and food poisoning method. In addition to this in vitro cytotoxicity of synthesized compounds against three human cancer lines Hep-G2, HCT-116 and QG-56 were also evaluated. Most of the compounds showed interesting antimicrobial and cytotoxic activity as compared to curcumin, that is, the compounds derived from 2-hydroxy benzaldehyde, 4-hydroxy benzaldehyde and 4-hydroxy-3-methoxy benzaldehyde showed the highest biological activity as compared to other compounds.

Topics: Anti-Infective Agents; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Drug Design; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Neoplasms; Pyrimidinones

Topics: Alzheimer Disease; Animals; Curcumin; Humans; Neoplasms

Histone deacetylase inhibitors (HDACi) are actively explored as new-generation epigenetic drugs but have low efficacy in cancer monotherapy. To reveal new mechanism for combination therapy, we show that HDACi induce cell death but simultaneously activate tumor-progressive genes to ruin therapeutic efficacy. Combined treatments to target tumorigenesis and HDACi-activated metastasis with low toxic modalities could develop new strategies for long-term cancer therapy.. Because metastasis is the major cause of cancer mortality, we measured cell migration activity and profiled metastasis-related gene expressions in HDACi-treated cancer cells. We developed low toxic combination modalities targeting tumorigenesis and HDACi-activated metastasis for preclinical therapies in mice.. We showed that cell migration activity was dramatically and dose dependently enhanced by various classes of HDACi treatments in 13 of 30 examined human breast, gastric, liver, and lung cancer cell lines. Tumor metastasis was also enhanced in HDACi-treated mice. HDACi treatments activated multiple PKCs and downstream substrates along with upregulated proapoptotic p21. For targeting tumorigenesis and metastasis with immediate clinical impact, we showed that new modalities of HDACi combined drugs with PKC inhibitory agent, curcumin or tamoxifen, not only suppressed HDACi-activated tumor progressive proteins and cell migration in vitro but also inhibited tumor growth and metastasis in vivo.. Treatments of different structural classes of HDACi simultaneously induced cell death and promoted cell migration and metastasis in multiple cancer cell types. Suppression of HDACi-induced PKCs leads to development of low toxic and long-term therapeutic strategies to potentially treat cancer as a chronic disease.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Movement; Cell Survival; Cell Transformation, Neoplastic; Combined Modality Therapy; Curcumin; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Neoplasm Metastasis; Neoplasms; Protein Kinase C; Tamoxifen

To utilize a novel type of polymer-drug conjugate micelle to enhance the delivery of low-potency curcumin.. Multiple curcumin molecules were conjugated to poly(lactic acid) (PLA) via tris(hydroxymethyl)aminomethane (Tris) linker producing the hydrophobic drug-binding block; methoxy-poly(ethylene glycol) (mPEG) was employed as the hydrophilic block. Micelles were characterized by size, loading capacity, stability, and critical micelle concentration (CMC). Human hepatocellular carcinoma (HepG2) cells were employed to assess cytotoxicity and intracellular targeting ability of micelles.. mPEG-PLA-Tris-Cur micelles were within nanorange (<100 nm). CMC of such micelles (2.3 ± 0.4 μg/mL) was 10 times lower than mPEG-PLA micelles (27.4 ± 0.8 μg/mL). Curcumin loading in mPEG-PLA-Tris-Cur micelles reached 18.5 ± 1.3% (w/w), compared to traditional mPEG-PLA micelles at 3.6 ± 0.4% (w/w). IC(50) of mPEG-PLA-Tris-Cur micelles (~22 μg/mL at curcumin-equivalent dose) was similar to unmodified curcumin. Placebo and drug-encapsulated conjugate micelles could be efficiently internalized to cytoplasmic compartment of HepG2 cells.. Micelle-forming polymer-drug conjugates containing multiple drug molecules were an efficient means to increase loading and intracellular delivery of low-potency curcumin.

Topics: Antineoplastic Agents; Cell Survival; Curcumin; Drug Carriers; Hep G2 Cells; Humans; Micelles; Neoplasms; Polyesters; Polyethylene Glycols

Organometallic ruthenium(II) complexes of general formula [(η(6)-arene)Ru(curcuminato)Cl], with arene being p-iPrC6 H4Me (1), C6H6 (2), and C6Me6 (3), were synthesized, characterized, and evaluated for their antitumor effects. Specifically, we explored their ability to regulate the proteasome, a validated pharmacological target in cancer treatment. Ruthenium complexes inhibited isolated proteasomes to various extents, with the biological activity of these complexes depending on the nature of the bound arene; in particular, [(η(6)-arene)Ru(curcuminato)Cl] 2 suppressed proteasomal activities more potently than 1, 3, or free curcumin. Each complex also inhibited proteasomes in cultured colon cancer cells and consequently triggered apoptosis, with the [(η(6)-benzene)Ru(curcuminato)Cl] complex 2 being the most active. The influence on the oxidative status of HCT116 cells and the DNA binding ability of the [(η(6)-arene)Ru(curcuminato)Cl] complexes were studied. Complex 2 showed the highest antioxidant capacity; moreover, complexes 1 and 2 were shown to bind isolated DNA with higher affinity (up to threefold) than free curcumin. Collectively, our results demonstrate that the complexation of curcumin with ruthenium(II) is a promising starting point for the development of curcumin-based anticancer drugs.

Topics: Antineoplastic Agents; Apoptosis; Curcumin; DNA; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Neoplasms; Oxidative Stress; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Ruthenium

Fine particulate matter (PM₂.₅) has been associated in humans with inflammation, oxidative stress and cancer. Studies had shown that curcumin could potentially inhibit these effects; however, there had been no in vivo or in vitro reports about the effects of curcumin on organisms exposed to PM₂.₅. This predictive study explored the possible biological functions and pathways involved in the mechanism of curcumin inhibition of the hazardous effects of PM₂.₅. For predictive analysis, microarray data were used to investigate the effect of PM₂.₅ on human bronchial epithelial cells (HBEC), and human target proteins of curcumin were retrieved from PubChem. Two protein-protein interaction (PPI) networks were established based upon differential genes and target proteins, respectively, and the common network of these two networks was found. Functional and pathway analysis of the common network was performed using the Ingenuity Pathways Analysis (IPA) software. The results suggested that the predictive effects of curcumin on HBEC exposed to PM₂.₅ were involved in bio-functions, including inflammatory response of airway, cancerogenesis, and apoptosis, and in pathways such as cancer, glucocorticoid receptor signaling, and NF-kappaB signaling. This study predicted for the first time that curcumin could be a potential therapeutic agent for protecting the human airway from the hazardous effects of PM₂.₅.

Topics: 14-3-3 Proteins; Bronchi; Curcumin; Databases, Chemical; Environmental Exposure; Epithelial Cells; Gene Expression Profiling; Gene Expression Regulation; Humans; Neoplasms; NF-kappa B; Particle Size; Particulate Matter; Phosphatidylinositol 3-Kinases; Protein Interaction Maps; Proto-Oncogene Proteins c-akt; Signal Transduction

Curcumin is reported to show potent in vitro anticancer effects in a surfeit of human cancer cell lines and majorly in the carcinogenesis of GIT, in animals. Its poor pharmacokinetics and stability limit its vivo clinical efficacy for the other systemic cancers. We recently reported on a 32-155 times enhancement in bioavailability of curcumin when incorporated into solid lipid nanoparticles (C-SLNs). Presently we report on a 54-85% reduction in IC 50 values with developed C-SLNs in comparison to free curcumin against a panel of human cancer cell lines (HL-60, A549, and PC3). Results demonstrate mechanisms similar to those claimed for free curcumin, including induction of cellular apoptosis by activation of caspases, release of cyctochrome c, loss of membrane potential, blockade of nuclear factor kappa B (NF-κB) activation, and upregulation of TNF-R for C-SLNs. However, the extent of cell death provided by C-SLNs in all these tests was significantly higher (p < 0.001). This may be attributed to the presentation of curcumin in a dispersible/soluble form which enhanced permeability across the cell surface. The display of significantly better in vitro anticancer effect coupled with high in vivo bioavailability points toward a great potential of using C-SLNs for cancer therapeutics.

Topics: Antineoplastic Agents; Apoptosis; Biological Availability; Blotting, Western; Caspases; Cell Cycle; Cell Proliferation; Curcumin; Flow Cytometry; Humans; Lipids; Membrane Potential, Mitochondrial; Microscopy, Fluorescence; Nanoparticles; Neoplasms; NF-kappa B; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents; Apoptosis; Curcumin; DNA; Electrophoresis, Agar Gel; Humans; Intercalating Agents; Neoplasms

Topics: Animals; Antineoplastic Agents; Apoptosis; Curcumin; DNA; Electrophoresis, Agar Gel; Humans; Intercalating Agents; Neoplasms

Nucleophosmin (NPM/B23) is a nucleolar phosphoprotein involved in cellular response to many different stimuli. Herein, we studied the molecular mechanism of NPM/B23 induction by curcumin, a natural AP-1 inhibitor with antitumor properties. Exposure to 5-30 μM curcumin significantly and dose-dependently increased the level of NPM/B23 in non-transformed NIH 3T3 cells but not HeLa cells and F9 cells. Besides, the transformed F9 and HeLa cells are more sensitive to curcumin-induced cell death and growth inhibition than NIH 3T3 cells. Overexpression of c-Jun, but not c-Fos, decreased ∼40% of NPM/B23 and enhanced the sensitivity of NIH 3T3 cells to 30 μM curcumin. Furthermore, down-regulation of NPM/B23 by transfection with NPM/B23 antisense plasmid enhanced the sensitivity to curcumin-induced cell death and growth inhibition. These results indicated that NPM/B23 expression regulates cellular sensitivity to curcumin. Besides, NPM/B23 knockdown may facilitate as a novel strategy to promote the sensitivity of cancer cells to curcumin.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Cell Line, Transformed; Cell Proliferation; Cell Survival; Curcumin; Embryonal Carcinoma Stem Cells; HeLa Cells; Humans; Mice; Neoplasms; NIH 3T3 Cells; Nuclear Proteins; Nucleophosmin; Oligonucleotides, Antisense; Osmolar Concentration; Proto-Oncogene Proteins c-jun; Signal Transduction; Transcription Factor AP-1; Up-Regulation

Curcumin has been studied as a potential drug for many diseases including cancer. One of the serious limitations projected on curcumin is its poor water solubility and the substantially low bioavailability. With a view to enhance the aqueous solubility of curcumin, we synthesized polyvinylpyrrolidone-curcumin conjugates. Polyvinylpyrrolidone was used for the conjugation considering its long history of safe usage as a biomaterial for various medical applications. The drug conjugates self-assembled in aqueous solution to form nanosized micellar aggregates. The formation of micellae stabilized curcumin against hydrolytic degradation. Another interesting feature of the conjugate was its cationic nature. The net zeta potential in the pH range from 3 to 7.4 was +25 to +20 mV, reflecting the potential stability of the conjugate micellae at physiological pH. We quantified cytotoxic potential of the conjugate by the MTT assay, using L929 fibroblast cells. The results showed that the conjugate had higher cytotoxicity than that of the free curcumin. It is expected that the relative enhanced cytotoxicities are the result of enhanced aqueous solubility and polymer-mediated drug internalization. The conjugate has the potential to circumvent limitations of curcumin and thereby to extrapolate further its applications as an effective anticancer drug.

Topics: Animals; Antineoplastic Agents; Cations; Cell Line, Tumor; Cell Survival; Curcumin; Drug Stability; Fibroblasts; Humans; Mice; Micelles; Neoplasms; Povidone; Solubility

The interest in nanosuspensions by the pharmaceutical industry is increasing given several nanosuspension products currently on the market for poorly soluble drugs. In this study, a novel dosage form for curcumin (CUR), CUR nanosuspension (CUR-NS), was successfully prepared by high pressure homogenization to improve CUR's cytotoxicity, as well as improve its application via intravenous injection. Characterization of the CUR-NS was evaluated by morphology, size, zeta potential, solubility, dissolution rate, and crystal state of drug. The nanoparticles for CUR-NS presented a sphere-like shape under transmission electron microscopy with an average diameter of 250.6 nm and the zeta potential of CUR-NS was -27.92 mV. Solubility and dissolution rate of CUR in the form of CUR-NS were significantly increased due to the small particle size and the crystalline state of CUR was preserved to increase its stability against degradation. Superior cytotoxicity in Hela and MCF-7 cells was obtained for CUR-NS compared with CUR solution. The safety evaluation showed that, compared with the CUR solution, CUR-NS provided less local irritation and phlebitis risks, lower rate of erythrocyte hemolysis. These findings suggest that CUR-NS may represent a promising new drug formulation for intravenous administration in the treatment of certain cancers.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chemical Phenomena; Chemistry, Pharmaceutical; Curcumin; Drug Stability; Erythrocytes; Freeze Drying; HeLa Cells; Hemolysis; Humans; Injections, Intravenous; Microscopy, Electron, Transmission; Nanoparticles; Nanotechnology; Neoplasms; Rabbits; Suspensions

Curcumin's benefits on tumorigenesis are thought to be mediated by its antiinflammatory activity; however, these effects have not been well characterized in a mouse model of colon cancer. We examined the effects of curcumin on intestinal inflammation in the Apc(Min/+) mouse. Apc(Min/+) mice were given a placebo or curcumin (2%) diet from 4 to 18 weeks of age (n = 10/group). C57BL/6 mice were used as a wild-type control (n = 10/group). Intestines were analyzed for polyp burden (sections 1, 4, and 5) and for mRNA expression, and concentration of interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and chemokine ligand 2 (CCL2) (sections 2 and 3). Plasma was collected for concentration of CCL2. Curcumin decreased total intestinal polyps by 75% (P < 0.05) in all size categories [>2 mm (65%), 1-2 mm (72%), <1 mm (82%); P < 0.05]. mRNA expression of IL-1β, IL-6, tumor necrosis factor-α, and CCL2 was elevated (P < 0.05) and curcumin blunted this increase (P < 0.05). Protein concentration of IL-1β, IL-6 (section 3), and CCL2 was increased (P < 0.05) and curcumin reduced this response for IL-1β (section 2) and CCL2 (P < 0.05). Curcumin also offset the increase in plasma CCL2 (P < 0.05). The benefits of curcumin in colon cancer may be at least in part mediated by its antiinflammatory activity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Curcumin; Cytokines; Diet; Female; Inflammation; Intestinal Mucosa; Intestines; Male; Mice; Mice, Inbred C57BL; Neoplasms; Random Allocation

The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chemical and metabolic instability. Non-enzymatic degradation has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative cyclization of the heptadienone moiety as a major pathway of degradation. Autoxidative transformation of curcumin was pH-dependent with the highest rate at pH 8 (2.2 μM/min) and associated with stoichiometric uptake of O(2). Oxidation was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nm; 7.5 μM/min), and the rate was increased ≈10-fold by the addition of 300 μM H(2)O(2). The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by the peroxidase activity. We propose a mechanism of enzymatic or autoxidative hydrogen abstraction from a phenolic hydroxyl to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H(2)(18)O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage products were negligible. Oxidation to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs. It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes to its cancer chemopreventive activity.

Topics: Animals; Antineoplastic Agents; Buffers; Cell Transformation, Neoplastic; Cells, Cultured; Curcumin; Cyclooxygenase 2; Humans; Macrophages; Mice; Neoplasms; Oxidation-Reduction; Oxygen; Placental Lactogen; Signal Transduction; Spodoptera

Curcumin is a polyphenol derived from the plant Curcuma longa that induces apoptotic cell death in malignant cancer cell lines. It has been shown previously that mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) plays an essential role in defense against oxidative stress by supplying NADPH for antioxidant systems. This study demonstrates that curcumin decreased the activity of IDPm, both as a purified enzyme and in cultured cells. It also shows that curcumin-induced apoptosis in the colon cancer cell line HCT116 is significantly enhanced by suppression of IDPm activity. Transfection of HCT116 cells with an IDPm small interfering RNA (siRNA) markedly decreased activity of IDPm, enhancing cellular susceptibility to curcumin-induced apoptosis, as reflected by DNA fragmentation, cellular redox status, mitochondria dysfunction and modulation of apoptotic marker proteins. Together, these results suggest that application of curcumin together with IDPm siRNA may be an effective combination modality in the treatment of cancer.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Curcumin; DNA Fragmentation; Drug Synergism; Escherichia coli; HCT116 Cells; HeLa Cells; Humans; Isocitrate Dehydrogenase; Mitochondria; Mutagenesis, Site-Directed; NADP; Neoplasms; Oxidation-Reduction; Oxidative Stress; Recombinant Proteins; RNA, Small Interfering; Transfection

This work reports the surface functionalization of polymeric PLGA nanoparticles by non-covalent insertion of a homo-bifunctional chemical crosslinker, bis(sulfosuccinimidyl) suberate (BS3) for targeted cancer therapy. We dissolved BS3 in aqueous solution of PVA during formulation of nanoparticles by a modified solid/oil/water emulsion solvent evaporation method. The non-covalent insertion of BS3 was confirmed by Fourier transform infrared (FTIR) spectroscopy. Curcumin and annexin A2 were used as a model drug and a cell specific target, respectively. Nanoparticles were characterized for particle size, zeta potential and surface morphology. The qualitative assessment of antibody attachment was performed by transmission electron microscopy (TEM) as well as confocal microscopy. The optimized formulation showed antibody attachment of 86%. However, antibody attachment was abolished upon blocking the functional groups of BS3. The availability of functional antibodies was evaluated by the presence of a light chain fraction after gel electrophoresis. We further evaluated the in vitro release kinetics of curcumin from antibody coated and uncoated nanoparticles. The release of curcumin is enhanced upon antibody attachment and followed an anomalous release pattern. We also observed that the cellular uptake of nanoparticles was significantly higher in annexin A2 positive cells than in negative cells. Therefore, these results demonstrate the potential use of this method for functionalization as well as to deliver chemotherapeutic agents for treating cancer.

Topics: Antibodies; Cell Line, Tumor; Cross-Linking Reagents; Curcumin; Drug Delivery Systems; Humans; Kinetics; Lactic Acid; Microscopy, Confocal; Nanoparticles; Neoplasms; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Spectroscopy, Fourier Transform Infrared; Succinimides; Surface Properties

Curcumin exhibits significant antitumorigenic activity in various preclinical models; data supporting its chemopreventive activity in humans, however, are lacking. To our knowledge, the first published results of a phase II chemoprevention study of curcumin are reported in this issue of the journal by Carroll and colleagues (beginning on page 354), who examined the effects of oral curcumin on various putative biomarkers of colonic tumorigenesis in smokers. This perspective discusses the potential significance and limitations of the current study findings in addressing the question of whether curcumin is clinically active as a chemopreventive agent.

Topics: Anticarcinogenic Agents; Apoptosis; Biological Availability; Biomarkers, Tumor; Chemoprevention; Clinical Trials as Topic; Curcumin; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Neoplasms; Research Design; Smoking; Treatment Outcome

Topics: Animals; Brassica; Breeding; Cooking; Curcumin; Diet; Fruit; Genetic Variation; Genistein; Genome, Human; Humans; Isothiocyanates; Metagenome; Mice; Neoplasms; Phytotherapy; Rats; Reproducibility of Results; Resveratrol; Risk Management; Stilbenes; Sulfoxides; Thiocyanates; Time Factors; Vegetables

Curcumin (CU) loaded solid lipid nanoparticles (SLNs) of fatty acids (FA) were prepared with a coacervation technique based on FA precipitation from their sodium salt micelles in the presence of polymeric non-ionic surfactants. Myristic, palmitic, stearic, and behenic acids, and different polymers with various molecular weights and hydrolysis grades were employed as lipid matrixes and stabilisers, respectively. Generally, spherical-shaped nanoparticles with mean diameters below 500 nm were obtained, and using only middle-high hydrolysis, grade-polymer SLNs with diameters lower than 300 nm were produced. CU encapsulation efficiency was in the range 28-81% and highly influenced by both FA and polymer type. Chitosan hydrochloride was added to FA SLN formulations to produce bioadhesive, positively charged nanoparticles. A CU-chitosan complex formation could be hypothesised by DSC analysis, UV-vis spectra and chitosan surface tension determination. A preliminary study on HCT-116 colon cancer cells was developed to evaluate the influence of CU-loaded FA SLNs on cell viability.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcuma; Curcumin; Drug Carriers; Fatty Acids; Humans; Nanoparticles; Neoplasms

This paper aims to investigate the metabolism and pharmacokinetics of curcumin, demethoxycurcumin and bisdemethoxycurcumin in mice tumor. To improve water solubility, nanoparticle formulations were prepared as curcuminoids-loaded solid lipid nanoparticles (curcuminoids-SLNs) and curcumin-loaded solid lipid nanoparticles (curcumin-SLNs). After intragastric administration to tumor-bearing ICR mice, the plasma and tumor samples were analyzed by liquid chromatography with ion trap mass spectrometry. We discovered that curcuminoids were mainly present as glucuronides in plasma, whereas in free form in tumor tissue. A validated LC/MS/MS method was established to determine the three free curcuminoids in tumor homogenate. Samples were separated on a Zorbax SB-C(18) column, eluted with acetonitrile-water (containing 0.1% formic acid), and detected by TSQ Quantum triple quadrupole mass spectrometer in selected reaction monitoring mode. The method showed good linearity (r(2)=0.997-0.999) over wide dynamic ranges (2-6000 ng/mL). Variations within- and between-batch never exceeded 11.2% and 13.4%, respectively. The extraction recovery rates ranged from 78.3% to 87.7%. The pharmacokinetics of curcuminoids in mice tumor fit two-compartment model and first order elimination. For curcumin-SLNs group, the dosing of 250 mg/kg of curcumin resulted in AUC((0-48 h)) of 2285 ngh/mL and C(max) of 209 ng/mL. For curcuminoids-SLNs group, the dosing equivalent to 138 mg/kg of curcumin resulted in higher tumor concentrations (AUC=2811 ngh/mL, C(max)=285 ng/mL). It appeared that co-existing curcuminoids improved the bioavailability of curcumin.

Topics: Animals; Area Under Curve; Biphenyl Compounds; Chromatography, Liquid; Curcumin; Diarylheptanoids; Drug Delivery Systems; Drug Stability; Lignans; Linear Models; Lipids; Male; Mice; Mice, Inbred ICR; Nanoparticles; Neoplasm Transplantation; Neoplasms; Reproducibility of Results; Tandem Mass Spectrometry

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; Chronic Disease; Clinical Trials as Topic; Contraindications; Curcumin; Herb-Drug Interactions; Humans; Inflammation; Medicine, Ayurvedic; Neoplasms; Plants, Medicinal

We report a nanoformulation of curcumin with a tripolymeric composite for delivery to cancer cells. The composite nanoparticles (NPs) were prepared by using three biocompatible polymers-alginate (ALG), chitosan (CS), and pluronic-by ionotropic pre-gelation followed by polycationic cross-linking. Pluronic F127 was used to enhance the solubility of curcumin in the ALG-CS NPs. Atomic force and scanning electron microscopic analysis showed that the particles were nearly spherical in shape with an average size of 100 +/- 20 nm. Fourier transform-infrared analysis revealed potential interactions among the constituents in the composite NPs. Encapsulation efficiency (%) of curcumin in composite NPs showed considerable increase over ALG-CS NPs without pluronic. The in vitro drug release profile along with release kinetics and mechanism from the composite NPs were studied under simulated physiological conditions for different incubation periods. A cytotoxicity assay showed that composite NPs at a concentration of 500 microg/mL were nontoxic to HeLa cells. Cellular internalization of curcumin-loaded composite NPs was confirmed from green fluorescence inside the HeLa cells. The half-maximal inhibitory concentrations for free curcumin and encapsulated curcumin were found to be 13.28 and 14.34 muM, respectively.. A nanoformulation of curcumin with a tri-component polymeric composite for delivery to cancer cells is reported in this paper. Cellular internalization of curcumin loaded composite nanoparticles was confirmed from green fluorescence inside the HeLa cells.

Topics: Alginates; Cell Death; Cell Survival; Chitosan; Curcumin; Drug Delivery Systems; Glucuronic Acid; HeLa Cells; Hexuronic Acids; Humans; Kinetics; Microscopy, Fluorescence; Nanocomposites; Nanoparticles; Neoplasms; Particle Size; Poloxamer; Spectroscopy, Fourier Transform Infrared

Topics: Animals; Antineoplastic Agents; Curcumin; Humans; Neoplasms

Immune dysfunction is well documented during tumor progression and likely contributes to tumor immune evasion. CD8(+) cytotoxic T lymphocytes (CTLs) are involved in antigen-specific tumor destruction and CD4(+) T cells are essential for helping this CD8(+) T cell-dependent tumor eradication. Tumors often target and inhibit T-cell function to escape from immune surveillance. This dysfunction includes loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells. Curcumin has previously been shown to have antitumor activity and some research has addressed the immunoprotective potential of this plant-derived polyphenol in tumor-bearing hosts. Here we examined the role of curcumin in the prevention of tumor-induced dysfunction of T cell-based immune responses. We observed severe loss of both effector and memory T-cell populations, downregulation of type 1 and upregulation of type 2 immune responses and decreased proliferation of effector T cells in the presence of tumors. Curcumin, in turn, prevented this loss of T cells, expanded central memory T cell (T(CM))/effector memory T cell (T(EM)) populations, reversed the type 2 immune bias and attenuated the tumor-induced inhibition of T-cell proliferation in tumor-bearing hosts. Further investigation revealed that tumor burden upregulated Treg cell populations and stimulated the production of the immunosuppressive cytokines transforming growth factor (TGF)-beta and IL-10 in these cells. Curcumin, however, inhibited the suppressive activity of Treg cells by downregulating the production of TGF-beta and IL-10 in these cells. More importantly, curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Overall, our observations suggest that the unique properties of curcumin may be exploited for successful attenuation of tumor-induced suppression of cell-mediated immune responses.

Topics: Adaptive Immunity; Animals; Antineoplastic Agents; CD4 Antigens; Cell Proliferation; Curcumin; Cytotoxicity, Immunologic; Down-Regulation; Drug Screening Assays, Antitumor; Forkhead Transcription Factors; Immunologic Memory; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Lymphocyte Depletion; Mice; Neoplasms; Survival Analysis; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Curcumin, the natural anticancer drug and its optimum potential is limited due to lack of solubility in aqueous solvent, degradation at alkaline pH and poor tissue absorption. In order to enhance its potency and improve bioavailability, we have synthesized curcumin loaded nanoparticulate delivery system. Unlike free curcumin, it is readily dispersed in aqueous medium, showing narrow size distribution 192 nm ranges (as observed by microscope) with biocompatibility (confocal studies and TNF-alpha assay). Furthermore, it displayed enhanced stability in phosphate buffer saline by protecting encapsulated curcumin against hydrolysis and biotransformation. Most importantly, nanoparticulate curcumin was comparatively more effective than native curcumin against different cancer cell lines under in vitro condition with time due to enhanced cellular uptake resulting in reduction of cell viability by inducing apoptosis. Molecular basis of apoptosis studied by western blotting revealed blockade of nuclear factor kappa B (NFkappaB) and its regulated gene expression through inhibition of IkappaB kinase and Akt activation. In mice, nanoparticulate curcumin was more bioavailable and had a longer half-life than native curcumin as revealed from pharmacokinetics study. Thus, the results demonstrated nanoparticulate curcumin may be useful as a potential anticancer drug for treatment of various malignant tumors.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Drug Stability; Humans; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasms; Solubility; Water

Curcumin (diferuloylmethane) is the main active ingredient of turmeric, a traditional herbal medicine and food of south Asia. Curcumin has been found to have a wide range of biological activities, including antioxidant, anti-inflammatory, chemopreventive and chemotherapeutic activities. Curcumin is currently being tested in clinical trials for treatment of various types of cancers, including multiple myeloma, pancreatic cancer and colon cancer. Although no toxicity associated with curcumin (even at very high doses) has been observed, the effects of curcumin in other solid tumors have been modest, primarily due to poor water solubility and poor bioavailability in tissues remote from the gastrointestinal tract. Therefore, there is a need for the discovery of curcumin analogs with better water solubility or greater bioavailability for the treatment of solid tumors such as prostate cancer. In this study, curcumin acetates and amino acid conjugates of curcumin were studied in terms of their proteasome inhibitory and antiproliferative effects against several human cancer cell lines. It was found that the water soluble amino acid conjugates of curcumin showed a potent antiproliferative effect and are potent proteasome inhibitors. Docking studies of the curcumin amino acid conjugates for proteasome inhibition were carried out to explain their biological activities. It is suggested that they may serve as the water soluble analogs of curcumin.

Topics: Acetates; Amino Acids; Antineoplastic Agents; Cell Line, Tumor; Curcuma; Curcumin; Enzyme Inhibitors; Humans; Models, Molecular; Neoplasms; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Binding; Solubility

To determine the reversal effects of ramification of curcumin hydrolyzed on multidrug-resistant cell line K562/A02, and explore its reversal mechanism.. After treatment with ramification of curcumin hydrolyzed, the sensitivity of K562/A02 cells to usuall chemotherapeutic drugs were determined by MTT. The expression of P-gp in K562/A02 and K562 cells was detected by immunohistochemical method. Intracellular mean fluorescence intensity (MFI) of DNR in K562 and K562/A02 cells was detected by Flow Cytometry.. After treatment with the ramification of curcumin, hydrolyzed (2.5 mg x L(-1)) IC50, of usuall chemotherapeutic drugs to K562/A02 decreased. The sensitivity of K562/A02 cells increased. The expression of the P-gp in K562/A02 cells decreased (P < 0.05); MFI of the DNR in K562/A02 cells more significantly increased (P < 0.05). The expression of mdrl-mRNA decreased.. The ramification of curcumin hydrolyzed have effects on the reversal multidrug-resistant of K562/A02 cells in vitro. It could enhance the sensitivity of K562/A02 cells to chemotherapeutic drugs and the mechanism might be associated with inhibiting P-gp-mediated drug efflux and increasing of intracellular concentration of chemotherapeutic drugs.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs, Chinese Herbal; Gene Expression; Humans; K562 Cells; Neoplasms

As cancer is a multifactor disease, it may require treatment with compounds able to target multiple intracellular components. We summarize here how curcumin is able to modulate many components of intracellular signaling pathways implicated in inflammation, cell proliferation and invasion and to induce genetic modulations eventually leading to tumor cell death. Clinical applications of this natural compound were initially limited by its low solubility and bioavailability in both plasma and tissues but combination with adjuvant and delivery vehicles was reported to largely improve bio-availability of curcumin. Moreover, curcumin was reported to act in synergism with several natural compounds or synthetic agents commonly used in chemotherapy. Based on this, curcumin could thus be considered as a good candidate for cancer prevention and treatment when used alone or in combination with other conventional treatments.

Topics: Antineoplastic Agents; Biological Availability; Cell Proliferation; Curcumin; Humans; Neoplasms; Signal Transduction

The poor selectivity of anticancer drugs often leads to their multiplicate dose-limiting toxicities in humans, which severely restricts their clinical application. In this study, a novel liposomal formulation of zedoary turmeric oil (ZTO) targeting the insulin receptor (IR) was prepared by covalently conjugating insulin to the terminal of the polyethylene glycol (PEG) chain of sterically stabilized liposomes. In vitro assays indicated that a higher uptake of insulin-modified sterically stabilized liposomes (ISSLs) was observed in SMMC-7721 hepatocarcinoma cells overexpressing insulin receptors. IC(50) values of ISSLs, NTLs (nontargeted liposomes), and ZTO injection (free ZTO) against SMMC-7721, determined by MTT assays, were 157.2, 256.7, and 43.3 microg x ml(-1), respectively. Plasma-clearance profiles of ZTO in the liposomal formulations were then compared with that of ZTO injection. The liposomal formulations showed much longer terminal half-lives (11.24 and 14.73 hours for ISSLs and NTLs, respectively) than that of ZTO injection (1.45 hours). All results above indicated the ISSLs were potentially useful for the treatment of IR (+) tumors and are worthy of further investigation.

Topics: Curcuma; Dosage Forms; Doxorubicin; Humans; Insulin; Liposomes; Neoplasms; Oils; Plant Extracts; Polyethylene Glycols

Topics: Curcuma; Herb-Drug Interactions; Humans; Neoplasms; Phytotherapy

Curcumin is a natural polyphenolic derogate extracted from spice turmeric, exhibiting anti-inflammatory and chemopreventive activities. It was described to interact with the signalosome-associated kinases and the proteasome-ubiquitin system, which both are involved in the osteoclastogenesis. Thus, we hypothesized that curcumin could diminish osteoclast differentiation and function.. For the experiments considering osteoclast differentiation and resorptional activities, preosteoclasts were cultured for 4 weeks and treated with curcumin at subapoptotic dosages. Derived mature osteoclasts were identified as large, multinucleated cells with expression of tartrate-resistant acid phosphatase activity. Formation of resorption lacunae, a hallmark of osteoclast activity, was quantified using dentine pits and light microscopy. The signaling pathways were examined by ELISA-based methods and by immunoblotting.. Both 1 and 10 microM curcumin abrogated osteoclast differentiation (by 56 and 81%) and function (by 56 and 99%) (P < 0.05) dose-dependently. The effects were accompanied by the inhibition of I kappaB phosphorylation and NF-kappaB activation. In contrast, subtoxic doses did not have any significant effects on proteasome inhibition.. This manuscript is the first report that describes the effects of curcumin toward human osteoclastogenesis, and builds the framework for clinical trials of curcumin in the treatment of cancer-induced lytic bone disease.

Topics: Antineoplastic Agents; Bone Diseases; Bone Resorption; Cell Differentiation; Cell Survival; Curcumin; Enzyme-Linked Immunosorbent Assay; Humans; I-kappa B Kinase; Neoplasms; Osteoclasts; Reference Values; Transcription Factors

Curcumin is a natural product currently in human clinical trials for a variety of neoplastic, preneoplastic, and inflammatory conditions. We previously observed that, in cultured cells, curcumin exhibits properties of an iron chelator. To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, mice were placed on diets containing graded concentrations of both iron and curcumin for 26 weeks. Mice receiving the lowest level of dietary iron exhibited borderline iron deficiency, with reductions in spleen and liver iron, but little effect on hemoglobin, hematocrit, transferrin saturation, or plasma iron. Against this backdrop of subclinical iron deficiency, curcumin exerted profound 2 effects on systemic iron, inducing a dose-dependent decline in hematocrit, hemoglobin, serum iron, and transferrin saturation, the appearance of microcytic anisocytotic red blood cells, and decreases in spleen and liver iron content. Curcumin repressed synthesis of hepcidin, a peptide that plays a central role in regulation of systemic iron balance. These results demonstrate that curcumin has the potential to affect systemic iron metabolism, particularly in a setting of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.

Topics: Animals; Antimicrobial Cationic Peptides; Antineoplastic Agents; Curcumin; Food, Formulated; Hematocrit; Hemoglobins; Hepcidins; Humans; Iron Chelating Agents; Iron, Dietary; Liver; Mice; Mice, Inbred C3H; Neoplasms; Spleen; Transferrin

Topics: Administration, Oral; Aldehydes; Biological Availability; Clinical Trials as Topic; Curcumin; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Hot Temperature; Humans; Neoplasms; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Curcumin (diferuloylmethane), a biologically active ingredient derived from rhizome of the plant Curcuma longa, has potent anticancer properties as demonstrated in a plethora of human cancer cell lines/animal carcinogenesis model and also acts as a biological response modifier in various disorders. We have reported previously that dietary supplementation of curcumin suppresses renal ornithine decarboxylase (Okazaki et al. Biochim Biophys Acta 1740:357-366, 2005) and enhances activities of antioxidant and phase II metabolizing enzymes in mice (Iqbal et al. Pharmacol Toxicol 92:33-38, 2003) and also inhibits Fe-NTA-induced oxidative injury of lipids and DNA in vitro (Iqbal et al. Teratog Carcinog Mutagen 1:151-160, 2003). This study was designed to examine whether curcumin possess the potential to suppress the oxidative damage caused by kidney-specific carcinogen, Fe-NTA, in animals. In accord with previous report, at 1 h after Fe-NTA treatment (9.0 mg Fe/kg body weight intraperitoneally), a substantial increased formation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts in renal proximal tubules of animals was observed. Likewise, the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and protein reactive carbonyl, an indicator of protein oxidation, were also increased at 1 h after Fe-NTA treatment in the kidneys of animals. The prophylactic feeding of animals with 1.0% curcumin in diet for 4 weeks completely abolished the formation of (i) HNE-modified protein adducts, (ii) 8-OHdG, and (iii) protein reactive carbonyl in the kidneys of Fe-NTA-treated animals. Taken together, our results suggest that curcumin may afford substantial protection against oxidative damage caused by Fe-NTA, and these protective effects may be mediated via its antioxidant properties. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antioxidants; Carcinogens; Chemoprevention; Curcumin; Deoxyguanosine; Ferric Compounds; Kidney; Kidney Tubules, Proximal; Male; Mice; Neoplasms; Nitrilotriacetic Acid; Oxidative Stress; Proteins

Topics: Breast Neoplasms; Curcumin; Exosomes; Female; Heat-Shock Proteins; Humans; Liver Cirrhosis; Neoplasms; Paracrine Communication

Curcumin, the yellow pigment of the spice turmeric, has emerged as a promising anticancer agent due to its antiproliferative and antiangiogenic properties. However, the molecular mechanism of action of this compound remains a subject of debate. In addition, curcumin's low bioavailability and efficacy profile in vivo further hinders its clinical development. This study focuses on the mechanism of action of EF24, a novel curcumin analog with greater than curcumin biological activity and bioavailability, but no increased toxicity. Treatment of MDA-MB231 breast and PC3 prostate cancer cells with EF24 or curcumin led to inhibition of HIF-1alpha protein levels and, consequently, inhibition of HIF transcriptional activity. This drug-induced HIF inhibition occurred in a VHL-dependent but proteasome-independent manner. We found that, while curcumin inhibited HIF-1alpha gene transcription, EF24 exerted its activity by inhibiting HIF-1alpha posttranscriptionally. This result suggested that the two compounds are structurally similar but mechanistically distinct. Another cellular effect that further differentiated the two compounds was the ability of EF24, but not curcumin, to induce microtubule stabilization in cells. EF24 had no stabilizing effect on tubulin polymerization in an in vitro assay using purified bovine brain tubulin, suggesting that the EF24-induced cytoskeletal disruption in cells may be the result of upstream signaling events rather than EF24 direct binding to tubulin. In summary, our study identifies EF24 as a novel curcumin-related compound possessing a distinct mechanism of action, which we believe contributes to the potent anticancer activity of this agent and can be further exploited to investigate the therapeutic potential of EF24.

Topics: Antineoplastic Agents; Benzylidene Compounds; Cell Hypoxia; Curcumin; Cytoskeleton; Dose-Response Relationship, Drug; Down-Regulation; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Epothilones; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Microtubules; Mitosis; Neoplasms; Paclitaxel; Piperidones; Proteasome Endopeptidase Complex; Tumor Cells, Cultured; Von Hippel-Lindau Tumor Suppressor Protein

In cultured cells, curcumin (CUR) causes cell death by interfering with mitosis and leading to fragmented nuclei and disrupted microtubules, a process named mitotic catastrophe. In order to clarify the role of the known CUR metabolites hexahydro-CUR (HHC) and CUR-glucuronide (CUR-gluc) in mitotic catastrophe, the effects of CUR were studied in three human cancer cell lines with different metabolism of CUR. In Ishikawa and HepG2 cells, CUR was metabolized to HHC and small amounts of octahydro-CUR (OHC), whereas the only metabolism in HT29 cells was the formation of CUR-gluc. Despite their different metabolism, all three cell systems responded to CUR with arrest in G2/M phase and mitotic catastrophe. Fractionation of the cells showed that concentrations of CUR were higher in the ER and cytosol than in the incubation medium by a factor of up to about 150 and 8, respectively. In contrast to CUR, the metabolite HHC and the products of spontaneous degradation did not elicit any effects in Ishikawa cells. These results imply that the causative agent of mitotic catastrophe is the parent CUR molecule, whereas reductive metabolism and chemical degradation render CUR inactive.

Topics: Biotransformation; Cell Cycle; Cell Death; Cell Line, Tumor; Curcumin; Cytosol; DNA Fragmentation; DNA, Neoplasm; Humans; Kinetics; Mitosis; Neoplasms

In milk caseins exists a natural nanostructure, which can be exploited as a carrier of hydrophobic drugs. Here we investigated the complex formation of curcumin with bovine casein micelles (CMs) and its use as a vehicle for drug delivery to cancer cells. DLS studies of the CM suspension that was stable in buffer solution (pH 7.4) showed an average size distribution of <200 nm. SEM and AFM studies showed that the particles were roughly spherical in shape. Steady-state fluorescence spectroscopy of the CM-curcumin complex formation revealed that curcumin molecules formed complexes with CMs (CM-curcumin complex) through hydrophobic interactions. The binding constant for the CM-curcumin interaction was calculated to be 1.48 x 10(4) M(-1), as determined by the curcumin fluorescence. Fluorescence quenching showed that curcumin molecules quench the intrinsic fluorescence of caseins upon binding. We evaluated the utility of CMs as carriers of curcumin by using in vitro cultured HeLa cells. Cytotoxicity studies of HeLa cells revealed that the IC50 of free curcumin and the CM-curcumin complex was 14.85 and 12.69 microM, respectively.

Topics: Caseins; Cell Survival; Curcumin; Drug Carriers; HeLa Cells; Humans; Micelles; Microscopy, Atomic Force; Microscopy, Fluorescence; Models, Chemical; Molecular Conformation; Nanoparticles; Neoplasms; Protein Binding; Time Factors

Glyoxalases (Glo1 and Glo2) are involved in the glycolytic pathway by detoxifying the reactive methylglyoxal (MGO) into D-lactate in a two-step reaction using glutathione (GSH) as cofactor. Inhibitors of glyoxalases are considered as anti-inflammatory and anti-carcinogenic agents. The recent finding that various polyphenols modulate Glo1 activity has prompted us to assess curcumin's potency as an Glo1 inhibitor.. Cultures of whole blood cells and tumor cell lines (PC-3, JIM-1, MDA-MD 231 and 1321N1) were set up to investigate the effect of selected polyphenols, including curcumin, on the LPS-induced cytokine production (cytometric bead-based array), cell proliferation (WST-1 assay), cytosolic Glo1 and Glo2 enzymatic activity, apoptosis/necrosis (annexin V-FITC/propidium iodide staining; flow cytometric analysis) as well as GSH and ATP content. Results of enzyme kinetics revealed that curcumin, compared to the polyphenols quercetin, myricetin, kaempferol, luteolin and rutin, elicited a stronger competitive inhibitory effect on Glo1 (K(i) = 5.1+/-1.4 microM). Applying a whole blood assay, IC(50) values of pro-inflammatory cytokine release (TNF-alpha, IL-6, IL-8, IL-1beta) were found to be positively correlated with the K(i)-values of the aforementioned polyphenols. Moreover, whereas curcumin was found to hamper the growth of breast cancer (JIMT-1, MDA-MB-231), prostate cancer PC-3 and brain astrocytoma 1321N1 cells, no effect on growth or vitality of human primary hepatocytes was elucidated. Curcumin decreased D-lactate release by tumor cells, another clue for inhibition of intracellular Glo1.. The results described herein provide new insights into curcumin's biological activities as they indicate that inhibition of Glo1 by curcumin may result in non-tolerable levels of MGO and GSH, which, in turn, modulate various metabolic cellular pathways including depletion of cellular ATP and GSH content. This may account for curcumin's potency as an anti-inflammatory and anti-tumor agent. The findings support the use of curcumin as a potential therapeutic agent.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Blood Cells; Cell Proliferation; Cell Survival; Cells, Cultured; Curcumin; Drug Evaluation, Preclinical; Enzyme Inhibitors; Flavonoids; Humans; Interleukin-1beta; L-Lactate Dehydrogenase; Lactoylglutathione Lyase; Lipopolysaccharides; Models, Biological; Neoplasms; Phenols; Polyphenols; Substrate Specificity

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Curcumin; Humans; India; Medicine, Ayurvedic; Nanoparticles; Neoplasms; Solubility; Water

A deoxy 11-mer oligonucleotide 5'-GTTAGGGTTAG-3', complementary to a repeat sequence of human telomerase RNA template has been linked through phosphate and a C-2 linker to a bioactive tetraglycine conjugate of curcumin, a well-known antitumor herbal spice component of turmeric. This molecule has been transfected into KB and HeLa cell lines and found to affect cell growth in the former. This DNA-curcumin-tetraglycine acts as a prodrug being targeted by antisense mechanism to telomerase.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; DNA, Antisense; Humans; Neoplasms; Prodrugs; Telomerase; Transfection

Curcumin, a well-known chemopreventive agent, has been shown to suppress the proliferation of a wide variety of tumor cells through a mechanism that is not fully understood. Cyclin E, a proto-oncogene that is overexpressed in many human cancers, mediates the G(1) to S transition, is a potential target of curcumin. We demonstrate in this report a dose- and time-dependent down-regulation of expression of cyclin E by curcumin that correlates with the decrease in the proliferation of human prostate and breast cancer cells. The suppression of cyclin E expression was not cell type dependent as down-regulation occurred in estrogen-positive and -negative breast cancer cells, androgen-dependent and -independent prostate cancer cells, leukemia and lymphoma cells, head and neck carcinoma cells, and lung cancer cells. Curcumin-induced down-regulation of cyclin E was reversed by proteasome inhibitors, lactacystin and N-acetyl-L-leucyl-L-leucyl-L-norleucinal, suggesting the role of ubiquitin-dependent proteasomal pathway. We found that curcumin enhanced the expression of tumor cyclin-dependent kinase (CDK) inhibitors p21 and p27 as well as tumor suppressor protein p53 but suppressed the expression of retinoblastoma protein. Curcumin also induced the accumulation of the cells in G1 phase of the cell cycle. Overall, our results suggest that proteasome-mediated down-regulation of cyclin E and up-regulation of CDK inhibitors may contribute to the antiproliferative effects of curcumin against various tumors.

Topics: Cell Line, Tumor; Curcumin; Cyclin E; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Humans; Male; Neoplasms; Oncogene Proteins; Proto-Oncogene Mas; Ubiquitin; Up-Regulation

Topics: Alzheimer Disease; Curcuma; Curcumin; History, 20th Century; History, Ancient; Humans; Medicine, Traditional; Neoplasms; Patents as Topic; Phytotherapy; Rhizome; Spices

Patients with advanced cancer exhibit multifaceted defects in their immune capacity, which are likely to contribute to an increased susceptibility to infections and disease progression. We demonstrated earlier that curcumin inhibits tumor growth and prevents immune cell death in tumor-bearing hosts. Here we report that tumor-induced immunodepletion involves apoptosis of thymic CD4+/CD8+ single/double positive cells as well as loss of circulating CD4+/CD8+ T cells. Administration of curcumin to tumor-bearing animals resulted in restoration of progenitor, effecter, and circulating T cells. In fact, tumor burden decreased the expression level of the pro-proliferative protein Bcl-2 while increasing the pro-apoptotic protein Bax in T cells. Curcumin down-regulated the Bax level while augmenting Bcl-2 expression in these cells, thereby protecting the immunocytes from tumor-induced apoptosis. A search for the upstream mechanism revealed down-regulation of the common cytokine receptor gamma chain (gammac) expression in T cells by tumor-secreted prostaglandin E2. As a result, Jak-3 and Stat-5a phosphorylation and to a lesser extent Stat-5b phosphorylation were also decreased in T cells. These entire phenomena could be reverted back by curcumin, indicating that this phytochemical restored the cytokine-dependent Jak-3/Stat-5a signaling pathway in T cells of tumor bearers. Overexpressed Stat-5a/constitutively active Stat-5a1*6 but not Stat-5b could efficiently elevate Bcl-2 levels and protect T cells from tumor-induced death, whereas C-terminal truncated Stat-5a713 overexpression failed to do so, indicating the importance of Stat-5a signaling in T cell survival. Thus, these results raise the possibility of inclusion of curcumin in successful therapeutic regimens against cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Curcumin; Dinoprostone; Down-Regulation; Enzyme Activation; Humans; Interleukin Receptor Common gamma Subunit; Janus Kinase 3; Lymphocyte Depletion; Mice; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Recovery of Function; Signal Transduction; STAT5 Transcription Factor

Dietary phytochemicals exhibit chemopreventive potential in vivo through persistent low-dose exposures, whereas mechanistic in vitro studies with these agents generally use a high-dose single treatment. Because the latter approach is not representative of an in vivo steady state, we investigated antitumor activity of curcumin, 3,3'-diindolylmethane (DIM), epigallocatechin gallate (EGCG), genistein, or indole-3-carbinol (I3C) in breast cancer MDA-MB-231 cells, exposed in long-term culture to low concentrations, achievable in vivo. Curcumin and EGCG increased cell doubling time. Curcumin, EGCG, and I3C inhibited clonogenic growth by 55% to 60% and induced 1.5- to 2-fold higher levels of the basal caspase-3/7 activity. No changes in expression of cell cycle-related proteins or survivin were found; however, I3C reduced epidermal growth factor receptor expression, contributing to apoptosis. Because some phytochemicals are shown to inhibit DNA and histone modification, modulation of expression by the agents in a set of genes (cadherin-11, p21Cip1, urokinase-type plasminogen activator, and interleukin-6) was compared with changes induced by inhibitors of DNA methylation or histone deacetylation. The phytochemicals modified protein and/or RNA expression of these genes, with EGCG eliciting the least and DIM the most changes in gene expression. DIM and curcumin decreased cadherin-11 and increased urokinase-type plasminogen activator levels correlated with increased cell motility. Curcumin, DIM, EGCG, and genistein reduced cell sensitivity to radiation-induced DNA damage without affecting DNA repair. This model has revealed that apoptosis and not arrest is likely to be responsible for growth inhibition. It also implicated new molecular targets and activities of the agents under conditions relevant to human exposure.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers, Tumor; Catechin; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Diet; DNA Damage; Gene Expression Regulation, Neoplastic; Genistein; Humans; Indoles; Neoplasm Proteins; Neoplasms; RNA, Neoplasm; Time Factors

Topics: Alzheimer Disease; Antioxidants; Capsaicin; Cinnamomum zeylanicum; Curcumin; Cystic Fibrosis; Health Promotion; Humans; Hypercholesterolemia; Neoplasms; Phytotherapy; Plant Structures; Plants, Medicinal; Salvia officinalis; Spices

Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1alpha and aryl hydrocarbon receptor nuclear translocator (ARNT), plays a key role in cell survival and angiogenesis in hypoxic tumors, and many efforts have been made to develop anticancer agents that target HIF-1alpha. However, although ARNT is also required for HIF-1 activity, ARNT has been disregarded as a therapeutic target. Curcumin is a commonly used spice and coloring agent with a variety of beneficial biological effects, which include tumor inhibition. In the present study, we tested the possibility that curcumin inhibits tumor growth by targeting HIF-1. The effects of curcumin on HIF-1 activity and expression were examined in cancer cell lines and in xenografted tumors. We found that curcumin inhibits HIF-1 activity and that this in turn down-regulates genes targeted by HIF-1. Moreover, of the two HIF-1 subunits, only ARNT was found to be destabilized by curcumin in several cancer cell types, and furthermore, ARNT expression rescued HIF-1 repression by curcumin. We also found that curcumin stimulated the proteasomal degradation of ARNT via oxidation and ubiquitination processes. In mice bearing Hep3B hepatoma, curcumin retarded tumor growth and suppressed ARNT, erythropoietin, and vascular endothelial growth factor in tumors. These results suggest that the anticancer activity of curcumin is attributable to HIF-1 inactivation by ARNT degradation.

Topics: Animals; Antineoplastic Agents, Phytogenic; Aryl Hydrocarbon Receptor Nuclear Translocator; Cell Division; Cell Hypoxia; Curcumin; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1; Male; Mice; Mice, Nude; Neoplasms; Oxidation-Reduction; Oxidative Stress; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Protein Subunits; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured; Ubiquitin

Curcumin, derived from the rhizome curcuma longa, is one of the primary ingredients in turmeric and curry powders that are used as spices in Middle Eastern and Asian countries, especially on the Indian subcontinent. More recently, laboratory studies have demonstrated that dietary curcumin exhibits various biological activities and significantly inhibits colon tumorigenesis and tumor size in animals. Curcumin displays both anti-inflammatory and antioxidant properties, giving it the potential to be considered in the development of cancer preventive strategies and applications in clinical research. Experimental studies have shown the biological activities of the compound, but much more information on pharmacokinetics, bioavailability, and food content are needed. Whether the amount of curcumin in turmeric and curry powders is sufficient to suggest effects on biological activities and cancer risk is unknown. To determine and compare the quantitative amounts of curcumin that are present in several brands of turmeric and curry powders, a high performance liquid chromatography technique was used to analyze 28 spice products described as turmeric or curry powders and two negative controls. Pure turmeric powder had the highest curcumin concentration, averaging 3.14% by weight. The curry powder samples, with one exception, had relatively small amounts of curcumin present, and the variability in content was great. The curcumin content of these seasoning products that are consumed as a component of the diet should be considered in evaluating baseline tissue concentration and response to curcumin supplementation, which is under study in chemoprevention trials.

Topics: Animals; Antineoplastic Agents; Curcuma; Curcumin; Food Analysis; Humans; Murraya; Neoplasms; Phytotherapy; Spices

To evaluate the quality of randomized controlled trials (RCTs) for Elemene injections, one ingredient of Chinese herb Curcuma wenyujin, for malignant tumors widely used in clinical practice in China.. We used a systematic sample of 127 reports of RCTs that used Elemene injections as an intervention. The quality of each report was assessed using the number of Consolidated Standards for Reporting of Trials (CONSORT) checklist items included, the frequency of allocation concealment and a 5-point quality assessment instrument (Jadad).. 69.44% of the CONSORT checklist items was included in the reports. Only 2 (1.57%) RCTs reported allocation concealment by sealed envelopes. 123 (96.85%) reports described baseline demographic and clinical characteristics of each group. But only 5 (3.94%) of 127 RCTs reported statistics analysis results of baseline data. None of the reports stated in the methods section that intention-to-treat (ITT) analysis was used, although 111 (87.40%) reports described the number of participants (denominator) in each group included in each analysis. Information regarding adverse events was reported in 83.46% of the RCTs. However the quality of reports were low as assessed by the Jadad scale.. The methodological quality of RCTs of Elemene injection against malignant tumors was low. Therefore, the effect of Elemene injection being used in clinical settings needs to be confirmed by further RCTs. Meanwhile, there is a need to supervise and urge researchers in China to conform to Good Clinical Practice (GCP) and CONSORT guidelines when reporting.

Topics: Antineoplastic Agents; Curcuma; Databases, Factual; Drugs, Chinese Herbal; Humans; Neoplasms; Randomized Controlled Trials as Topic; Research Design; Sesquiterpenes

NAD(P)H:quinone oxidoreductase 1 (NQO1) regulates the stability of the tumor suppressor WT p53. NQO1 binds and stabilizes WT p53, whereas NQO1 inhibitors including dicoumarol and various other coumarins and flavones induce ubiquitin-independent proteasomal p53 degradation and thus inhibit p53-induced apoptosis. Here, we show that curcumin, a natural phenolic compound found in the spice turmeric, induced ubiquitin-independent degradation of WT p53 and inhibited p53-induced apoptosis in normal thymocytes and myeloid leukemic cells. Like dicoumarol, curcumin inhibited the activity of recombinant NQO1 in vitro, inhibited the activity of endogenous cellular NQO1 in vivo, and dissociated NQO1-WT p53 complexes. Neither dicoumarol nor curcumin dissociated the complexes of NQO1 and the human cancer hot-spot p53 R273H mutant and therefore did not induce degradation of this mutant. NQO1 knockdown by small-interfering RNA induced degradation of both WT p53 and the p53 R273H mutant. The results indicate that curcumin induces p53 degradation and inhibits p53-induced apoptosis by an NQO1-dependent pathway.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cells, Cultured; Curcumin; Humans; Mice; Mutation, Missense; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Thymus Gland; Tumor Suppressor Protein p53; Ubiquitin

Epidemiological studies have long hinted at the possibility that what we eat greatly influences our state of health, in particular our relative risk of developing cancer. In recent years there has been an exponential increase in the number of studies investigating how individual components of the diet interact at the molecular level to determine the fate of a cell. It is now apparent that many such molecules can preferentially inhibit the growth of tumour cells, by inducing cell cycle arrest or apoptosis. The number of signalling pathways and molecular targets involved is continually expanding. Consequently, the picture is becoming ever more complicated, not least because results often appear to be cell-type specific, dose-response relationships are critical, and any one agent appears to have multiple mechanisms of action. In addition most studies have been conducted in cell culture, often with physiologically unachievable concentrations of single agents, making extrapolation to the clinical situation difficult. In this review the mechanisms of action of a few well-studied dietary polyphenols (curcumin, epigallocatechin gallate and resveratrol) and indole-3 carbinol are considered in the light of these issues.

Topics: Apoptosis; Catechin; Cell Cycle; Curcumin; Flavonoids; Humans; Indoles; Mitogen-Activated Protein Kinases; Neoplasms; NF-kappaB-Inducing Kinase; Phenols; Polyphenols; Protein Serine-Threonine Kinases; Signal Transduction; STAT Transcription Factors

A series of curcumin analogs (1-3, 5a-5t) was synthesized through the condensation of appropriately protected hydroxybenzaldehydes with acetylacetone, followed by deprotection. The antioxidant activity of these analogs was determined by superoxide free radical nitroblue tetrazolium and DPPH free radical scavenging methods and the polyhydroxycurcuminoids (5l-5s) displayed excellent antioxidant activity. These analogs showed cytotoxicity to lymphocytes and promising tumor-reducing activity on Dalton's lymphoma ascites tumor cells.

Topics: Animals; Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Curcumin; Free Radical Scavengers; Free Radicals; Inhibitory Concentration 50; Mice; Molecular Structure; Neoplasms; Oxidation-Reduction; Structure-Activity Relationship; Superoxides; Xenograft Model Antitumor Assays

A lot of information has been gathered on cellular mechanisms by which chemopreventive phytochemicals, such as curcumin (a spice in curry) or epigallocatechin gallate (extracted from tea), interfere with carcinogenesis. A comparison of this knowledge with what we know about molecularly targeted chemotherapeutic agents suggests that it might be worthwhile to investigate the usefulness of such phytochemicals in the treatment of established malignant diseases. Phytochemicals use a plethora of antisurvival mechanisms, boost the host's anti-inflammatory defence, and sensitise malignant cells to cytotoxic agents. The restricted systemic availability of agents such as curcumin and epigallocatechin gallate, needs to be taken into account if they are to be developed as cochemotherapeutic drugs.

Topics: Antineoplastic Agents, Phytogenic; Catechin; Curcumin; Humans; Neoplasms

Inhibition of defined molecular steps of tumorigenesis by natural nontoxic compounds may be an efficient means to tackle the population cancer burden. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively nontoxic plant-derived polyphenol. This review considers the following properties of curcumin: anticancer effects in animal model systems; metabolism; biological structure and pharmacokinetics; biological properties implicated in chemoprevention; antioxidant properties; influences upon Phase I and II carcinogen-metabolizing enzymes; signal transduction properties and the neoplastic phenotype; apoptosis evasion, cell proliferation, de-differentiation, migration and invasion and clinical studies. This review will summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention.

Topics: Antineoplastic Agents; Apoptosis; Cell Transformation, Neoplastic; Curcumin; Humans; Neoplasms

In a previous study, we observed that some synthetic curcumin analogs inhibited complex formations between Fos-Jun heterodimer and activator protein-1 (AP-1) DNA. These curcumin analogs have been observed to repress the AP-1 transcription in AP-1-transfected cells and they also inhibited the increased expression of Jun/AP-1 protein by 12-O-tetradecanoylphorbol-13-acetate (TPA) in the same cells. After the AP-1 inhibition by curcumin analogs in TPA-treated HT-1080 human fibrosarcoma cells, a decrease in mRNA expression of c-jun and MMP3 (stromelysin-1) has been observed. We also observed that curcumin analogs down-regulated the expression of MMP-9 (gelatinase-B), correlating with cellular invasion and migration in conditions such as tumor invasion and metastasis, through the electrophoretic mobility shift assay and gelatin zymography methods. Curcumin analogs showed an inhibitory effect on angiogenesis by various test methods including chicken chorioallantoic membrane assay, wound migration assay, invasion assay, and tube formation assay. Through the reverse transcriptase-polymerase chain reaction experiment, we confirmed that curcumin analogs down-regulated the expression of angiogenesis-associated genes, VEGF and MMP-9.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Chick Embryo; Curcumin; Down-Regulation; Humans; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Promoter Regions, Genetic; Proto-Oncogene Proteins c-jun; RNA, Messenger; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Transcription, Genetic; Umbilical Cord; Vascular Endothelial Growth Factor A

In vivo expression of cell survival factors protein kinase C (PKC), nuclear factor kappaB (NFkappaB), and extracellular signal-regulated kinase (Erk), which may contribute to the development of radioresistance following radiotherapy, was looked for. Their modulation with natural compounds (curcumin, rutin or nicotinamide) was attempted in mice bearing a serially transplanted fibrosarcoma. Expression of protein kinase C was isoform specific. No translocation of any of the isozymes was noticed following gamma-irradiation as has been reported elsewhere. None of the isoforms could be significantly inhibited by the modulators. However, significant inhibition of radiation-induced ERK and NFkappaB was observed with both curcumin and nicotinamide. Therefore we conclude that use of inhibitors of MAP kinases or NFkappaB may be a more promising strategy to enhance tumour cell killing or to prevent the development of radioresistance during radiotherapy.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Cell Survival; Curcumin; Cytosol; Extracellular Signal-Regulated MAP Kinases; Male; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Transplantation; Neoplasms; NF-kappa B; Niacinamide; Protein Isoforms; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-alpha; Protein Kinase C-delta; Protein Transport; Rutin; Signal Transduction

There have been considerable efforts to search for naturally occurring substances for the intervention of carcinogenesis. Many components from dietary or medicinal plants have been identified that possess substantial chemopreventive properties. Curcuma, a yellow pigment from Curcuma longa, exhibits anti-inflammatory, antitumor, and antioxidative properties. Although its precise mode of action has not been elucidated so far, studies have shown that chemopreventive action of curcuma might be due to its ability to induce apoptosis (programmed cell death) in cancer cells. This original study was conducted in order to estimate whether curcuma enhances the radiation sensitivity of cancer cells. For this purpose, curcuma (concentrations ranging from 0 to 200 microM) was applied to human cancer cell cultures (HeLa, K-562 and IM-9) with or without X-irradiation (doses comprised between 0 and 8 Gy). Cell proliferation was monitored by trypan blue exclusion. For the estimation of apoptosis, changes in cell morphology and flow cytometry analysis (DNA content and presence of the sub-G1 peak) were performed. Microscopic examination of the curcuma-treated cells (with concentrations above 100 microM) showed a characteristic morphology of apoptosis. Furthermore, cells treated with curcuma exhibited a sub-G1 peak from which the magnitude was proportional to the concentration of curcuma. X-irradiation alone induced polyploidisation and apoptosis of the three cell lines, proportional to the doses of irradiation with a marked difference in radiation sensitivity between the cell lines (IM-9 < K-562 < HELA). However, when radiation and curcuma were applied together, our results showed that in HELA, K-562 and IM-9, curcuma showed a radiation sensitising effect only at the dose of 200 micro M. This result may open a perspective of synergical therapy at the condition to also address the intrinsic toxicity of curcuma on normal cells.

Topics: Apoptosis; Cell Division; Cell Line, Tumor; Curcuma; DNA; Dose-Response Relationship, Drug; Flow Cytometry; G1 Phase; HeLa Cells; Humans; K562 Cells; Neoplasms; Plant Extracts; Polyploidy; X-Rays

Scientific research provides documented evidence that fatty acid metabolites have profound impact on carcinogenesis. Intervention into dioxygenase pathways might therefore effect development, metastasis and progression of many types of cancers. This work delivers the first 3D structural data and explains how curcumin interacts with the fatty acid metabolizing enzyme, soybean lipoxygenase. Curcumin binds to lipoxygenase in a non-competitive manner. Trapped in that complex, it undergoes photodegradation in the X-rays, but utilizes enzyme catalytic ability to form the peroxy complex Enz-Fe-O-O-R as 4-hydroperoxy-2-methoxy-phenol, that later transforms into 2-methoxycyclohexa-2,5-diene-1,4-dione. Our observations about this radiation and time-dependent inhibition add new information to the role that curcumin might play in cancer prevention and treatment.

Topics: Animals; Curcumin; Glycine max; Kinetics; Lipoxygenase; Mice; Neoplasms; Protein Conformation; Rabbits; Rats; X-Rays

Research on cancer chemoprevention is an important approach for decreasing both the incidence and number of deaths from cancer. The use of tamoxifen to prevent breast cancer, finasteride to prevent prostate cancer, and aspirin to prevent colon cancer are recent examples of cancer chemoprevention. This article describes research from my laboratory and related research from other laboratories on the effects of enzyme induction on chemical carcinogenesis as an approach to cancer chemoprevention, as well as studies on the inhibitory effects of curcumin, caffeine, (-)-epigallocatechin gallate (EGCG), and tea in animal models of carcinogenesis. The later substances appear to work, at least in part, by enhancing apoptosis in DNA-damaged cells or in tumors. The results of our studies and those of others provide a rationale for clinical trials on the potential chemopreventive effects of curcumin, caffeine, EGCG, and tea on the formation of cancer of the skin, mouth, esophagus, stomach, and colon in people with precancerous lesions and a high risk of developing these cancers. It was pointed out that several compounds that are effective cancer chemopreventive agents in one experimental setting can enhance carcinogenesis in another experimental setting. These results suggest that it may be necessary to tailor the cancer chemopreventive regimen to individual subjects with known carcinogen exposures or to high cancer risk individuals with mechanistically understood pathways of carcinogenesis so that chemopreventive agents with known mechanisms of action can be better customized to the individual and selected on a more rational basis.

Topics: Animals; Anticarcinogenic Agents; Caffeine; Catechin; Chemoprevention; Curcumin; Enzyme Induction; Enzyme Inhibitors; Humans; Neoplasms

Curcumin, a well-known dietary pigment derived from Curcuma longa, has been shown to be a potent antiinflammatory, antioxidant, and anticarcinogenic compound. The present study was designed to investigate the cytotoxic potential of curcumin against a range of human tumor cell lines in an attempt to understand its mechanism of action, which may lead to its possible therapeutic applications. We have shown that different cancer cell lines differ in their sensitivity to curcumin. Cell lines established from malignancies like leukemia, breast, colon, hepatocellular, and ovarian carcinomas underwent apoptosis in the presence of curcumin, whereas cell lines from lung, kidney, prostate, cervix, CNS malignancies, and melanomas showed resistance to the cytotoxic effects of curcumin. Sensitivity of the cancer cell lines to curcumin correlated with the generation of superoxide radicals as determined by the reduction of ferricytochrome C. Curcumin-resistant tumor cell lines showed significantly higher production of Hsp70, thus mounting a stress response and protecting the cells from the apoptotic cell death. These observations yield clues toward understanding the regulation of the cell death machinery by the stress proteins. Interestingly, curcumin had no effect on nontransformed cell lines, which showed neither superoxide generation nor the induction of a stress response. These observations demonstrate that curcumin is an interesting molecule with varied actions, depending on the cell type.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line; Colonic Neoplasms; Curcumin; Cytoprotection; Drug Resistance, Neoplasm; fas Receptor; Female; Fibroblasts; HSP70 Heat-Shock Proteins; Humans; Leukemia; Liver Neoplasms; Neoplasms; Ovarian Neoplasms; Rats; Reactive Oxygen Species; Tumor Cells, Cultured

In recent years, there have been considerable efforts to search for naturally occurring substances for intervention of carcinogenesis. Many components from medicinal or dietary plants have been identified to possess potential chemopreventive properties. For instance, curcumin, a yellow colouring agent from turmeric (Curcuma longa Linn., Zingiberaceae) has been shown to inhibit tumor formation in diverse animal models. Alpinia oxyphylla Miquel that also belongs to ginger family has been used in oriental herbal medicine. In the present work, we have evaluated the anti-tumor promoting potential of yakuchinone A (1-[4'-hydroxy-3'-methoxyphenyl]-7-phenyl-3-heptanone) and yakuchinone B (1-[4'-hydroxy-3'-methoxyphenyl]-7-phenylhept-1-en-3-one), major pungent ingredients of A. oxyphylla. Thus, topical application of yakuchinone A or B significantly suppressed TPA-induced epidermal ornithine decarboxylase activity. They also reduced TPA-stimulated production of tumor necrosis factor-alpha in cultured human promyelocytic leukemia (HL-60) cells. Both compounds blunted the TPA-induced superoxide generation in differentiated HL-60 cells in a concentration-related manner and also inhibited lipid peroxidation in rat brain homogenates. Furthermore, yakuchinone A and yakuchinone B nullified the activation of the activator protein-1 (AP-1) in immortalized mouse fibroblast cells in culture. These findings indicate that pungent diarylheptanoids from A. oxyphylla have anti-tumor promotional properties that can contribute to their chemopreventive potential.

Topics: 3T3 Cells; Animals; Brain; Carcinogens; Curcumin; Diarylheptanoids; Guaiacol; HL-60 Cells; Humans; In Vitro Techniques; Lipid Peroxidation; Male; Mice; Neoplasms; Ornithine Decarboxylase Inhibitors; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Superoxides; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

The antitumor activity of four investigational natural products (camptothecin, harringtonin, cantharidin and curcumae) obtained from China were tested on human tumor biopsies in an in vitro soft agar clonogenic assay system. Significant antitumor activity was seen with camptothecin against human ovarian cancer and some other adenocarcinomas. Antitumor activity was also observed for harringtonin against adenocarcinoma and sarcoma. Both drugs also appeared to show activity in melanoma and mesothelioma. However, cantharidin and curcumae were relatively ineffective on the human tumors tested. For purposes of comparing the intensity of antitumor effects with standard cytotoxic drugs to those of the four new agents, the ID50 values were calculated. The ratio of ID50S of new drugs to the standard agents doxorubicin, cis-platinum and vinblastine (ID50 of the standard drug/ID50 of tested drug) were 10.2, 64.1 and 1.9 for camptothecin and 1.5, 10.3 and 0.9 for harrington respectively. A relationship was observed between the duration of drug exposure (1 hr prior to plating vs continuous contact in the agar) and inhibition of clonogenic tumor cells for camptothecin, harringtonin and doxorubicin.

Topics: Alkaloids; Antineoplastic Agents; Camptothecin; Cantharidin; Catechols; Cell Survival; Colony-Forming Units Assay; Curcumin; Dose-Response Relationship, Drug; Harringtonines; Humans; Neoplasms