curcumin and Prostatic-Neoplasms

Dimethylcurcumin (ASC-J9) is a curcumin analogue capable of inhibiting prostate cancer cell proliferation. The mechanism is associated with the unique role of ASC-J9 in enhancing androgen receptor (AR) degradation. So far, ASC-J9 has been investigated in typical AR-associated diseases such as prostate cancer, benign prostatic hypertrophy, bladder cancer, renal diseases, liver diseases, cardiovascular diseases, cutaneous wound, spinal and bulbar muscular atrophy, ovarian cancer and melanoma, exhibiting great potentials in disease control. In this review, the effects and molecular mechanisms of ASC-J9 on various AR-associated diseases are summarized. Importantly, the effects of ASC-J9 and AR antagonists enzalutamide/bicalutamide on prostate cancer are compared in detail and crucial differences are highlighted. At last, the pharmacological effects of ASC-J9 are summarized and the future applications of ASC-J9 in AR-associated disease control are discussed.

Topics: Androgen Receptor Antagonists; Curcumin; Humans; Kidney Neoplasms; Male; Prostatic Neoplasms; Radiation Tolerance; Receptors, Androgen; Signal Transduction; Urinary Bladder Neoplasms

Prostate cancer (PCa) is a heterogeneous disease and ranked as the second leading cause of cancer-related deaths in males worldwide. The global burden of PCa keeps rising regardless of the emerging cutting-edge technologies for treatment and drug designation. There are a number of treatment options which are effectively treating localised and androgen-dependent PCa (ADPC) through hormonal and surgery treatments. However, over time, these cancerous cells progress to androgen-independent PCa (AIPC) which continuously grow despite hormone depletion. At this particular stage, androgen depletion therapy (ADT) is no longer effective as these cancerous cells are rendered hormone-insensitive and capable of growing in the absence of androgen. AIPC is a lethal type of disease which leads to poor prognosis and is a major contributor to PCa death rates. A natural product-derived compound, curcumin has been identified as a pleiotropic compound which capable of influencing and modulating a diverse range of molecular targets and signalling pathways in order to exhibit its medicinal properties. Due to such multi-targeted behaviour, its benefits are paramount in combating a wide range of diseases including inflammation and cancer disease. Curcumin exhibits anti-cancer properties by suppressing cancer cells growth and survival, inflammation, invasion, cell proliferation as well as possesses the ability to induce apoptosis in malignant cells. In this review, we investigate the mechanism of curcumin by modulating multiple signalling pathways such as androgen receptor (AR) signalling, activating protein-1 (AP-1), phosphatidylinositol 3-kinases/the serine/threonine kinase (PI3K/Akt/mTOR), wingless (Wnt)/ß-catenin signalling, and molecular targets including nuclear factor kappa-B (NF-κB), B-cell lymphoma 2 (Bcl-2) and cyclin D1 which are implicated in the development and progression of both types of PCa, ADPC and AIPC. In addition, the role of microRNAs and clinical trials on the anti-cancer effects of curcumin in PCa patients were also reviewed.

Topics: Androgens; Clinical Trials as Topic; Curcumin; Humans; Male; MicroRNAs; Neoplasm Proteins; Prostatic Neoplasms; RNA, Neoplasm; Wnt Signaling Pathway

Cancer is a condition characterized by remarkably enhanced rates of cell proliferation paired with evasion of cell death. These deregulated cellular processes take place following genetic mutations leading to the activation of oncogenes, the loss of tumor suppressor genes, and the disruption of key signaling pathways that control and promote homeostasis. Plant extracts and plant-derived compounds have historically been utilized as medicinal remedies in different cultures due to their anti-inflammatory, antioxidant, and antimicrobial properties. Many chemotherapeutic agents used in the treatment of cancer are derived from plants, and the scientific interest in discovering plant-derived chemicals with anticancer potential continues today. Curcumin, a turmeric-derived polyphenol, has been reported to possess antiproliferative and proapoptotic properties. In the present review, we summarize all the in vitro and in vivo studies examining the effects of curcumin in prostate cancer.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms

Cancer is a life-threatening disease and is the second leading cause of death around the world. The increasing threats of drug-resistant cancers indicate that there is an urgent need for the improvement or development of more effective anticancer agents. Curcumin, a phenolic compound originally derived from turmeric plant (

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Colonic Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; Signal Transduction; Structure-Activity Relationship

Topics: Adult; Aged; Anticarcinogenic Agents; Black or African American; Curcumin; Garlic; Health Status Disparities; Humans; Male; Middle Aged; Phytotherapy; Plants, Medicinal; Prostatic Neoplasms; Vernonia

Accurate. Since sCD30 levels and sCD26/sCD30 ratios may contribute to the activity of the disease, they may be used to assess ITP disease activity.. hBMSCs and hFOB1.19 cells modulate the phenotype of PC3 prostate cancer cells and the expression of CD59 by activating the RANK/RANKL/OPG signaling pathway.. Results showed that the EEG responses at lower levels of the independent variables were significantly high than at higher levels; except for oxygen content, the EEG responses at lower levels were considerably lower than at a higher level. It also showed that an upsurge in the physical demand increased lifting frequency and replication and caused decreasing in alpha power, theta/beta, alpha/beta, (theta + alpha)/beta, (theta + alpha)/(alpha + beta) and increasing in the theta power and the gamma power. Furthermore, several interactions among independent variables had significant effects on the EEG responses.. The EEG implementation for the investigation of neural responses to physical demands allows for the possibility of newer nontraditional and faster methods of human performance monitoring. These methods provide effective and reliable results as compared to other traditional methods. This study will safeguard the physical capabilities and possible health risks of industrial workers. And the applications of these tasks can occur in almost all working environments (factories, warehouses, airports, building sites, farms, hospitals, offices, etc.) that are at high altitudes. It can include lifting boxes at a packaging line, handling construction materials, handling patients in hospitals, and cleaning.

Topics: Action Potentials; Adolescent; Adult; Aged; Alanine Transaminase; Analgesics; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Arrhythmias, Cardiac; Atrial Fibrillation; Biological Transport; Biomarkers; Blood Gas Analysis; Blood-Brain Barrier; Blotting, Western; Bone and Bones; Bone Marrow; Bone Neoplasms; Brain; Breast Neoplasms; Calcium; Carbon Tetrachloride; Cartilage, Articular; Case-Control Studies; CD59 Antigens; CDC2 Protein Kinase; Celastrus; Cell Cycle; Cell Division; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemical Fractionation; Colitis, Ulcerative; Colon; Computer Simulation; Curcumin; Cyclin B1; Cymenes; Cytokines; Dextran Sulfate; Dipeptidyl Peptidase 4; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Ectodysplasins; Electroencephalography; Endothelial Cells; Epithelial Cells; Epithelial-Mesenchymal Transition; Exosomes; Female; Flavonoids; G2 Phase; Gene Expression Regulation; Glial Cell Line-Derived Neurotrophic Factor; Heart Atria; Heart Conduction System; Heart Ventricles; HeLa Cells; Hemodynamics; Humans; Image Interpretation, Computer-Assisted; Indoles; Inflammation; Interleukin-1beta; Interleukin-6; Iridoid Glycosides; Ki-1 Antigen; Lens, Crystalline; Lifting; Liver; Liver Cirrhosis; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Microelectrodes; Middle Aged; Models, Cardiovascular; Multiparametric Magnetic Resonance Imaging; Myeloid Differentiation Factor 88; NADPH Oxidase 1; Neoplasm Grading; NF-kappa B; Osteoarthritis; Osteoblasts; Osteoclasts; Oxidative Stress; Oxygen; Patch-Clamp Techniques; PC-3 Cells; Permeability; Peroxidase; Plant Extracts; Plant Leaves; Prostate; Prostatic Neoplasms; Protective Agents; Proto-Oncogene Proteins c-akt; Psychophysics; Purpura, Thrombocytopenic, Idiopathic; Rabbits; Rats; Rats, Sprague-Dawley; Recovery of Function; Retrospective Studies; RNA, Long Noncoding; ROC Curve; Safety; Shoes; Signal Transduction; Sodium; Sonication; Spinal Cord; Spinal Cord Injuries; Syringa; Tight Junctions; Tissue Inhibitor of Metalloproteinase-1; Toll-Like Receptor 2; Transforming Growth Factor beta2; Transient Receptor Potential Channels; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Umbilical Cord; Up-Regulation; Ventricular Function; Young Adult

Primary prostate cancer, also known as prostate adenocarcinoma (PCa), is a devastating cancer in men worldwide. Europe and developing countries of Asia have fewer reported cases of prostate cancer compared to increasing cases in the United States with higher incidence in Black men. Risk factors associated with prostate cancer are aging, genetics, lifestyle, high body mass index as well as carcinogenic exposure to carbon-containing fuels, tobacco, and charbroiled meats. Hormone therapy and radical prostatectomy are commonly implemented treatments. The >20.000 prostate cancer deaths of 2013 suggest that there exists a need for enhanced chemopreventive and therapeutic agents for prostate cancer treatment. Fruits, vegetables, and red wines contain high levels of polyphenolic levels. Consumption of these products may provide chemoprevetion of PCa. Curcumin, the major compound from the turmeric rhizome Curcuma longa has long been used for medicinal purposes as an antiseptic and wound healing. This review focuses on curcumin's therapeutic effectiveness in vitro and in vivo in prostate cancer models. The review will highlight the mechanisms of actions of curcumin in the signaling pathways of prostate cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Curcumin; Humans; Male; Prostatic Neoplasms; Structure-Activity Relationship

To evaluate the evidence from randomised trials for the efficacy and safety of phytotherapeutic interventions in the management of biochemically recurrent (BCR) prostate cancer, indicated by prostate-specific antigen (PSA) progression, numbers progressing to/time to initiation of androgen-deprivation therapy or salvage therapy.. MEDLINE (Ovid), EMBASE (Ovid), AMED (Ovid), CINAHL (EBSCO) and the Cochrane Library databases were searched. Clinical trials investigating phytotherapeutic interventions as dietary supplements or dietary components, including multi-component herbal formulations, in men with BCR prostate cancer were located. Eight of nine authors contacted for further information responded. Methodological quality was assessed using the Cochrane Collaboration's risk of bias assessment tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews was followed.. Of 23 full-text articles assessed for eligibility, five met the criteria for inclusion. Two studies were placebo controlled; two were active control trials; and one a high-/low-dose trial. The interventions were administered as isolated phytochemicals (sulphoraphane), phytotherapeutic extracts [Pomi-T (pomegranate, turmeric, green tea and broccoli sprout extract), soy, lycopene, and POMx (pomegranate extract)], or plant-derived dietary items (soy and lycopene). All studies found serum PSA levels to stabilise, decrease or rise more slowly in a significant number of men, and three studies reported stabilising or lengthening of PSA-doubling time. Studies were generally of good quality, but sample sizes were predominantly small, and durations short.. High-quality studies in this area are lacking. Sulphoraphane, lycopene, soy isoflavones, POMx, and Pomi-T are safe and well tolerated. There is limited evidence that they can affect PSA dynamics. No recommendation can be made for the use of these agents in managing prostate cancer morbidity and mortality until high-quality, fully powered studies are available. Recommendations are made for improving reproducibility and translation of findings with regard to study population, study endpoints, design, and the reporting of phytotherapeutic interventions.

Topics: Antineoplastic Agents, Phytogenic; Brassica; Carotenoids; Curcuma; Glycine max; Humans; Isothiocyanates; Lycopene; Lythraceae; Male; Phytotherapy; Plant Extracts; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Sulfoxides; Tea

The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa.

Topics: Animals; Curcumin; Humans; Male; Neoplasm Proteins; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction

Prostate cancer possesses the highest occurrence rate and is the second-paramount disease that causes cancer-affiliated death among men in the United States. Approximately 30,000 men die each year of castration-resistant prostate cancer due to the inevitable progression of resistance to first-line treatment with docetaxel. The safety profile of dietary curcumin in humans has been well-documented, and its therapeutic prospect in treating prostate cancer, especially for castration-resistant prostate cancer, has been evidenced in several cell culture systems and human xenograft mouse models. The critical disadvantage of curcumin as a drug candidate is its low bioavailability caused by poor water solubility and rapid in vivo metabolism. Curcumin is characteristic of regulating multiple targets, representing a good example for the philosophy to search for multitargeted drugs in the realm of drug design and drug development. This feature, together with its potential in treating castration-resistant prostate cancer and its safety profile, enables curcumin to serve as an ideal lead compound for the design and syntheses of curcumin-based agents with improved potential for the clinical therapies of prostate cancer. Several researches aiming to improve its bioavailability and potency resulted in the discovery and development of a wealth of curcumin-based compounds with an enhanced anticancer potential and/or an improved pharmacokinetic profile. This review starts with a brief summarization of the prospect of curcumin in treating prostate cancer and its mechanisms of action, then provides an in-depth overview of current development of curcumin-based anti-prostate cancer agents and their structure-activity relationships, and ends with the syntheses and pharmacokinetic studies of curcumin.

Topics: Animals; Antineoplastic Agents; Biological Availability; Curcumin; Humans; Male; Prostatic Neoplasms; Solubility; Structure-Activity Relationship

The androgen receptor (AR) is a ligand-activated transcription factor that is expressed in primary and metastatic prostate cancers. There are advances in endocrine therapy for prostate cancer that are based on improved understanding of AR function.. PubMed has been used to include most important publications on targeting the AR in prostate cancer. AR expression may be downregulated by agents used for chemoprevention of prostate cancer or, in models of advanced prostate cancer, by antisense oligonucleotides. New drugs that inhibit the steroidogenic enzyme CYP17A1 (abiraterone acetate) or diminish nuclear translocation of the AR (enzalutamide) have been shown to improve patients' survival in prostate cancer. However, it is clear that there is a development of resistance to these novel therapies. They may include increased expression of truncated, constitutively active AR or activation of the signaling pathway of signal transducers and activators of transcription.. Although introduction of novel drugs have improved patients' survival, there is a need to investigate the mechanisms of resistance further. The role of truncated AR and compensatory activation of signaling pathways as well as the development of scientifically justified combination therapies seems to be issues of a high priority.

Topics: Androgen Antagonists; Anilides; Antibodies, Neutralizing; Anticarcinogenic Agents; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Curcumin; Flutamide; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Male; Molecular Targeted Therapy; Nitriles; Oligonucleotides, Antisense; Phenylthiohydantoin; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Tosyl Compounds

Chemopreventive interventions are steadily emerging as an important aspect of cancer management and control. Herein, we have discussed the major epidemiological and clinical studies advocating the role of androgen inhibitors, flavonoids and antioxidants in preventing prostate cancer (PCa). Androgen inhibitors have lately been discussed not only in treatment of PCa, but also as preventive agents especially after trials with Finasteride and Dutasteride. Flavonoids such as silibinin, green tea polyphenols, genistein, curcumin have shown great promise, but avenues to improve their bioavailability are requisite. Agents with antioxidant potentials like lycopene, selenium, and vitamin E have also been explored. Antioxidant trials have yielded mixed results or benefitted only a subgroup of population, although further studies are needed to establish them as preventive agent. Although a majority of the trials resulted in positive outcomes supporting their role as preventive agents; one should be cautious of neutral or negative results as well. For clinical applicability of these agents, we need to identify the ideal target population, time of intervention, appropriate dosage, and extent of intervention required. Incoherency of data with these agents urges for a stringent study design and thorough interpretation to accurately judge the necessity and feasibility of the preventive measures.

Topics: Androgen Antagonists; Animals; Anticarcinogenic Agents; Antioxidants; Azasteroids; Carotenoids; Chemoprevention; Clinical Trials as Topic; Curcumin; Disease Models, Animal; Dutasteride; Finasteride; Flavonoids; Genistein; Humans; Lycopene; Male; Phytochemicals; Polyphenols; Prostate; Prostatic Neoplasms; Risk Factors; Selenium; Silybin; Silymarin; Tea; Vitamin E

Prostate cancer continues to be one of the most commonly diagnosed diseases and the second leading cause of cancer-related deaths among men in the United States. Options exist to treat localized disease, including surgery, radiation therapy, and hormonal therapy, but clinical management of advanced prostate cancer is challenging. In the past few decades, chemoprevention involving naturally-occurring compounds has emerged as a promising and cost-effective approach to reduce incidence and morbidity of prostate cancer by inhibiting the precancerous events before the occurrence of clinical disease. The present review focuses on summarizing the recent advances in studies of major dietary phytochemicals and their role in prostate cancer development.

Topics: Animals; Anticarcinogenic Agents; Capsaicin; Carotenoids; Chemoprevention; Curcumin; Humans; Lycopene; Male; Phytochemicals; Prostatic Neoplasms; Resveratrol; Stilbenes

Prostate cancer is is the most common solid neoplasm and it is now recognized as one of the most important medical problems facing the male population. Due to its long latency and its identifiable preneoplastic lesions, prostate cancer is an ideal target tumor for chemoprevention. Different compounds are available and certainly polyphenols represent those with efficacy against prostate cancer. This review take a look at activity and properties of major polyphenolic substances, such as epigallocatechin-3-gallate, curcumin, resveratrol and the flavonoids quercetin and genistein. Although the current studies are limited, mechanisms of action of polyphenols added with the lack of side effects show a a start for future strategies in prostate chemoprevention.

Topics: Antioxidants; Catechin; Curcumin; Flavonoids; Genistein; Humans; Male; Polyphenols; Prostatic Neoplasms; Quercetin; Resveratrol; Stilbenes

Complementary and alternative medicine (CAM) use is common among adults, and recent reports suggest that 25%-50% of prostate cancer (PCa) patients use at least one CAM modality. The most common CAM modalities used by PCa patients are vitamin and herbal preparations with purported antitumor effects despite only modest underlying preclinical or clinical evidence of efficacy. In this review we provide a brief overview of the basic scientific and clinical studies underlying the most common herbal and vitamin preparations including common antioxidants, pomegranate extract, green tea, turmeric, resveratrol, silibinin, and herbal combination preparations. When available, prostate cancer clinical trial data are reviewed. Importantly, we have compared the concentration of these agents used in in vitro experiments to that likely to be achievable in humans. From the available data we conclude that there is insufficient evidence to support the use of CAMs for the treatment of prostate cancer patients outside of a clinical trial. The purpose of this review is to more rigorously evaluate CAM therapy in prostate cancer and educate oncologists and patients. This review focuses on examples from the general classes of agents in common use.

Topics: Antioxidants; Beverages; Complementary Therapies; Curcuma; Humans; Lythraceae; Male; Plant Extracts; Prostatic Neoplasms; Resveratrol; Selenium; Silybin; Silymarin; Stilbenes; Tea; Vitamin E; Vitamins

Topics: Animals; Anticarcinogenic Agents; Carotenoids; Curcumin; Humans; Isoflavones; Lycopene; Male; Prostatic Neoplasms; Resveratrol; Stilbenes; Vitamin E

Accumulating data clearly indicate that induction of apoptosis is an important event for chemoprevention of cancer by naturally occurring dietary agents. In mammalian cells, apoptosis has been divided into two major pathways: the extrinsic pathway, activated by pro-apoptotic receptor signals at the cellular surface; and the intrinsic pathway, which involves the disruption of mitochondrial membrane integrity. This process is strictly controlled in response to integrity of pro-death signaling and plays critical roles in development, maintenance of homeostasis, and host defense in multicellular organisms. For chemoprevention studies, prostate cancer (PCa) represents an ideal disease due to its long latency, its high incidence, tumor marker availability, and identifiable preneoplastic lesions and risk groups. In this article, we highlight the studies of various apoptosis-inducing dietary compounds for prevention of PCa in vitro in cell culture, in preclinical studies in animals, and in human clinical trials.

Topics: Adenocarcinoma; Aged; Animals; Apoptosis; Carotenoids; Catechin; Clinical Trials as Topic; Curcumin; Drug Screening Assays, Antitumor; Flavonoids; Flavonols; Genistein; Humans; Lycopene; Lythraceae; Male; Mice; Mice, Nude; Mice, Transgenic; Middle Aged; Neoplasm Proteins; Pentacyclic Triterpenes; Phytotherapy; Plant Extracts; Prostatic Neoplasms; Resveratrol; Stilbenes; Tumor Cells, Cultured

Complementary and alternative therapies for neoplastic diseases treatment and prevention receive increasing attention from the medical community. Prostate cancer (PC) is the most frequently diagnosed malignancy and the second major cause of male death in industrialized countries. The chemopreventive properties and clinical safety of curcumin, a polyphenolic derivative, have already been established. However, curcumin regimen value in addition to conventional hormone refractory (HR) PC treatment remains largely unknown. This review article summarizes mechanisms by which curcumin may decrease HRPC aggressive proliferation and potentiate activity of taxane therapy. Our analysis suggests that curcumin alone has a therapeutic value in HRPC. In combination with a taxane agent, this compound may enhance cytotoxicity and retard PC cell resistance to taxane. As a consequence, a rationale is provided for considering the possible benefits of curcumin regimen in combination with taxane therapy in HRPC patients.

Topics: Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged-Ring Compounds; Cell Cycle; Curcumin; Drug Resistance, Neoplasm; Hormones; Humans; Male; Neovascularization, Pathologic; Prostatic Neoplasms; Taxoids

The androgen receptor (AR) plays a crucial role in the physiological and pathological functions of androgen. As a transcription factor, the AR modulates androgen activity by regulating the transcription of target genes that are involved in numerous physiological functions and pathological disorders, such as acne vulgaris, androgenetic alopecia, benign prostate hyperplasia (BPH), and prostate cancers. Although many natural and synthetic curcumin analogues have been reported to possess anticancer activity through a common cytotoxic property against proliferating tumor cells, none has been reported to inhibit cancer cell growth through a more specific mechanism or target in the cancer cells. Recently, new curcumin analogues were studied extensively regarding their synthesis, structure-activity (i.e., anticancer activity) relationships, and mechanism of action. These compounds, such as ASC-J9 and its analogues (3 and 4), have now been shown to inhibit prostate cancer proliferation through a novel mechanism of enhancing AR degradation.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Humans; Hydrolysis; Male; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction

Vanilloids are natural molecules identified in a plethora of foods normally ingested through the diet. They mediate apoptosis through a direct pathway (independent of TRPV-1, the receptor for vanilloids) and through an indirect pathway, i.e., thanks to the interaction with TRPV-1 and the successive intracellular calcium growth [Ca2+]i. Some vanilloids, such as capsaicin, dihydrocapsaicin and resiniferatoxin (the ultrapotent analogue of capsaicin, extractable from Euphorbia resinifera), may be considered as coenzyme Qantagonists: in fact, they inhibit the run of the electrons through the electron transport chain, so determining an excess of reactive oxygen species (ROS). A second effect of the interaction between the vanilloids and TRPV-1 receptor may be reported: it is the fast decrease of the transmembrane mitochondrial potential (delta psi m). Through the direct pathway, on the contrary, the vanilloids induce apoptosis also interacting with caspases, particularly caspase 1 and 3. On the whole, the vanilloids are able to lead to the intracellular calcium growth and consequently to the evidence of precocious and late elements of apoptosis.

Topics: Apoptosis; Calcium Signaling; Capsaicin; Caspases; Curcumin; Diterpenes; Enzyme Inhibitors; Humans; Male; Prostatic Neoplasms; TRPV Cation Channels

Clinical potential of curcumin in radiotherapy (RT) setting is outstanding and of high interest. The main purpose of this randomized controlled trial (RCT) was to assess the beneficial role of nanocurcumin to prevent and/or mitigate radiation-induced proctitis in prostate cancer patients undergoing RT. In this parallel-group study, 64 eligible patients with prostate cancer were randomized to receive either oral nanocurcumin (120 mg/day) or placebo 3 days before and during the RT course. Acute toxicities including proctitis and cystitis were assessed weekly during the treatment and once thereafter using CTCAE v.4.03 grading criteria. Baseline-adjusted hematologic nadirs were also analyzed and compared between the two groups. The patients undergoing definitive RT were followed to evaluate the tumor response. Nanocurcumin was well tolerated. Radiation-induced proctitis was noted in 18/31 (58.1%) of the placebo-treated patients versus 15/33 (45.5%) of nanocurcumin-treated patients (p = 0.313). No significant difference was also found between the two groups with regard to radiation-induced cystitis, duration of radiation toxicities, hematologic nadirs, and tumor response. In conclusion, this RCT was underpowered to indicate the efficacy of nanocurcumin in this clinical setting but could provide a considerable new translational insight to bridge the gap between the laboratory and clinical practice.

Topics: Aged; Aged, 80 and over; Curcumin; Double-Blind Method; Humans; Male; Middle Aged; Proctitis; Prostatic Neoplasms; Radiation Injuries; Radiotherapy

The anti-cancer activities of curcumin are well-documented from preclinical studies using prostate cancer models. Our objective was to evaluate the anti-cancer activity of oral curcumin in patients with prostate cancer.. This randomized, double-blind, placebo-controlled trial was performed on patients with prostate cancer who received intermittent androgen deprivation (IAD). Participants who finished the first on-treatment period of IAD were randomized into a curcumin or placebo group. The patients took oral curcumin (1440 mg/day) or placebo for six months and were followed up until the beginning of the second on-treatment. The primary end-point was duration of the first off-treatment. The secondary end-points were change in PSA and testosterone levels during 6 months, PSA progression rate, and health-related quality of life (HRQOL) scores at 6 months. Safety assessments included adverse event, adverse drug reaction, and serious adverse event.. A total of 97 participants were randomized 1:1 to curcumin (n = 49) and placebo (n = 48) groups. Among them, 82 patients (84.5%) were evaluable for the analysis (39 and 43 patients in the curcumin and placebo groups, respectively). The median off-treatment duration was 16.3 months (95% confidence interval [CI] 12.3-20.3 months) and 18.5 months (95% CI 12.5-23.0 months) in the curcumin and placebo groups, respectively. There was no significant difference in the curve of off-treatment duration between the two groups (P = 0.4816). The proportion of patients with PSA progression during the active curcumin treatment period (6 months) was significantly lower in the curcumin group than the placebo group (10.3% vs 30.2%, P = 0.0259). The change of PSA, testosterone levels during 6 months, and HRQOL scores at 6 months were not different between curcumin and placebo groups. Adverse events were higher in the placebo group (16 of 46 vs 7 of 45 patients, P = 0.0349). No significant differences in the adverse drug reaction were found between the two groups.. Six months' intake of oral curcumin did not significantly affect the overall off-treatment duration of IAD. However, PSA elevation was suppressed with curcumin intake during the curcumin administration period. Curcumin at this dose was well tolerated and safe.

Topics: Administration, Oral; Aged; Androgen Antagonists; Antineoplastic Agents, Phytogenic; Curcumin; Double-Blind Method; Drug Monitoring; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Testosterone; Treatment Outcome

Men with biochemical recurrence of prostate cancer following local therapies often use natural supplements in an attempt to delay metastases and/or avoid the need for more aggressive treatments with undesirable side-effects. While there is a growing body of research into phytotherapeutic agents in this cohort, with some promising results, as yet no definitive recommendations can be made. This pilot study was undertaken to assess the feasibility of a fully-powered study to examine the effects of this phytotherapeutic intervention (containing turmeric, resveratrol, green tea and broccoli sprouts) on PSA doubling time in men with biochemical recurrence with a moderate PSA rise rate.. A double blind, randomized, placebo-controlled parallel trial was conducted with 22 men with biochemically recurrent prostate cancer and a moderate rise rate (PSA doubling time of 4-15 months and no evidence of metastases from conventional imaging methods). Patients were randomized to either the active treatment arm or placebo for 12 weeks. The primary endpoints were feasibility of study recruitment and procedures, and measurement of proposed secondary endpoints (prostate symptoms, quality of life, anxiety, and depression as measured on the EORTC QLQ-C30 and PR-25, the IPSS and HADS). Data were collected to estimate PSA-log slopes and PSA-doubling times, using a mixed model, for both the pre-intervention and post-intervention periods.. Adherence to study protocol was excellent, and the phytotherapeutic intervention was well-tolerated, with similar numbers of mild-to-moderate adverse events in the active and placebo arms. Both the intervention and data collection methods were acceptable to participants. No statistical difference between groups on clinical outcomes was expected in this pilot study. There was between-subject variation in the PSA post treatment, but on average the active treatment group experienced a non-significant increase in the log-slope of PSA (pre-treatment doubling time = 10.2 months, post-treatment doubling time = 5.5 months), and the placebo group experienced no change in the log-slope of PSA (pre-treatment doubling time = 10.8 months, post-treatment doubling time = 10.9 months).. The findings suggest that a fully powered study of this combination is feasible in men with biochemically recurrent prostate cancer and a moderate PSA rise rate. Prostate 77:765-775, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Aged; Antineoplastic Agents, Phytogenic; Behavioral Symptoms; Biomarkers, Tumor; Brassica; Curcuma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Quality of Life; Radiotherapy; Resveratrol; Stilbenes; Symptom Assessment; Tea; Time Factors; Treatment Outcome

Curcumin is an antioxidant agent with both radiosensitizing and radioprotective properties. The aim of the present study was to evaluate the effect of curcumin supplementation on oxidative status of patients with prostate cancer who undergo radiotherapy. Forty patients treated with radiotherapy for prostate cancer were randomized to the curcumin (CG, n = 20) or placebo group (PG, n = 20). They received curcumin (total 3 g/day) or placebo during external-beam radiation therapy of up to 74 Gy. Plasma total antioxidant capacity (TAC) and activity of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) were measured at baseline and 3 mo after radiotherapy completion. Analysis of covariance was used to compare the variables between groups following the intervention. Serum PSA levels and MRI/MRS images were investigated. In CG, TAC significantly increased (P < 0.001) and the activity of SOD decreased (P = 0.018) after radiotherapy compared with those at baseline. In CG, however, the activity of SOD had a significant reduction (P = 0.026) and TAC had a significant increase (P = 0.014) compared with those in PG. PSA levels were reduced to below 0.2 ng/ml in both groups, 3 mo after treatment, however, no significant differences were observed between the 2 groups regarding treatment outcomes.

Topics: Aged; Aged, 80 and over; Catalase; Curcumin; Dietary Supplements; Double-Blind Method; Humans; Magnetic Resonance Spectroscopy; Male; Oxidation-Reduction; Prostate-Specific Antigen; Prostatic Neoplasms; Superoxide Dismutase

Polyphenol-rich foods such as pomegranate, green tea, broccoli and turmeric have demonstrated anti-neoplastic effects in laboratory models involving angiogenesis, apoptosis and proliferation. Although some have been investigated in small, phase II studies, this combination has never been evaluated within an adequately powered randomised controlled trial.. In total, 199 men, average age 74 years, with localised prostate cancer, 60% managed with primary active surveillance (AS) or 40% with watchful waiting (WW) following previous interventions, were randomised (2:1) to receive an oral capsule containing a blend of pomegranate, green tea, broccoli and turmeric, or an identical placebo for 6 months.. The median rise in PSA in the food supplement group (FSG) was 14.7% (95% confidence intervals (CIs) 3.4-36.7%), as opposed to 78.5% in the placebo group (PG) (95% CI 48.1-115.5%), difference 63.8% (P=0.0008). In all, 8.2% of men in the FSG and 27.7% in the PG opted to leave surveillance at the end of the intervention (χ2 P=0.014). There were no significant differences within the predetermined subgroups of age, Gleason grade, treatment category or body mass index. There were no differences in cholesterol, blood pressure, blood sugar, C-reactive protein or adverse events.. This study found a significant short-term, favourable effect on the percentage rise in PSA in men managed with AS and WW following ingestion of this well-tolerated, specific blend of concentrated foods. Its influence on decision-making suggests that this intervention is clinically meaningful, but further trials will evaluate longer term clinical effects, and other makers of disease progression.

Topics: Aged; Aged, 80 and over; Brassica; Curcuma; Dietary Supplements; Disease Progression; Double-Blind Method; Humans; Kallikreins; Lythraceae; Male; Middle Aged; Polyphenols; Prostate-Specific Antigen; Prostatic Neoplasms; Tea

Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9® and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 μm Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9® led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-β1/Smad3/MMP9 pathway, but ASC-J9® and cryptotanshinone showed promising anti-invasion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9® to battle PCa metastasis at the castration-resistant stage.

Topics: Androgen Receptor Antagonists; Androgens; Anilides; Animals; Benzamides; Cell Line, Tumor; Curcumin; Down-Regulation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Experimental; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms; Smad3 Protein; Tosyl Compounds; Transforming Growth Factor beta1; Transplantation, Heterologous; Xenograft Model Antitumor Assays

Sustained chronic inflammation in the prostate promotes prostate carcinogenesis. Since an elevated level of prostate-specific antigen (PSA) per se reflects the presence of inflammation in the prostate, intervention to improve the PSA value might potentially have beneficial effects for the prevention of the development of prostate cancer. Isoflavones and curcumin have anti-inflammatory and anti-oxidant properties. We examined the biological effects of soy isoflavones and curcumin on LNCaP cells. After that, we conducted a clinical trial for men who received prostate biopsies, but were not found to have prostate cancer, to evaluate the effects of soy isoflavones and curcumin on serum PSA levels.. The expression of androgen receptor and PSA were examined in LNCaP cells before and after treatment of isoflavones and/or curcumin. Eighty-five participants were randomized to take a supplement containing isoflavones and curcumin or placebo daily in a double-blind study. Subjects were subdivided by the cut-off of their baseline PSA value at 10 microg/ml. We evaluated values of PSA before and 6 months after treatment.. The production of PSA were markedly decreased by the combined treatment of isoflavones and curcumin in prostate cancer cell line, LNCaP. The expression of the androgen receptor was also suppressed by the treatment. In clinical trials, PSA levels decreased in the patients group with PSA >or= 10 treated with supplement containing isoflavones and curcumin (P = 0.01).. Our results indicated that isoflavones and curcumin could modulate serum PSA levels. Curcumin presumably synergizes with isoflavones to suppress PSA production in prostate cells through the anti-androgen effects.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Cell Line, Tumor; Curcumin; Double-Blind Method; Humans; Isoflavones; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen

Curcumin, a dietary polyphenol isolated from turmeric, is a potent phytochemical possessing intrinsic anticancer activities against various cancer types including prostate cancer. However, low water solubility and bioavailability of the compound are major challenges against its medical use. The objective of this study is to evaluate the therapeutic potential of curcumin-loaded emulsome nanoparticular system, i.e. CurcuEmulsomes, for the treatment of androgen dependent LNCaP prostate cancer cell line.. Presented safety and anticancer activity of CurcuEmulsomes on LNCaP cell line highlights the potential of CurcuEmulsomes to benefit intrinsic anticancer activities of curcumin in androgen dependent prostate cancer therapy.

Topics: Androgens; Apoptosis; Cell Line, Tumor; Curcumin; Humans; Male; Nanoparticles; Prostatic Neoplasms; Receptors, Androgen

Prostate cancer (PC) is emerging as one of the leading causes of mortality and morbidity worldwide. Curcumin (CUR) is a well-known phytochemical, and scorpion venom (SV) is a natural peptide with proven anticancer properties. However, these natural bioactive agents are limited by low solubility, low bioavailability, poor thermal stability, and short half-lives. Therefore, the aim of this study was to fabricate SV-conjugated CUR phytosomes as promising functionalized nanovesicles and assess their anticancer efficacy in human prostatic cancer PC3 cells. CUR-Phytosome-SV was fabricated using experimental design software in which the zeta potential and particle sizes were used as dependent variables. The anticancer effect of the fabricated formulation was determined by performing a tetrazolium (MTT) assay, cell cycle analysis, annexin V staining, and examining the expression levels of Bcl-associated X-protein (Bax), p53, caspase-3, B-cell lymphoma 2 (Bcl-2), nuclear factor kappa beta (NF-kB), and tumor necrosis factor alpha (TNF-α). The particle size of the nanoconjugates was found to be in the range of 137.5 ± 7.9 to 298.4 ± 11.9 nm, and the zeta potential was 2.9 ± 0.1 to 26.9 ± 1.2 mV. The outcome of the MTT assay showed that curcumin-Phospholipon

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Humans; Male; PC-3 Cells; Prostatic Neoplasms; Scorpion Venoms

In men, prostate cancer (PC) is the second most common cause of cancer-related death. However, paclitaxel resistance is a major challenge in advanced PC. Curcumin, a natural antioxidant, has been demonstrated to have cytotoxic effects on cancer stem cells (CSCs). The goal of this study is to explore if curcumin can help lower chemoresistance to paclitaxel through the regulation of miR-148a-mediated apoptosis in prostate CSCs.. The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and 4',6-diamidino-2-phenylindole (DAPi) labeling were used to determine cell survival. Immunohistochemistry was used to detect the expression of P-glycoprotein protein (P-gp) and CD44 proteins. Finally, real-time PCR was used to evaluate the regulatory effects of curcumin and paclitaxel on miR-148a and its target genes.. Curcumin and paclitaxel co-treatment significantly reduced the IC. Curcumin may restore paclitaxel sensitivity by raising miR-148a expression and inhibiting its target genes.

Topics: Antioxidants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bromides; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Insulin Receptor Substrate Proteins; Male; MicroRNAs; Neoplastic Stem Cells; Paclitaxel; Prostate; Prostatic Neoplasms; Ribosomal Protein S6 Kinases, 90-kDa

Cell viability, glycolytic activity, Annexin V-PE binding activity, reactive oxygen species levels, mitochondrial membrane potential, ATP content, Western blot analysis, and spheroid viability were measured for this study.. Acidic pH-tolerant prostate cancer cells, PC-3AcT and DU145AcT, increased cytotoxicity with ERK1/2 inhibition in a curcumin concentration-dependent manner at concentrations that resulted in >90% cell viability in normal prostate epithelial HPrEC cells. ERK1/2 inhibition by curcumin and/or PD98059 suppressed cell growth, reduced glucose consumption, and downregulated the expression of key regulatory enzymes in glucose metabolism including hexokinases, phosphofructokinase, and pyruvate dehydrogenase. In addition, these compounds caused loss of mitochondrial membrane potential with increased intracellular ROS levels, decreased levels of complexes I, III, and IV in the mitochondrial electron transport chain, and cellular ATP depletion, leading to upregulation of marker proteins in apoptosis (cleaved caspase-3 and cleaved PARP) and necroptosis (p-MLKL and p-RIP3). The results of curcumin and/or PD98059 treatment in 3D cultures showed similar trends to those in 2D cultures.. Taken together, the results provide mechanistic evidence for the antiglycolytic and cytotoxic roles of curcumin through inhibition of the MEK/ERK signaling pathway in prostate carcinoma cells preadapted to acidic conditions.

Topics: Adenosine Triphosphate; Carcinoma; Cell Line, Tumor; Curcumin; Glycolysis; Humans; Male; MAP Kinase Signaling System; Prostate; Prostatic Neoplasms

Prostate cancer remains one of the main causes of death for men worldwide. Despite recent advances in cancer treatment, patients develop resistance after an initial period of optimal efficacy. Nowadays, it is accepted that natural compounds can result in health benefits with a preventive or adjuvant effect. The purpose of this study was to evaluate the effects of curcumin (CU), a bioactive compound in the spice turmeric, and lactoferrin (LF), a natural glycoprotein with immunomodulatory properties, on DU145 and PC3. Prostate cancer cells were cultured with and without LF (175 μM) and CU (2.5 μg/mL and 5 μg/mL), alone and in combination. Cell viability, migration ability, death receptors (DRs), and integrins (α3, β1) gene expression were evaluated, as well as human annexin V quantification and Akt phosphorylation. Differences among cells group, defined according to the treatment used, were assessed with ANOVA. The results showed that the effects of CU and LF are different between the two prostatic cell lines analyzed. In DU145, a reduction in cell proliferation and migration is reported both in the presence of single and combined treatments. In PC3 cells, there is a significant reduction in proliferation in the presence of CU alone, while the inhibition of migration is mainly related to the LF treatment and its combination with CU, compared to untreated cells. Moreover, the reduction in gene expression of integrins and Akt pathway activation were observed mostly in the presence of the CU and LF combination, including the upregulation of DR and annexin V levels, with greater significance for the DU145 cells. In conclusion, our results suggest that CU and LF may have a potentially beneficial effect, mainly when administered in combination, leading to a reduction in cancer cells' aggressiveness.

Topics: Annexin A5; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Lactoferrin; Male; Prostatic Neoplasms

Topics: Apoptosis; Cell Adhesion; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Clone Cells; Curcumin; Human Umbilical Vein Endothelial Cells; Humans; Integrins; Light; Male; Neoplasm Metastasis; Prostatic Neoplasms

Bisphenol A (BPA) is a chemical agent which can exert detrimental effects on the male reproductive system, especially the prostate gland. In this study we described the efficacy of the dietary agent curcumin, alone or combined with piperine, to suppress the impact of BPA on the prostate. Adult gerbils were divided into nine experimental groups (n = 7 each group), regarding control (water and oil), exposed to BPA (50 μg/kg/day in water) or curcumin (100 mg/kg) and/or piperine (20 mg/kg). To evaluate the effects of the phytotherapic agents, the other groups received oral doses every two days, BPA plus curcumin (BCm), piperine (BP), and curcumin + piperine (BCmP). BPA promoted prostatic inflammation and morphological lesions in ventral and dorsolateral prostate lobes, associated with an increase in androgen receptor-positive cells and nuclear atypia, mainly in the ventral lobe. Curcumin and piperine helped to minimize these effects. BPA plus piperine or curcumin showed a reduction in nuclear atypical phenotype, indicating a beneficial effect of phytochemicals. Thus, these phytochemicals minimize the deleterious action of BPA in prostatic lobes, especially when administered in association. The protective action of curcumin and piperine consumption is associated with weight loss, anti-inflammatory potential, and control of prostate epithelial cell homeostasis.

Topics: Alkaloids; Animals; Benzhydryl Compounds; Benzodioxoles; Carcinogenesis; Curcumin; Endocrine Disruptors; Gerbillinae; Male; Phenols; Phytochemicals; Piperidines; Polyunsaturated Alkamides; Prostate; Prostatic Neoplasms; Protective Agents

Side effects and chemotherapy resistance, demand new therapeutics with minimal side effects. Here, we investigated the combined effect of curcumin and metformin on the LNCaP prostate cancer cell line. LNCaP cells were treated with curcumin, metformin, and their combination at different concentrations. Cell viability was assessed by MTT assay and expression of

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Male; Metformin; Prostatic Neoplasms

Early studies indicated that ASC-J9®, an androgen receptor (AR) degradation enhancer, could suppress the prostate cancer (PCa) progression. Here we found ASC-J9® could also suppress the PCa progression via an AR-independent mechanism, which might involve modulating the tumor suppressor ATF3 expression.. The lentiviral system was used to modify gene expression in C4-2, CWR22Rv1 and PC-3 cells. Western blot and Immunohistochemistry were used to detect protein expression. MTT and Transwell assays were used to test the proliferation and invasion ability.. ASC-J9® can suppress PCa cell proliferation and invasion in both PCa C4-2 and CWR22Rv1 cells via altering the ATF3 expression. Further mechanistic studies reveal that ASC-J9® can increase the ATF3 expression via decreasing Glutamate-cysteine ligase catalytic (GCLC) subunit expression, which can then lead to decrease the PTK2 expression. Human clinical studies further linked the ATF3 expression to the PCa progression. Preclinical studies using in vivo mouse model also proved ASC-J9® could suppress AR-independent PCa cell invasion, which could be reversed after suppressing ATF3.. ASC-J9® can function via altering ATF3/PTK2 signaling to suppress the PCa progression in an AR-independent manner.

Topics: Activating Transcription Factor 3; Animals; Cell Line, Tumor; Cell Proliferation; Curcumin; Focal Adhesion Kinase 1; Humans; Male; Mice; Mice, Nude; Neoplasm Invasiveness; Prostatic Neoplasms; Signal Transduction; Xenograft Model Antitumor Assays

Prostate cancer is one of the prominent causes of cancer mortality in men all over the world and a challenge to treat. In this study, transferrin (Tf) bioconjugated solid lipid nanoparticles (SLNs) were developed and loaded with curcumin (CRC) for active targeting of prostate cancer cells. Curcumin is an anticancer agent, but its clinical applications are impeded due to the poor water solubility and bioavailability. Prepared blank Tf-SLNs showed minimal cytotoxicity while Tf-CRC-SLNs demonstrated significant in-vitro anti-proliferative activity compared to CRC-SLNs alone. Cellular uptake of Tf-CRC-SLNs were found to be significantly higher (p < 0.05/=0.01) compared to unconjugated SLNs or pure drug alone. Bioconjugated Tf-CRC-SLNs also showed improved early apoptotic and late apoptotic or early necrotic populations (6.4% and 88.9% respectively) to CRC-SLNs and CRC solution. Most importantly, in-vivo studies with Tf-CRC-SLNs in mice bearing prostate cancer revealed significant tumour regression (392.64 mm

Topics: Animals; Curcumin; Drug Carriers; Humans; Lipids; Male; Mice; Nanoparticles; Particle Size; Pharmaceutical Preparations; Prostatic Neoplasms

Functional nanocarriers which are able to simultaneously vectorize drugs to the site of interest and exert their own cytotoxic activity represent a significant breakthrough in the search for effective anticancer strategies with fewer side effects than conventional chemotherapeutics. Here, we propose previously developed, self-assembling dextran-curcumin nanoparticles for the treatment of prostate cancer in combination therapy with Doxorubicin (DOXO). Biological effectiveness was investigated by evaluating the cell viability in either cancer and normal cells, reactive oxygen species (ROS) production, apoptotic effect, interference with the cell cycle, and the ability to inhibit cell migration and reverse the epithelial to mesenchymal transition (EMT). The results proved a significant enhancement of curcumin efficiency upon immobilization in nanoparticles: IC

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Movement; Cell Proliferation; Cells, Cultured; Curcumin; Dextrans; Doxorubicin; Drug Delivery Systems; Epithelial-Mesenchymal Transition; Humans; Male; Nanoparticles; PC-3 Cells; Prostatic Neoplasms

Herbal medicines (HMs) often exert integration effects, including synergistic, additive and antagonistic effects, in such ways that they act on multiple targets and multiple pathways on account of their multiple components. Turmeric, made from the rhizome of Curcuma longa L., is a well-known HM prescribed in the polyherbal formulas for cancer treatment in traditional Chinese medicines (TCMs). However, neither the multiple anticancer compounds of turmeric nor the integration effects of these components are fully known.. This work aims to develop a systematic approach to reveal the integration effect mechanisms of multiple anticancer compounds in turmeric against prostate cancer PC3 cells.. Combination index and omics technologies were applied to profile the integration effect mechanisms of bioactive compounds in proportions naturally found in turmeric. PC3 cell line (a prostate cancer cell line) fishing and high resolution mass spectrometry were employed to screen and identify the anticancer compounds from turmeric. The combinations which contain different cell-bound compounds in natural proportions were prepared for further evaluation of anti-cancer activity by using cell viability assays, and assessment of cell apoptosis and cell cycle analysis. Combination index analysis was applied to study the integration effects of the anticancer compounds in their natural proportions. Finally, quantitative glycoproteomics/proteomics and Western blot were implemented to reveal the potential synergistic effect mechanisms of the anticancer compounds based on their natural proportions in turmeric.. Three curcuminoids (curcumin, CUR; demethoxycurcumin, DMC; bisdemethoxycurcumin, BDMC) in turmeric were discovered and shown to possess significant synergistic anticancer activities. Combination index analysis revealed an additive effect of CUR combined with DMC or BDMC and a slight synergistic effect of DMC combined with BDMC in natural proportions in turmeric, while a combination of all three curcuminoids (CUR, DMC and BDMC) at a ratio of 1:1:1 yielded superior synergistic effects. Interestingly, the presence of BDMC and DMC are essential for synergistic effect. Glycoproteomics and proteomics demonstrated that different curcuminoids regulate various protein pathways, such as ribosome, glycolysis/gluconeogenesis, biosynthesis of amino acids, and combination of CUR + DMC + BDMC showed the most powerful effects on down-regulation of protein expression.. Our analytical approach provides a systematic understanding of the holistic activity and integration effects of the anti-cancer compounds in turmeric and three curcuminoids of turmeric showed a synergistic effect on PC3 cells.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Curcuma; Diarylheptanoids; Drug Synergism; Glycomics; Glycoproteins; Humans; Male; PC-3 Cells; Plant Extracts; Prostatic Neoplasms; Protein Interaction Maps; Proteomics; Signal Transduction

Photodynamic therapy (PDT) is a minimally invasive approach to treat various forms of cancer, based on the ability of certain non-toxic molecules (photosensitizers) to generate reactive oxygen species (ROS) after excitation by light of a certain wavelength and eventually induce strong phototoxic reactions against malignant cells and other pathogens. Curcumin is one of the most extensively investigated phytochemicals with a wide range of therapeutic properties and has been shown to induce strong photocytotoxic effects in micromolar concentrations against a variety of cancer cell lines. Curcumin (1) is comparatively evaluated with the naturally occurring bisdemethoxy Curcumin (2), which lacks the two methoxy groups, as well as two newly synthesized curcuminoids, the cinnamaldehyde derivative (3) and the dimethylamino one (4), designed to increase the absorption maximum and hence the tissue penetration. The synthetic curcuminoids were successfully synthesized in sufficient amounts and their photophysical properties such as absorption, fluorescence, photobleaching and free radical generation were investigated. Compound 4 exhibited a significant increase in peak absorption (497 nm) and strong fluorescent emission signals were recorded for all curcuminoids. Photobleaching of 4 was comparable to 1 whereas 2 and 3 showed more extended photobleaching but much higher ROS production in very short irradiation times. Compounds 2 and 4 exhibited specific intracellular localization. After dark and light cytotoxicity experiments against LNCaP prostate cancer cell line for all curcuminoids, concentration of 3 μM and irradiance of 6 mW cm-2 were selected for the PDT application which resulted in remarkable results with very short LD50. Curcuminoids 2 and 4 exhibited a significant dose-dependent PDT effect. The biphasic dose-response photodynamic effect observed for 1 and 3 may provide a strategy against prolonged and sustained photosensitivity.

Topics: Cell Line, Tumor; Cell Survival; Curcumin; Humans; Light; Male; Microscopy, Confocal; Photobleaching; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms; Reactive Oxygen Species

The present study investigated the antitumor activity and chemopreventive effects of a nanoparticle formulation of curcumin in preclinical models of mouse Pten-deficient prostate cancer. The antitumor activity of the nanoparticle curcumin was evaluated in mouse castration-naïve (7113-D3) and castration-resistant prostate cancer (2945-E10) derived cell lines in vitro. Cell viability was reduced in both cell lines in a dose and time-dependent manner. The effects of long-term dietary supplementation with the nanoparticle curcumin formulation were evaluated in a conditional Pten-deficient mouse model. Prostate tissues from Pten-deficient prostate cancers were obtained after sixteen weeks of dietary supplementation of 76 mg/kg/day or 380 mg/kg/day nanoparticle curcumin. Daily supplementation of nanoparticle curcumin did not affect mouse bodyweights or spleen size but did result in enlargement of the liver. Dietary supplementation did not influence tumor burden, however, mice fed high-dose curcumin had lower cancer cell proliferation rates at 12 and 16 weeks of age. Together, these results show that daily supplementation of a nanoparticle formulation of curcumin is tolerable and suggest that curcumin could have chemopreventive activity in early-stage prostate cancer.

Topics: Animals; Cell Line, Tumor; Chemoprevention; Curcumin; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Nanoparticles; Prostatic Neoplasms; PTEN Phosphohydrolase

Prostate cancer (PC) is the most common type of newly diagnosed malignancy in men. Combined chemotherapy has been shown to be an effective strategy for the treatment of PC therapy. Lipid-polymer hybrid nanoparticles (LPNs) are core-shell nanoparticles composed of a polymer core and a lipid shell, which are reported to provide significant advantages for combined PC therapy. This study synthesized an aptamer conjugated ligand and designed an aptamer-functionalized, curcumin (CUR) and cabazitaxel (CTX) co-delivered LPNs (APT-CUR/CTX-LPNs). APT-CUR/CTX-LPNs had a mean size of 121.3 ± 4.2 nm and a positive surface charge (23.5 ± 2.6 mV). Both CUR and CTX were sustained released from LPNs. Aptamer-functionalized APT-CUR/CTX-LPNs exhibited good cell inhibition ability, high tumor accumulation, and remarkable tumor inhibition efficiency at the drug ratio of 2:5 (CUR:CTX). The novel LPNs offers great promise for the double drugs delivery to the prostate cancer cells and tumor xenograft in vivo, showing the potential of synergistic combination therapy for prostate cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aptamers, Nucleotide; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Lipids; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Polymers; Prostatic Neoplasms; Taxoids; Xenograft Model Antitumor Assays

Curcumin (Cur) exhibits biological activities that support its candidacy for cancer treatment. However, there are limitations to its pharmacological effects, such as poor solubility and bioavailability. Notably, the use of Cur analogs has potential for addressing these limitations. Dehydrozingerone (DZG) is a representative of the half-chemical structure of Cur, and many reports have indicated that it is anticancer in vitro. We, therefore, have hypothesized that DZG could inhibit prostate cancer progression both in vitro and in vivo. Results revealed that DZG decreased cell proliferation of rat castration-resistant prostate cancer, PLS10 cells, via induction of the cell cycle arrest in the G1 phase in vitro. In the PLS10 xenograft model, DZG significantly decreased the growth of subcutaneous tumors when compared to the control via the inhibition of cell proliferation and angiogenesis. To prove that DZG could improve the limitations of Cur, an in vivo pharmacokinetic was determined. DZG was detected in the serum at higher concentrations and remained up to 3 h after intraperitoneal injections, which was longer than Cur. DZG also showed superior in vivo tissue distribution than Cur. The results suggest that DZG could be a candidate of the Cur analog that can potentially exert anticancer capabilities in vivo and thereby improve its bioavailability.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biological Availability; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Particle Size; Prostatic Neoplasms; Rats; Styrenes

Prostate cancer is one of the most common tumors in the world and the fifth leading cause of male cancer death. Although the treatment of localized androgen-dependent prostate cancer has been successful, the efficacy of androgen-independent metastatic disease is limited. Curcumin, a natural product, has been found to inhibit the proliferation of prostate cancer cells.. To design curcumin analogs with higher biological activity and lower toxicity and side effects for the treatment of prostate cancer.. In this study, the three dimensional-quantitative structure activity relationship (3DQSAR) and molecular docking studies were performed on 34 curcumin analogs as anti-prostate cancer compounds. We introduced OSIRIS Property Explorer to predict drug-related properties of newly designed compounds.. The optimum CoMSIA model exhibited statistically significant results: the cross-validated correlation coefficient q2 is 0.540 and non-cross-validated R2 value is 0.984. The external predictive correlation coefficient Rext 2 is 0.792. The information of structure-activity relationship can be obtained from the CoMSIA contour maps. In addition, the molecular docking study of the compounds for 3ZK6 as the protein target revealed important interactions between active compounds and amino acids.. Compound 28i may be a new type of anti-prostate cancer drug with higher biological activity and more promising development.

Topics: Antineoplastic Agents; bcl-X Protein; Curcumin; Drug Design; Humans; Male; Molecular Docking Simulation; Prostatic Neoplasms; Quantitative Structure-Activity Relationship

Prostate cancer (PCa) is one of the most common cancers in older men and is associated with high mortality. Despite advances in screening for early detection of PCa, a large proportion of patients continue to be diagnosed with metastatic disease, with ~20% of men showing a high tumor grade and stage. Medicinal plant extracts have a great potential to prevent/treat PCa, as well as to reduce its incidence/prevalence and improve survival rates. One of the most promising extracts is curcumin, which is a major, nontoxic, bioactive compound of

Topics: Capsules; Cell Line, Tumor; Curcumin; Humans; Male; Plant Extracts; Polylactic Acid-Polyglycolic Acid Copolymer; Prostatic Neoplasms

The androgen receptor is one of the key targets for prostate cancer treatment. Despite its less satisfactory effects, chemotherapy is the most common treatment option for metastatic and/or castration-resistant patients. There are constant needs for novel anti-prostate cancer therapeutic/prevention agents. Curcumin, a known chemo-preventive agent, was shown to inhibit prostate cancer cell growth. This study aimed to unravel the inhibitory effect of curcumin in prostate cancer through analyzing the alterations of expressions of curcumin targeting genes clusters in androgen-dependent LNCaP cells and androgen-independent metastatic C4-2B cells. Hierarchical clustering showed the highest number of differentially expressed genes at 12 h post treatment in both cells, suggesting that the androgen-dependent/independent manner of curcumin impacts on prostate cancer cells. Evaluation of significantly regulated top canonical pathways highlighted that Transforming growth factor beta (TGF-β), Wingless-related integration site (Wnt), Phosphoinositide 3-kinase/Protein Kinase B/ mammalian target of rapamycin (PIK3/AKT(PKB)/mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling were primarily inhibited, and Phosphatase and tensin homolog (PTEN) dependent cell cycle arrest and apoptosis pathways were elevated with curcumin treatment. The short term (3-24 h) and long term (48 h) effect of curcumin treatment revealed 31 and four genes modulated in both cell lines. TGF-β signaling, including the androgen/TGF-β inhibitor Prostate transmembrane protein androgen-induced 1 (

Topics: Androgens; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Computational Biology; Curcumin; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Hormones; Humans; Male; Prostatic Neoplasms; Proto-Oncogene Mas; Signal Transduction

The aim of this study was to characterize curcumin (CUR)-loaded CD133 aptamer A15 liposomes for their antitumor activity in vitro and in vivo.. The modified CUR liposomes were prepared by the thin-film hydration technique.. The particles showed spherical shape under electron microscopy with sizes <100 nm. Initial drug burst release was observed within 2 hrs and then the drug was continuously released over 48 hrs. No aggregation or precipitation of liposomes was observed during storage for 3 months. In vitro results showed that blank LPs had lower cellular cytotoxicity. Both liposomes of CUR (with or without A15 modified) exhibited a similar trend of cellular cytotoxicity at the same concentration. With the extension of incubation time, A15-CUR LPs showed a greater inhibitory effect on cells. Cell internalization in DU145 cells was higher for A15-CUR LPs than others. An in vivo study using DU145 prostate carcinoma bearing mice showed that A15-CUR LPs reduced tumor growth more than other forms of CUR.. These results indicate that A15 modified CUR liposomes are a promising candidate for antitumor drug delivery.

Topics: AC133 Antigen; Animals; Antineoplastic Agents; Aptamers, Nucleotide; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Drug Delivery Systems; Drug Screening Assays, Antitumor; Humans; Liposomes; Male; Mice; Mice, Nude; Molecular Structure; Nanoparticles; Neoplasms, Experimental; Optical Imaging; Prostatic Neoplasms

To explore the effects of curcumin (CCM) on tumor growth and immune function in mice bearing RM-1 prostate cancer cells.. A prostate cancer model was established in 50 C57BL/6 mice by subcutaneous inoculation of RM-1 cells. The model mice were randomly assigned to intraperitoneal injection of 10% dimethyl sulfoxide at 0.2 ml (the model control group), cyclophosphamide at 20 mg/kg (the CTX group), or CCM at 50 mg/kg (the low-dose CCM group), 100 mg/kg (the medium-dose CCM group) or 200 mg/kg (the high-dose CCM group), respectively, all once a day for 14 successive days, followed by measurement of the tumor weight, calculation of the tumor-inhibition rate, and detection of immunological indicators.. The tumor weight was significantly decreased in the CTX (［1.32 ± 0.06］ g), low-dose CCM (［1.1.54 ± 0.08］ g), medium-dose CCM (［1.48 ± 0.08］ g), and high-dose CCM groups (［1.42 ± 0.07］ g) as compared with that in the model control group (［2.09 ± 0.10］ g) (P < 0.05 or P < 0.01), with no statistically significant differences among the former four groups (P > 0.05). The tumor-inhibition rates in the CTX and low-, medium- and high-dose CCM groups were 36.84%, 27.27%, 29.18% and 32.06%, respectively. All the immunological indicators except the CD4+/CD8+ ratio were remarkably reduced in the CTX group as compared with those in the model control (P < 0.01), but increased in the CCM groups in comparison with those in the CTX group (P < 0.01).. Curcumin has an anti-tumor effect and enhances immune function in prostate cancer-bearing mice.

Topics: Animals; Cell Line, Tumor; Curcumin; Cyclophosphamide; Male; Mice; Mice, Inbred C57BL; Prostatic Neoplasms; Tumor Burden

Chemotherapy with docetaxel remains the effective therapy to suppress castration resistant prostate cancer (CRPC) in some patients. However, most chemotherapy with docetaxel eventually fails with the development of docetaxel resistance after 18-weeks of treatment. Here we found docetaxel treatment might have an adverse effect of increasing the androgen receptor (AR) protein level in the CRPC cells, and combining docetaxel with anti-AR therapy using AR-shRNA or the AR degradation enhancer ASC-J9® may increase docetaxel sensitivity to better suppress the CRPC cell growth. Mechanism dissection found docetaxel might have the adverse effect of increasing the AR protein stability via suppressing the AR ubiquitination due to the increased AR phosphorylation. The consequence of such increased AR protein may then lead to increase p21 expression via transcriptional regulation. Preclinical studies with in vitro cells lines also demonstrated that targeting AR with ASC-J9® led to suppressing the AR-increased p21 expression to improve the docetaxel sensitivity in the CRPC cells that already developed docetaxel resistance. Together, these results suggest that a combined therapy of docetaxel and ASC-J9® is a novel therapy to better suppress CRPC in patients that already developed docetaxel resistance.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Docetaxel; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; Proteolysis; Receptors, Androgen; Tumor Cells, Cultured

While androgen deprivation therapy (ADT) and radiotherapy (RT) are currently used together to treat locally advanced prostate cancer (PCa), RT might have the adverse effect of increasing the PCa androgen receptor (AR) protein expression, which might then increase the resistance to continued RT.. We used multiple assays for RT sensitivity, protein and RNA expression of AR and related DDR genes, ROS level, DNA damage/repair level, cell cycle and apoptosis. All statistical comparisons were analyzed with t-test or one-way ANOVA.. We demonstrated that RT induced AR expression in C4-2 and CWR22Rv-1 cells. We found that combining RT and ASC-J9. Targeting ionizing radiation (IR)-increased AR with the AR degradation enhancer, ASC-J9

Topics: Animals; Cell Line, Tumor; Cell Movement; Curcumin; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Prostatic Neoplasms; Proteolysis; Radiation; Radiation Tolerance; Radiation-Sensitizing Agents; Radiotherapy; Receptors, Androgen; Signal Transduction; Xenograft Model Antitumor Assays

Curcumin is a phytochemical which exhibits significant inhibitory effect in multiple cancers including prostate cancer. MicroRNA-34a (miR-34a) was found to be a master tumor suppressor miRNA and regulated the growth of cancer cells. To date, however, the role of miR-34a in the anticancer action of curcumin against prostate cancer has been rarely reported. In the present study, we showed that curcumin altered the expression of cell cycle-related genes (cyclin D1, PCNA, and p21) and inhibited the proliferation of prostate cancer cells. Furthermore, we found that curcumin significantly upregulated the expression of miR-34a, along with the downregulated expression of β-catenin and c-myc in three prostate cancer cell lines. Inhibition of miR-34a activated β-catenin/c-myc axis, altered cell cycle-related genes expression and significantly suppressed the antiproliferation effect of curcumin in prostate cancer cells. Findings from this study revealed that miR-34a plays an important role in the antiproliferation effect of curcumin in prostate cancer.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; MicroRNAs; Prostate; Prostatic Neoplasms; Xenograft Model Antitumor Assays

Various natural compounds including epigallocatechin gallate (EGCG) and curcumin (CU) have potential in developing anticancer therapy. However, their clinical use is commonly limited by instability and low tissue distribution. EGCG and CU combined treatment can improve the efficacy with synergistic effects. To improve the synergistic effect and overcome the limitations of low tissue distribution, we applied a dual cancer-targeted nanoparticle system to co-deliver EGCG and CU. Nanoparticles were composed of hyaluronic acid, fucoidan, and poly(ethylene glycol)-gelatin to encapsulate EGCG and CU. Furthermore, a dual targeting system was established with hyaluronic acid and fucoidan, which were used as agents for targeting CD44 on prostate cancer cells and P-selectin in tumor vasculature, respectively. Their effect and efficacy were investigated in prostate cancer cells and a orthotopic prostate tumor model. The EGCG/CU-loaded nanoparticles bound to prostate cancer cells, which were uptaken more into cells, leading to a better anticancer efficiency compared to the EGCG/CU combination solution. In addition, the releases of EGCG and CU were regulated by their pH value that avoided the premature release. In mice, treatment of the cancer-targeted EGCG/CU-loaded nanoparticles significantly attenuated the orthotopic tumor growth without inducing organ injuries. Overall, the dual-targeted nanoparticle system for the co-delivery of EGCG and CU greatly improved its synergistic effect in cancer therapy, indicating its great potential in developing treatments for prostate cancer therapy.

Topics: Animals; Catechin; Curcumin; Drug Delivery Systems; Humans; Hyaluronan Receptors; Male; Mice; Mice, SCID; Neoplasm Proteins; Neoplasms, Experimental; P-Selectin; PC-3 Cells; Prostatic Neoplasms; Xenograft Model Antitumor Assays

Our earlier studies indicate that (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones and (1E,4E)-1,5-bis(1-alkyl-1H-benzo[d]imidazol-2-yl)penta-1,4-diene-3-ones exhibit up to 121-fold greater antiproliferative potency than curcumin in human prostate cancer cell models, but only 2-10 fold increase in mouse plasma concentrations. The present study aims to further optimize them as anti-prostate cancer agents with both good potency and bioavailability. (1E,4E)-1,5-Bis(1H-imidazol-2-yl)penta-1,4-diene-3-one, the potential metabolic product of (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones, was synthesized and evaluated for its anti-proliferative activity. The promising potency of 1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones was completely abolished by removing the 1-alkyl group, suggesting the critical role of an appropriate group on the N1 position. We then envisioned that N-aryl substitution to exclude the C-H bond on the carbon adjacent to the N1 position (α-H) may increase the metabolic stability. Consequently, seven (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones and three (1E,4E)-1,5-bis(1-aryl-1H-benzo[d]imidazol-2-yl)penta-1,4-dien-3-ones, as well as three (1E,4E)-1,5-bis(1-aryl-1H-pyrrolo[3,2-b]pyridine-2-yl)penta-1,4-dien-3-ones, were synthesized through a three-step transformation, including N-arylation via Ullmann condensation, formylation, and Horner-Wadsworth-Emmons reaction. Six optimal (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones exhibit 24- to 375-fold improved potency as compared with curcumin. Replacement of the imidazole with bulkier benzoimidazole and 4-azaindole results in a substantial decrease in the potency. (1E,4E)-1,5-Bis(1-(2-methoxyphenyl)-1H-imidazol-2-yl)penta-1,4-dien-3-one (17d) was established as an optimal compound with both superior potency and good bioavailability that is sufficient to provide the therapeutic efficacy necessary to suppress in vivo tumor growth.

Topics: Alkadienes; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Design; Drug Screening Assays, Antitumor; Drug Stability; Half-Life; Humans; Male; Microsomes, Liver; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship

Curcumin can suppress human prostate cancer (HuPCa) cell proliferation and invasion. However, it is not known whether curcumin can inhibit HuPCa stem cell (HuPCaSC) proliferation and invasion.. We used methyl thiazolyl tetrazolium and Transwell assays to examine the proliferation and invasion of the HuPCaSC lines DU145 and 22Rv1 following curcumin or dimethyl sulfoxide (control) treatment. The microRNA (miRNA) expression levels in the DLK1-DIO3 imprinted genomic region in the cells and in tumor tissues from patients with PCa were examined using microarray and quantitative PCR.. The median inhibitory concentration of curcumin for HuPCa cells significantly inhibited HuPCaSC proliferation and invasion in vitro. The miR-770-5p and miR-1247 expression levels in the DLK1-DIO3 imprinted gene cluster were significantly different between the curcumin-treated and control HuPCaSCs. Overexpression of these positive miRNAs significantly increased the inhibition rates of miR-770-5p- and miR-1247-transfected HuPCaSCs compared to the control miR-Mut-transfected HuPCaSCs. Lastly, low-tumor grade PCa tissues had higher miR-770-5p and miR-1247 expression levels than high-grade tumor tissues.. Curcumin can suppress HuPCaSC proliferation and invasion in vitro by modulating specific miRNAs in the DLK1-DIO3 imprinted gene cluster.

Topics: Antineoplastic Agents; Calcium-Binding Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Genomic Imprinting; Humans; Intercellular Signaling Peptides and Proteins; Iodide Peroxidase; Male; Membrane Proteins; MicroRNAs; Multigene Family; Neoplasm Invasiveness; Neoplastic Stem Cells; Prostatic Neoplasms

The carcinogenesis of prostate cancer (PCa) in TRAMP model is highly correlated with hypermethylation in the promoter region of Nrf2 and the accompanying reduced transcription of Nrf2 and its regulated detoxifying genes. We aimed to investigate the effects of (3E,5E)-3,5-bis-(3,4,5-trimethoxybenzylidene)-tetrahydro-thiopyran-4-one (F10) and (3E,5E)-3,5-bis-(3,4,5-trimethoxy-benzylidene)-tetrahydropyran-4-one (E10), two synthetic curcumin derivatives, on restoring Nrf2 activity in TRAMP C1 cells. HepG2-C8 cells transfected with an antioxidant-response element (ARE)-luciferase vector were treated with F10, E10, curcumin, and sulforaphane (SFN) to compare their effects on Nrf2-ARE pathways. We performed real-time quantitative PCR and Western blotting to investigate the effects of F10 and E10 on Nrf2, correlated phase II detoxification genes. We also measured expression and activity of DNMTand HDAC enzymes. Enrichment of H3K27me3 on the promoter region of Nrf2 was explored with a chromatin immunoprecipitation (ChIP) assay. Methylation of the CpG region in Nrf2 promoter was doubly examined by bisulfite genomic sequencing (BGS) and methylation DNA immunoprecipitation (MeDIP). Compared with curcumin and SFN, F10 is more potent in activating Nrf2-ARE pathways. Both F10 and E10 enhanced level of Nrf2 and the correlated phase II detoxifying genes. BGS and MeDIP assays indicated that F10 but not E10 hypomethylated the Nrf2 promoter. F10 also downregulated the protein level of DNMT1, DNMT3a, DNMT3b, HDAC1, HDAC4, and HDAC7 and the activity of DNMTs and HDACs. F10 but not E10 effectively reduced the accumulation of H3k27me3 on the promoter of Nrf2. F10 and E10 can activate the Nrf2-ARE pathway and increase the level of Nrf2 and correlated phase II detoxification genes. The reactivation effect on Nrf2 by F10 in TRAMP C1 may come from demethylation, decrease of HDACs, and inhibition of H3k27me3 accumulation.

Topics: Animals; Antioxidants; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Epigenesis, Genetic; Male; Mice; Molecular Structure; NF-E2-Related Factor 2; Oxidative Stress; Prostatic Neoplasms; Signal Transduction; Structure-Activity Relationship; Tumor Cells, Cultured

Intratumoral androgen biosynthesis has been recognized as an essential factor of castration-resistant prostate cancer. The present study investigated the effects of curcumin on the inhibition of intracrine androgen synthesis in prostate cancer. Human prostate cancer cell lines, LNCaP and 22Rv1 cells were incubated with or without curcumin after which cell proliferation was measured at 0, 24, 48 and 72 hours, respectively. Prostate tissues from the transgenic adenocarcinoma of the mouse prostate (TRAMP) model were obtained after 1-month oral administration of 200 mg/kg/d curcumin. Testosterone and dihydrotestosterone concentrations in LNCaP prostate cancer cells were determined through LC-MS/MS assay. Curcumin inhibited cell proliferation and induced apoptosis of prostate cancer cells in a dose-dependent manner. Curcumin decreased the expression of steroidogenic acute regulatory proteins, CYP11A1 and HSD3B2 in prostate cancer cell lines, supporting the decrease of testosterone production. After 1-month oral administration of curcumin, Aldo-Keto reductase 1C2 (AKR1C2) expression was elevated. Simultaneously, decreased testosterone levels in the prostate tissues were observed in the TRAMP mice. Meanwhile, curcumin treatments considerably increased the expression of AKR1C2 in prostate cancer cell lines, supporting the decrease of dihydrotestosterone. Taken together, these results suggest that curcumin's natural bioactive compounds could have potent anticancer properties due to suppression of androgen production, and this could have therapeutic effects on prostate cancer.

Topics: Androgens; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cholesterol Side-Chain Cleavage Enzyme; Curcumin; Dihydrotestosterone; Female; Humans; Hydroxysteroid Dehydrogenases; Male; Mice; Mice, Inbred C57BL; Progesterone Reductase; Prostate; Prostatic Neoplasms; Receptors, Androgen; Testosterone

The androgen-deprivation therapy (ADT) to either reduce the androgen biosynthesis (for example, Abiraterone) or to prevent binding of androgen to the androgen receptor (AR), for example using Casodex or Enzalutamide, which may result in .decrease of the prostate cancer (PCa) cell growth, yet may also increase the PCa cell invasion. In contrast, the recently identified AR degradation enhancer ASC-J9

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Male; Mice; Neoplasm Invasiveness; Phosphorylation; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; STAT3 Transcription Factor; Sumoylation; Xenograft Model Antitumor Assays

The process of optimization and fabrication of nanoparticle synthesis for preclinical studies can be challenging and time consuming. Traditional small scale laboratory synthesis techniques suffer from batch to batch variability. Additionally, the parameters used in the original formulation must be re-optimized due to differences in fabrication techniques for clinical production. Several low flow microfluidic synthesis processes have been reported in recent years for developing nanoparticles that are a hybrid between polymeric nanoparticles and liposomes. However, use of high flow microfluidic synthetic techniques has not been described for this type of nanoparticle system, which we will term as nanolipomer. In this manuscript, we describe the successful optimization and functional assessment of nanolipomers fabricated using a microfluidic synthesis method under high flow parameters.. The optimal total flow rate for synthesis of these nanolipomers was found to be 12 ml/min and flow rate ratio 1:1 (organic phase: aqueous phase). The PLGA polymer concentration of 10 mg/ml and a DSPE-PEG lipid concentration of 10% w/v provided optimal size, PDI and stability. Drug loading and encapsulation of a representative hydrophobic small molecule drug, curcumin, was optimized and found that high encapsulation efficiency of 58.8% and drug loading of 4.4% was achieved at 7.5% w/w initial concentration of curcumin/PLGA polymer. The final size and polydispersity index of the optimized nanolipomer was 102.11 nm and 0.126, respectively. Functional assessment of uptake of the nanolipomers in C4-2B prostate cancer cells showed uptake at 1 h and increased uptake at 24 h. The nanolipomer was more effective in the cell viability assay compared to free drug. Finally, assessment of in vivo retention in mice of these nanolipomers revealed retention for up to 2 h and were completely cleared at 24 h.. In this study, we have demonstrated that a nanolipomer formulation can be successfully synthesized and easily scaled up through a high flow microfluidic system with optimal characteristics. The process of developing nanolipomers using this methodology is significant as the same optimized parameters used for small batches could be translated into manufacturing large scale batches for clinical trials through parallel flow systems.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Drug Evaluation, Preclinical; Equipment Design; Humans; Lab-On-A-Chip Devices; Lactic Acid; Liposomes; Male; Mice; Nanoparticles; Phosphatidylethanolamines; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostatic Neoplasms

The high incidence of prostate carcinogenesis has prompted the search for novel effective treatment approaches. We have employed curcumin (Curc) and diethylstilbestrol (DES) to synthesize a series of polyacetal (PA)-based combination conjugates for prostate cancer (PCa) treatment. Given their bihydroxyl functionalities, Curc and DES molecules were incorporated into a PA mainchain using a one-pot reaction between diols and divinyl ethers. The PA-conjugates released both drugs under acidic conditions, such as those found in the tumor microenvironment, endosomes, or lysosomes, while remaining stable at neutral pH 7.4. The drug ratio was optimized to achieve anticancer drug synergism with elevated cytotoxicity against LNCaP-hormone-dependent human PCa cells conferred via the induction of S phase cell cycle arrest by the upregulation of p53 and CDK inhibitors p21Waf/CIP1 and downregulation of cyclin D1. The application of rationally designed PA-Curc-DES combination conjugates represents a potentially exciting new treatment for prostate cancer.

Topics: Acetals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Delayed-Action Preparations; Diethylstilbestrol; Humans; Male; Neoplasm Proteins; Polymers; Prostatic Neoplasms; S Phase Cell Cycle Checkpoints

Metastatic castration-resistant prostate cancer is commonly treated with chemotherapy, whose effect is less than satisfactory. This raised the need for novel agents for the treatment of prostate cancer. In the present study, five phthalimide-based curcumin derivatives were synthesized and completely characterized to assess improved stability, pharmacodynamics, and radical scavenging ability. To investigate the potential application in anti-cancer therapy, the anti-proliferative activity of the synthesized molecules was determined on aggressive prostate tumor cells. We demonstrated that the K3F21 derivative has increased potency compared to curcumin, in terms of GI50, anti-proliferative and anti-migrating activities. K3F21 inhibits anchorage-dependent and -independent growth of prostate cancer cells by altering the expression of key genes controlling cell proliferation, such as Cylins D1, B1 and B2, and apoptosis, among which Puma, Noxa, and Bcl-2 family members. Finally, the anti-cancer activity of K3F21 was demonstrated by the analysis of cancer-associated PI3K/AKT, ERK, and p38 signaling pathways.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Disease Progression; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Male; Molecular Structure; Phthalimides; Prostatic Neoplasms; Signal Transduction

To systematically investigate the structure-activity relationships of 1,7-diheteroarylhepta-1,4,6-trien-3-ones in three human prostate cancer cell models and one human prostate non-neoplastic epithelial cell model, thirty five 1,7-diarylhepta-1,4,6-trien-3-ones with different terminal heteroaromatic rings have been designed for evaluation of their anti-proliferative potency in vitro. These target compounds have been successfully synthesized through two sequential Horner-Wadsworth-Emmons reactions starting from the appropriate aldehydes and tetraethyl (2-oxopropane-1,3-diyl)bis(phosphonate). Their anti-proliferative potency against PC-3, DU-145 and LNCaP human prostate cancer cell lines can be significantly enhanced by the manipulation of the terminal heteroaromatic rings, further demonstrating the utility of 1,7-diarylhepta-1,4,6-trien-3-one as a potential scaffold for the development of anti-prostate cancer agents. The optimal analog 40 is 82-, 67-, and 39-fold more potent than curcumin toward the three prostate cancer cell lines, respectively. The experimental data also reveal that the trienones with two different terminal aromatic rings possess greater potency toward three prostate cancer cell lines, but also have greater capability of suppressing the proliferation of PWR-1E benign human prostate epithelial cells, as compared to the corresponding counterparts with two identical terminal rings and curcumin. The terminal aromatic rings also affect the cell apoptosis perturbation.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Hydrocarbons, Aromatic; Male; Prostate; Prostatic Neoplasms; Structure-Activity Relationship; Trientine

Accumulating evidence suggests that natural bioactive compounds, alone or in combination with traditional chemotherapeutic agents, could be used as potential therapies to fight cancer. In this study, we employed four natural bioactive compounds (curcumin, resveratrol, melatonin, and silibinin) and studied their role in redox control and ability to promote apoptosis in androgen sensitive and insensitive prostate cancer cells. Here is shown that curcumin and resveratrol promote ROS production and induce apoptosis in LNCaP and PC-3. An increase in reactive species is a trigger event in curcumin-induced apoptosis and a consequence of resveratrol effects on other pathways within these cells. Moreover, here we demonstrated that these four compounds affect differently one of the main intracellular redox regulator, the thioredoxin system. Exposure to curcumin and resveratrol promoted TRX1 oxidation and altered its subcellular location. Furthermore, resveratrol diminished TRX1 levels in PC-3 cells and increased the expression of its inhibitor TXNIP. Conversly, melatonin and silibinin only worked as cytostatic agents, reducing ROS levels and showing preventive effects against TRX oxidation. All together, this work explores the effect of compounds currently tested as chemo-preventive agents in prostate cancer therapy, on the TRX1 redox state and function. Our work shows the importance that the TRX system might have within the differences found in their mechanisms of action. These bioactive compounds trigger different responses and affect ROS production and redox systems in prostate cancer cells, suggesting the key role that redox-related pathways might play in processes like differentiation or survival in prostate cancer.

Topics: Apoptosis; Carrier Proteins; Cell Line, Tumor; Cell Survival; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Male; Melatonin; Prostatic Neoplasms; Reactive Oxygen Species; Resveratrol; Silybin; Silymarin; Stilbenes; Thioredoxins

Curcumin is a potent antitumor agent. The objective of this study was to explore the interaction between curcumin and PGK1, an oncogene in the FOXD3/miR-143 axis, in prostate cancer therapy.. MiRNA microarray analysis was used to identify miRNAs upregulated by curcumin treatment. MiR-143 was dramatically upregulated by curcumin. Cells were treated with antimiR-143 in combination to curcumin, followed by examining cell viability and migration. Bioinformatics analysis was used to investigate target genes of miR-143. The interaction between miR-143 and PGK1 was evaluated with dual-luciferase assay. Since FOXD3 is important in the regulation of miR-143, we explored whether curcumin regulated FOXD3 expression. FOXD3 was also ectopically overexpressed to investigate its effects on curcumin's regulation of miR-143.. Curcumin treatment significantly upregulated miR-143 and decreased prostate cancer cell proliferation and migration. Those effects were attenuated by anti-miR-143 transfection. Both miR-143 overexpression and curcumin treatment inhibited PGK1 expression and ectopic expression of PGK1 antagonized curcumin's antitumor effects. FOXD3 was upregulated by miR-143. Ectopic expression of FOXD3 synergized with curcumin in upregulating miR-143 expression.. Curcumin inhibits prostate cancer by upregulating miR-143. PGK1 is downregulated by miR-143, and FOXD3 upregulation is essential for the antitumor effect of curcumin.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Survival; Computational Biology; Curcumin; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Gene Transfer Techniques; Humans; Lentivirus; Male; Microarray Analysis; MicroRNAs; Phosphoglycerate Kinase; Prostatic Neoplasms

Curcumin has been reported as a radiosensitizer in prostate cancer. But the underlying mechanism is not well understood. In this study, we firstly assessed how curcumin affects the expression of miR-143/miR-145 cluster. Then, we investigated whether miR-143 is involved in regulation of radiosensitivity and its association with autophagy in prostate cancer cells. Our data showed that PC3, DU145 and LNCaP cells treated with curcumin had significantly restored miR-143 and miR-145 expression. Curcumin showed similar effect as 5-AZA-dC on reducing methylation of CpG dinucleotides in miR-143 promoter. In addition, curcumin treatment reduced the expression of DNMT1 and DNMT3B, which contribute to promoter hypermethylation of the miR-143/miR-145 cluster. Therefore, we infer that curcumin can restore miR-143 and miR-145 expression via hypomethylation. MiR-143 overexpression and curcumin pretreatment enhanced radiation induced cancer cell growth inhibition and apoptosis. MiR-143 and curcumin remarkably reduced radiation-induced autophagy in PC3 and DU145 cells. MiR-143 overexpression alone also reduced the basal level of autophagy in DU145 cells. Mechanistically, miR-143 can suppress autophagy in prostate cancer cells at least via downregulating ATG2B. Based on these findings, we infer that curcumin sensitizes prostate cancer cells to radiation partly via epigenetic activation of miR-143 and miR-143 mediated autophagy inhibition.

Topics: Autophagy; Cell Line, Tumor; Curcumin; Epigenesis, Genetic; Humans; Male; Methylation; MicroRNAs; Prostatic Neoplasms; Radiation Tolerance

Curcumin and resveratrol are naturally occurring polyphenolic compounds having anti-cancer potential. However, their poor aqueous solubility and bioavailability limit their clinical use. Entrapment of hydrophobic drugs into hydrophilic nanoparticles such as calcium alginate presents a means to deliver these drugs to their target site. Curcumin and resveratrol-loaded calcium alginate nanoparticles were prepared by emulsification and cross-linking process. The nanoparticles were characterized for particle size, zeta potential, moisture content, physical state of the drugs, physical stability, and entrapment efficiency. An UPLC method was developed and validated for the simultaneous analysis of curcumin and resveratrol. Alginate nanoformulation was tested for in vitro efficacy on DU145 prostate cancer cells. The particle size of the nanosuspension and freeze-dried nanoparticles was found to be 12.53 ± 1.06 and 60.23 ± 15 nm, respectively. Both DSC and powder XRD studies indicated that curcumin as well as resveratrol were present in a non-crystalline state, in the nanoparticles. The entrapment efficiency for curcumin and resveratrol was found to be 49.3 ± 4.3 and 70.99 ± 6.1%, respectively. Resveratrol showed a higher percentage of release than curcumin (87.6 ± 7.9 versus 16.3 ± 3.1%) in 24 h. Curcumin was found to be taken up by the cells from solution as well as the nanoparticles. Resveratrol had a poor cellular uptake. The drug-loaded nanoparticles exhibit cytotoxic effects on DU145 cells. At high concentration, drug solution exhibited greater toxicity than nanoparticles. The alginate nanoformulation was found to be safe for intravenous administration.

Topics: Alginates; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Liberation; Glucuronic Acid; Hexuronic Acids; Humans; Male; Nanoparticles; Particle Size; Prostatic Neoplasms; Resveratrol; Stilbenes

Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Calreticulin; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Chromatography, High Pressure Liquid; Curcumin; Down-Regulation; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Male; Prostatic Neoplasms; Protein Disulfide-Isomerases; Proteomics; Signal Transduction; Up-Regulation

Background Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has demonstrated that these polyphenols play an important role in the maintenance of health and prevention of diseases, in addition to its therapeutic benefits such as anti-tumor, anti-inflammatory, and anti-oxidant activities. Materials and methods This study is devoted to the enhancement of the solubility and bioavailability of curcumin nanoparticles prepared by a process based on a wet-milling technique and then examine in vitro against prostate cancer cell line 3 (PC3), human embryonic kidney cell line (HEK), human erythrocytes (red blood cells (RBCs)), and against fourth different bacterial strains two gram-positive (Micrococcus luteus ATCC 9341, Staphylococcus aureus ATCC 29213), two gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853). Results The cell viability curve, the half maximal inhibitory concentration (IC

Topics: Anti-Infective Agents; Antineoplastic Agents; Bacteria; Cell Line; Curcumin; HEK293 Cells; Humans; Male; Nanoparticles; Prostatic Neoplasms

Curcumin is more soluble in ethanol, dimethylsulfoxide, methanol and acetone than in water. In this study, nanocurcumin combined with 8 mT AC static magnetic field was used to enhance cellular uptake, bioavailability, and ultimate efficiency of curcumin against prostate cancer cell line (PC3), four bacteria strains (two Gram positive: Micrococcus luteus ATCC 9341, Staphylococcus aureus ATCC 29213 and two Gram negative: Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853), mammalian cell line (HEK) and human erythrocytes (RBC). The efficiency (E%) between IC

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Bacteria; Biological Availability; Biological Transport; Cell Line, Tumor; Cell Membrane Permeability; Curcumin; Erythrocytes; Humans; Magnetic Fields; Male; Nanoparticles; Prostatic Neoplasms

Vesicular stomatitis virus (VSV) matrix (M) protein mutants have been studied as oncolytic agents due to their capacity to effectively kill cancer cells while exhibiting low virulence in vivo. Despite encouraging results, many cancer cells maintain resistance to oncolytic VSV mutants in part due to residual antiviral responses. We sought to determine whether combination of VSV with natural agents with anti-tumor properties, such as curcumin, resveratrol, and flavokavain B, would enhance tumor cell killing in a prostate cancer model. Our results revealed that pretreatment with curcumin potentiated VSV-induced oncolysis of PC-3 prostate cancer cells in cell culture and in a mouse model of prostate cancer. The ability of curcumin to synergize with VSV in PC-3 cells correlated with a cumulative decrease in the expression of the anti-apoptotic protein, Bcl-xl, and in the phosphorylation of NF-κB. Although curcumin did not impact the expression of type I IFN in infected cells, it inhibited the phosphorylation and activation of STAT1, a key player in the IFN response pathway, leading to an overall increase in virus-infected cells. These results suggest that curcumin sensitizes prostate cancer cells to the oncolytic effects of VSV by modulating antiviral responses and components of the intrinsic apoptotic pathway.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Humans; Interferon Type I; Male; Mice; NF-kappa B; Oncolytic Virotherapy; Oncolytic Viruses; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; Vesicular stomatitis Indiana virus; Virus Replication; Xenograft Model Antitumor Assays

Prostate cancer is one of the most common malignancies in men, and it urgently demands precise interventions that target the signaling pathways implicated in its initiation, progression, and metastasis. The Notch-1 signaling pathway is closely associated with the pathophysiology of prostate cancer. This study investigated the antitumor effects and mechanisms of curcumin, which is a well-known natural compound from curcuminoids, in prostate cancer cells. Viability, proliferation, and migration were analyzed in two prostate cancer cell lines, DU145 and PC3, after curcumin treatment. Whether the Notch-1 signaling pathway is involved in the antitumor effects of curcumin was examined. Curcumin inhibited the survival and proliferation of PC3 and DU145 cells in a dose- and time-dependent manner and inhibited DU145 migration. Curcumin did not affect the expression of Notch-1 or its active product NICD, but it did inhibit the expression of MT1-MMP and MMP2 proteins in DU145 cells. We found that curcumin inhibited the DNA-binding ability of NICD in DU145 cells. In conclusion, curcumin inhibited the survival and metastasis of prostate cancer cells via the Notch-1 signaling pathway.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Gene Expression Profiling; Humans; Male; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Neoplasm Metastasis; Prostatic Neoplasms; Receptor, Notch1; Signal Transduction; Time Factors

Combination therapy is increasingly used as a primary cancer treatment regimen. In this report, we designed EGFR peptide decorated nanoparticles (NPs) to co-deliver docetaxel (DTX) and pH sensitive curcumin (CUR) prodrug for the treatment of prostate cancer.. EGFR peptide (GE11) targeted, pH sensitive, DTX and CUR prodrug NPs (GE11-DTX-CUR NPs) had an average diameter of 167nm and a zeta potential of -37.5mV. The particle size of the NPs was adequately maintained in serum and a sustained drug release pattern was observed. Improved inhibition of cancer cell and tumor tissue growth was shown in the GE11-DTX-CUR NPs group compared to the other groups.. It can be summarized that DTX and CUR prodrug could be delivered into tumor cells simultaneously by the GE 11 targeting and the EPR effect of NPs. The resulting GE11-DTX-CUR NPs is a promising system for the synergistic antitumor treatment of prostate cancer.

Topics: Aconitic Acid; Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Coumarins; Curcumin; Docetaxel; Drug Delivery Systems; Drug Liberation; Drug Stability; Drug Synergism; Endocytosis; Humans; Inhibitory Concentration 50; Lactic Acid; Male; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Particle Size; Peptides; Polyethylene Glycols; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prodrugs; Prostatic Neoplasms; Proton Magnetic Resonance Spectroscopy; Taxoids; Thiazoles

Docetaxel is the most commonly used chemotherapeutic agent to target androgen signaling in metastatic prostate cancer (PCa); however, prolonged treatment with docetaxel results in drug-resistant cancer cells. Combination therapies have the potential of increasing the effectiveness of drug treatment as well as decreasing the side effects. Curcumin is a nontoxic organic compound with multifaceted chemopreventive potential. In this study, we evaluated whether curcumin can reinforce the effect of docetaxel on PCa cells. The PCa cell lines DU145 and PC3 were treated with curcumin and docetaxel alone or in combination. After completion of the treatment cell proliferation and the expression of pro-survival and anti-apoptotic markers and the signaling molecules were analyzed. The combined treatment of curcumin and docetaxel inhibited the proliferation and induced apoptosis significantly higher than the curcumin and docetaxel-treated group alone. Interestingly, the combined treatment with curcumin and docetaxel modulates the expression of RTKs, PI3K, phospho-AKT, NF-kappa B, p53, and COX-2. These results suggest that curcumin can be a potential therapeutic contender in enhancing the efficacy of docetaxel in PCa treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Curcumin; Docetaxel; Humans; Male; Prostatic Neoplasms; Taxoids

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

The anti-cancer property of curcumin, an active component of turmeric, is limited due to its poor solubility, stability and bioavailability. To enhance its efficacy, we designed a novel series of twenty-four monocarbonyl curcumin analogue-1,2,3-triazole conjugates and evaluated their anti-cancer activity towards endocrine related cancers. The new compounds (17-40) were synthesized through CuAAC click reaction and SAR analysis carried out. Out of these all, compound 17 showed most significant anti-cancer activity against prostate cancer cells with IC50 values of 8.8μM and 9.5μM in PC-3 and DU-145 cells, respectively. Another compound 26 showed significant anti-cancer activity against breast cancer cells with IC50 of 6μM, 10μM and 6.4μM in MCF-7, MDA-MB-231 and 4T1 cells, respectively while maintaining low toxicity towards non-cancer originated cell line, HEK-293. Compounds 17 and 26 arrested cell cycle and induced mitochondria-mediated apoptosis in cancer cells. Further, both of these compounds significantly down-regulated cell proliferation marker (PCNA), inhibited activation of cell survival protein (Akt phosphorylation), upregulated pro-apoptotic protein (Bax) and down-regulated anti-apoptotic protein (Bcl-2) in their respective cell lines. In addition, in vitro stability, solubility and plasma binding studies of the compounds 17 and 26 showed them to be metabolically stable. Thus, this study identified two new curcumin monocarbonyl-1,2,3-triazole conjugate compounds with more potent activity than curcumin against breast and prostate cancers.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Click Chemistry; Curcumin; Down-Regulation; Drug Screening Assays, Antitumor; Female; Half-Life; HEK293 Cells; Humans; Male; Membrane Potential, Mitochondrial; Proliferating Cell Nuclear Antigen; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Triazoles

In search of more effective chemotherapeutics for the treatment of castration-resistant prostate cancer and inspired by curcumin analogues, twenty five (1E,3E,6E,8E)-1,9-diarylnona-1,3,6,8-tetraen-5-ones bearing two identical terminal heteroaromatic rings have been successfully synthesized through Wittig reaction followed by Horner-Wadsworth-Emmons reaction. Twenty-three of them are new compounds. The WST-1 cell proliferation assay was employed to assess their anti-proliferative effects toward both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Eighteen out of twenty-five synthesized compounds possess significantly improved potency as compared with curcumin. The optimal compound, 78, is 14- to 23-fold more potent than curcumin in inhibiting prostate cancer cell proliferation. It can be concluded from our data that 1,9-diarylnona-1,3,6,8-tetraen-5-one can serve as a new potential scaffold for the development of anti-prostate cancer agents and that pyridine-4-yls and quinolin-4-yl act as optimal heteroaromatic rings for the enhanced potency of this scaffold. Two of the most potent compounds, 68 and 75, effectively suppress PC-3 cell proliferation by activating cell apoptosis and by arresting cell cycle in the G0/G1 phase.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Design; Drug Screening Assays, Antitumor; Humans; Male; Prostate; Prostatic Neoplasms

Docetaxel (DTX) remains the only effective drug for prolonging survival and improving quality of life of metastatic castration-resistant prostate cancer (mCRPC) patients. Combination anticancer therapy encapsulating DTX and another extract of traditional Chinese medicine is one nano-sized drug delivery system promising to generate synergistic anticancer effects, to maximize the treatment effect, and to overcome multi-drug resistance. The purpose of this study is to construct lipid-polymer hybrid nanoparticles (LPNs) as nanomedicine for co-encapsulation of DTX and curcumin (CUR).. DTX and CUR co-encapsulated LPNs (DTX-CUR-LPNs) were constructed. DTX-CUR-LPNs were evaluated in terms of particles size, zeta potential, drug encapsulation, and drug delivery. The cytotoxicity of the LPNs was evaluated on PC-3 human prostate carcinoma cells (PC3 cells) by MTT assays. In vivo anti-tumor effects were observed on the PC3 tumor xenografts in mice.. The particle size of DTX-CUR-LPNs was 169.6 nm with a positive zeta potential of 35.7 mV. DTX-CUR-LPNs showed highest cytotoxicity and synergistic effect of two drugs in tumor cells in vitro. In mice-bearing PC-3 tumor xenografts, the DTX-CUR-LPNs inhibited tumor growth to a greater extent than other contrast groups, without inducing any obvious side effects.. According to these results, the novel nanomedicine offers great promise for the dual drugs delivery to the prostate cancer cells, showing the potential of synergistic combination therapy for prostate cancer.

Topics: Animals; Cell Line, Tumor; Curcumin; Docetaxel; Drug Carriers; Drug Delivery Systems; Heterografts; Humans; Lipids; Male; Mice; Nanomedicine; Particle Size; Polymers; Prostatic Neoplasms; Taxoids

In the present study, we aimed to investigate the anticancer properties of Theracurmin®, a novel form of the yellow curry pigment curcumin, as well as explore the molecular mechanisms of the potential anticancer effects of Theracurmin® on human prostate cancer and bladder cancer cells in vitro. The proliferation of cancer cells was examined by using the Cell Counting Kit-8. The clonogenic growth potential was determined by clonogenic assay. Cell cycle distribution was evaluated by flow cytometry using propidium iodide staining. Western blot analysis was applied to explore the expression patterns of molecules associated with apoptotic cell death and cell cycle checkpoint. We noted that Theracurmin® and curcumin exhibited similar anticancer effects in both androgen-dependent and -independent human prostate cancer cells in a dose- and time-dependent manner. These agents reduced cell viability and clonogenic growth potential by inducing apoptosis and cell cycle disturbance in human prostate cancer cells. Theracurmin® and curcumin also exerted marked anticancer effects on human bladder cancer cells, even in cisplatin-resistant T24R2 cells, in a dose- and time-dependent manner. Moreover, Theracurmin® and curcumin treatment decreased cell viability and clonogenicity via induction of apoptotic cell death and cell cycle dysregulation in human bladder cancer cells. In conclusion, our study suggests that Theracurmin® has potential as an anticancer agent in complementary and alternative medicine for these urological cancers.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Male; Prostatic Neoplasms; Urinary Bladder Neoplasms

It has previously been shown that curcumin can effectively inhibit prostate cancer proliferation and progression in TRAMP mice, potentially acting through the hypomethylation of the Nrf2 gene promoter and hence activation of the Nrf2 pathway to enhance cell antioxidative defense. FN1 is a synthetic curcumin analogue that shows stronger anticancer activity than curcumin in other reports. We aimed to explore the epigenetic modification of FN1 that restores Nrf2 expression in TRAMP-C1 cells. Stably transfected HepG2-C8 cells were used to investigate the effect of FN1 on the Nrf2- antioxidant response element (ARE) pathway. Real-time quantitative PCR and Western blotting were applied to study the influence of FN1 on endogenous Nrf2 and its downstream genes. Bisulfite genomic sequencing (BGS) and methylated DNA immunoprecipitation (MeDIP) were then performed to examine the methylation profile of the Nrf2 promoter. An anchorage-independent colony-formation analysis was conducted to examine the tumor inhibition activity of FN1. Epigenetic modification enzymes, including DNMTs and HDACs, were investigated by Western blotting. The luciferase reporter assay indicated that FN1 was more potent than curcumin in activating the Nrf2-ARE pathway. FN1 increased the expression of Nrf2 and its downstream detoxifying enzymes. FN1 significantly inhibited the colony formation of TRAMP-C1 cells. BGS and MeDIP assays revealed that FN1 treatment (250 nM for 3 days) reduced the percentage of CpG methylation of the Nrf2 promoter. FN1 also downregulated epigenetic modification enzymes. In conclusion, our results suggest that FN1 is a novel anticancer agent for prostate cancer. In the TRAMP-C1 cell line, FN1 can increase the level of Nrf2 and downstream genes via activating the Nrf2-ARE pathway and inhibit the colony formation potentially through the decreased expression of keap1 coupled with CpG demethylation of the Nrf2 promoter. This CpG demethylation effect may come from decreased epigenetic modification enzymes, such as DNMT1, DNMT3a, DNMT3b, and HDAC4.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; CpG Islands; Curcumin; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Kelch-Like ECH-Associated Protein 1; Male; Mice; NF-E2-Related Factor 2; Prostate; Prostatic Neoplasms

Early studies suggested that prostate cancer (PCa) stem/progenitor (S/P) cells might play key roles to promote the tumor initiation and metastasis. Yet their linkage to the failure of androgen deprivation therapy (ADT), however, remains unclear. Here we demonstrated that the ADT with anti-androgens Casodex (also known as Bicalutamide) and Enzalutamide (also known as MDV3100), but not the newly identified AR degradation enhancer, ASC-J9(®), increased PCa S/P population, which might then lead to enhance the PCa cell invasion. Targeting AR with ASC-J9(®), and not targeting androgens with Casodex or Enzalutamide, led to suppress PCa S/P cell invasion. Mechanism dissection revealed ASC-J9(®) could suppress S/P cell invasion via altering the EZH2/STAT3 and/or AKT/EZH2/STAT3 signals. Together, these results suggest that targeting PCa S/P cells with ASC-J9(®) or inhibitors to interrupt the EZH2/STAT3 and/or Akt/EZH2/STAT3 signals may become a new therapy to overcome the unwanted side effects of Casodex or Enzalutamide to further suppress the PCa metastasis.

Topics: Androgen Antagonists; Anilides; Animals; Antineoplastic Agents, Hormonal; Benzamides; Cell Line, Tumor; Cell Movement; Curcumin; Enhancer of Zeste Homolog 2 Protein; Humans; Male; Mice, Nude; Neoplasm Invasiveness; Neoplastic Stem Cells; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Side-Population Cells; Signal Transduction; STAT3 Transcription Factor; Tosyl Compounds; Xenograft Model Antitumor Assays

Epigenetic repression of Androgen Receptor (AR) gene by hypermethylation of its promoter causes resistance in prostate cancer (CaP) to androgen deprivation therapy with anti-androgens. Some dietary phytocompounds like quercetin (Q) and curcumin (C) with reported DNMT-inhibitory activity were tested for their ability to re-express the AR in AR-negative CaP cell lines PC3 and DU145. Combined treatment with Q+C was much more effective than either Q or C in inhibiting DNMT, causing global hypomethylation, restoring AR mRNA and protein levels and causing apoptosis via mitochondrial depolarization of PC3 and DU145. The functional AR protein expressed in Q+C treated cells sensitized them to dihydrotestosterone (DHT)-induced proliferation, bicalutamide-induced apoptosis, bound to androgen response element to increase luciferase activity in gene reporter assay and was susceptible to downregulation by AR siRNA. Bisulfite sequencing revealed high methylation of AR promoter CpG sites in AR-negative DU145 and PC3 cell lines that was significantly demethylated by Q+C treatment, which restored AR expression. Notable synergistic effects of Q+C combination in re-sensitizing androgen refractory CaP cells to AR-mediated apoptosis, their known safety in clinical use, and epidemiological evidences relating their dietary consumption with lower cancer incidences indicate their potential for use in chemoprevention of androgen resistance in prostate cancer.

Topics: Androgen Antagonists; Androgens; Apoptosis; Cell Line; Cell Line, Tumor; Cell Proliferation; Curcumin; Dihydrotestosterone; DNA Methylation; Down-Regulation; Drug Synergism; Epigenetic Repression; Humans; Male; Promoter Regions, Genetic; Prostatic Neoplasms; Quercetin; Receptors, Androgen; RNA, Messenger

Curcumin has received immense attention over the past decades because of its diverse biological activities and recognized as a promising drug candidate in a large number of diseases. However, its clinical application has been hindered due to extremely low aqueous solubility, chemical stability, and cellular uptake. In this study, we discovered quite a new function of curcumin, i.e. pH-responsive endosomal disrupting activity, derived from curcumin's self-assembly. We selected anticancer activity as an example of biological activities of curcumin, and investigated the contribution of pH-responsive property to its anticancer activity. As a result, we demonstrated that the pH-responsive property significantly enhances the anticancer activity of curcumin. Furthermore, we demonstrated a utility of the pH-responsive property of curcumin as delivery nanocarriers for doxorubicin toward combination cancer therapy. These results clearly indicate that the smart curcumin assemblies act as promising nanoplatform for development of curcumin-based therapeutics.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Drug Carriers; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Prostatic Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Curcumin as an effective anticancer bioactive extract has been proved to induce apoptosis in many cancer cells. Notch signaling regulates prostate cancer apoptosis, but it is still unknown whether curcumin induces apoptosis in DU-145 cells by regulating Notch pathway. The aim of this study was to investigate the effect of curcumin on regulating Notch signaling and provide basic data for using curcumin in prostate cancer therapy.. Notch pathway signal related proteins Notch 1, Jagged-1 and NICD were detected using Western blotting and RT-PCR. The proliferation and apoptosis were determined by MTT method and Elisa kits after curcumin treatment, respectively. Dual-Luciferase Reporter Assay was carried out to confirm that curcumin could target Notching signaling. In order to study whether Notch 1 expression could be downregulated by curcumin, Notch 1 siRNA and Notch 1 plasmid were used in Notch 1 down-regulation and over-expression. The effects of curcumin on cell cycle distribution and apoptosis related proteins expression were analyzed by flow cytometry and western blotting, separately.. We found that Notch 1 signaling was down regulated in Notch 1 siRNA or Notch 1 plasmid transfected 145 cells after curcumin treatment. Curcumin induced G0/G1 arrest in DU-145 cells, and G0/G1 phase related regulatory factors Cyclin D1 and CDK2 expressions were inhibited. Meanwhile, p21 and p27 were up regulated. The apoptosis related protein p53 expression was increased, and apoptosis suppressor Bcl-2 was inhibited in DU-145 after curcumin treatment. Additionally, Caspase-3 and Caspase-9 were activated by curcumin.. Curcumin induced apoptosis and G0/G1 arrest in DU-145 cells by down regulating Notch signaling.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Down-Regulation; G1 Phase; Humans; Male; Prostatic Neoplasms; Receptor, Notch1; Resting Phase, Cell Cycle; Signal Transduction

Doxorubicin (DOX) is a widely used drug in cancer treatment. Despite its popularity, it suffers from systemic side effects and susceptibility to drug resistance. Curcumin (CURC), on the other hand, is a drug that recently gained popularity due to its wide range of biological activities, including anti-inflammatory and anti-cancer activities. Limitations to its clinical translation include its poor water solubility and the need for administration of high doses. Combinatory anti-cancer therapy has been proposed as a common approach to overcome one or more of these challenges. In this work, we propose a combinatory DOX and CURC anti-cancer therapy of prostate cancer cells in vitro. DOX and CURC were administered in the free drug and nanocapsule form, respectively. Cell size and complexity, cytotoxicity and apoptosis were studied by flow cytometry, MTT assay and sub-G1 quantification, respectively. Cellular uptake of CURC nanocapsules (CURC NCs) was quantified by fluorescence microscopy and high-performance liquid chromatography fluorescence detection. Results showed that in vitro treatment with CURC NCs in the presence of subtherapeutic concentrations of DOX, led to significant increase in prostate cancer cells (PC3) apoptosis and death. This was likely due to significantly enhanced CURC uptake by the cells. The study presents a good rationale for pursuing combinatory CURC/DOX therapy in pre-clinical tumor animal models in the near future.

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Carriers; Humans; Male; Nanocapsules; Prostatic Neoplasms; Solubility

Anti-androgenic drugs are treatments for androgen-related disorders such as benign prostatic hyperplasia, acne, hirsutism, and androgenic alopecia. Germacrone (1), a sesquiterpene isolated from hexane extracts of Curcuma aeruginosa Roxb. rhizome, is an androgen inhibitor of steroid 5-alpha reductase in- vitro. Here, we used the similarity of germacrone's ,t,B-unsaturated carbonyl to testosterone's α,β-unsaturated carbonyl to find germacrene analogs obtained from this plant and by semi-synthesis that might be more potent steroid 5-alpha reductase inhibitors. 8-Hydroxy germacrene B (4) was -13-fold more potent than its parent, I and the most potent (ICso, 0.15 ± 0.022 mM) among 9 compounds tested. The conformation of its cyclodecadiene ring and the α,β-unsaturated ketone/hydroxy in the germacrene molecule might be crucial role for its anti-androgen activity. Moreover, I and 4 showed mild cytotoxic effect on prostate cancer cells. Neither compound was cytotoxic towards human dermal papilla cells at 100 μg/mL. We show that this SAR strategy created promising anti-androgenics for androgen dependent disorders and may create further analogues with further improvements in selectivity and clinical efficacy.

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Cell Line, Tumor; Curcuma; Humans; Male; Molecular Structure; Prostatic Neoplasms; Rhizome; Sesquiterpenes, Germacrane; Testosterone

Epigallocatechin gallate (EGCG) and curcumin are well known to naturally-occurring anticancer agents. The aim of this study was to verify the combined beneficial anticancer effects of curcumin and EGCG on PC3 prostate cancer cells, which are resistant to chemotherapy drugs and apoptosis inducers. EGCG showed weaker inhibitory effect on PC3 cell proliferation than two other prostate cancer cell lines, LNCaP and DU145. Co-treatment of curcumin improved antiproliferative effect of EGCG on PC3 cells. The protein expressions of p21 were significantly increased by the co-treatment of EGCG and curcumin, whereas it was not changed by the treatment with each individual compound. Moreover, treatments of EGCG and curcumin arrested both S and G2/M phases of PC3 cells. These results suggest that the enhanced inhibitory effect of EGCG on PC3 cell proliferation by curcumin was mediated by the synergic up-regulation of p21-induced growth arrest and followed cell growth arrest.

Topics: Antineoplastic Combined Chemotherapy Protocols; Catechin; Cell Cycle Checkpoints; Cell Division; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; Humans; Male; Prostatic Neoplasms; Up-Regulation

The nuclear factor κB (NF-κB) is a powerful activator of angiogenesis, invasion and metastasis. Transactivation and nuclear localisation of NF-κB is an index of recurrence in prostate cancer. Vasoactive intestinal peptide (VIP) exerts similar effects in prostate cancer models involving increased expression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) which are related to NF-κB transactivation. Here we studied differential mechanisms of VIP-induced NF-κB transactivation in non-tumour RWPE-1 and tumour LNCaP and PC3 human prostate epithelial cells. Immunofluorescence studies showed that VIP increases translocation of the p50 subunit of NF-κB1 to the nucleus, an effect that was inhibited by curcumin. The signalling transduction pathways involved are different depending on cell transformation degree. In control cells (RWPE1), the effect is mediated by protein kinase A (PKA) activation and does not implicate extracellular signal-regulated kinase (ERK) or phosphoinositide 3-kinase (PI3-K) pathways whereas the opposite is true in tumour LNCaP and PC3 cells. Exchange protein directly activated by cAMP (EPAC) pathway is involved in transformed cells but not in control cells. Curcumin blocks the activating effect of VIP on COX-2 promoter/prostaglandin E2 (PGE2) production and VEGF expression and secretion. The study incorporates direct observation on COX-2 promoter and suggests that VIP effect on VEGF may be indirectly mediated by PGE2 after being synthesised by COX-2, thus amplifying the initial signal. We show that the signalling involved in VIP effects on VEGF is cAMP/PKA in non-tumour cells and cAMP/EPAC/ERK/PI3K in tumour cells which coincides with pathways mediating p50 nuclear translocation. Thus, VIP appears to use different pathways for NF-κB1 (p50) transactivation in prostate epithelial cells depending on whether they are transformed or not. Transformed cells depend on pro-survival and pro-proliferative signalling pathways involving ERK, PI3-K and cAMP/EPAC which supports the potential therapeutic value of these targets in prostate cancer.

Topics: Cell Line; Cell Nucleus; Curcumin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 2; Dinoprostone; Extracellular Signal-Regulated MAP Kinases; Guanine Nucleotide Exchange Factors; Humans; Male; NF-kappa B p50 Subunit; Phosphatidylinositol 3-Kinases; Prostate; Prostatic Neoplasms; Receptors, Vasoactive Intestinal Peptide; Signal Transduction; Transcriptional Activation; Vascular Endothelial Growth Factor A; Vasoactive Intestinal Peptide

Curcumin has poor in vivo absorption and bioavailability, highlighting a need for new curcumin analogues with better characteristics in these aspects. The aim of this study is to determine the anti-cancer properties of four selected curcumin analogues, on the cytotoxicity, proliferative and apoptotic effects on androgen-independent human prostate cancer cells (PC-3 and DU 145). Initial cytotoxicity screening showed MS17 has the highest cell inhibitory effect, with EC50 values of 4.4 ± 0.3 and 4.1 ± 0.8 µM, followed by MS13 (7.5 ± 0.1 and 7.4 ± 2.6 µM), MS49 (14.5 ± 1.2 and 12.3 ± 2.3 µM) and MS40E (28.0 ± 7.8 and 30.3 ± 1.9 µM) for PC-3 and DU 145 cells, respectively. Time-dependent analysis also revealed that MS13 and MS17 displayed a greater anti-proliferative effect than the other compounds. MS17 was chosen based on the high selectivity index value for further analysis on the morphological and biochemical hallmarks of apoptosis. Fluorescence microscopy analysis revealed apoptotic changes in both treated prostate cancer cells. Relative caspase-3 activity increased significantly at 48 h in PC-3 and 12 h in DU 145 cells. Highest enrichment of free nucleosomes was noted at 48 h after treatment with MS17. In conclusion, MS17 demonstrated anti-proliferative effect and induces apoptosis in a time and dose-dependent manner suggesting its potential for development as an anti-cancer agent for androgen-independent prostate cancer.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Male; Prostatic Neoplasms

Curcumin is a phytochemical with diverse molecular targets and is well known for its anti-tumor potential. However, it has limited application in cancer therapy because curcumin undergoes rapid oxidative degradation at physiological conditions resulting in poor stability and bio-availability. In this study, we were able to suppress curcumin's oxidative degradation by encapsulating it in a nanoparticle that also acts as a radical scavenger. We prepared curcumin-loaded pH-sensitive redox nanoparticles (RNP(N)) by self-assembling amphiphilic block copolymers conjugated with reactive oxygen species (ROS) scavenging nitroxide radicals to ensure the delivery of minimally degraded curcumin to target regions. In vitro analysis confirmed that the entrapment of both curcumin and nitroxide radicals in the hydrophobic core of RNP(N) suppressed curcumin degradation in conditions mimicking the physiological environment. Evaluation of apoptosis-related molecules in the cells, such as ceramides, caspases, apoptosis-inducing factor, and acid ceramidase revealed that curcumin loaded RNP(N) induced strong apoptosis compared to free curcumin. Lastly, intravenous injection of curcumin loaded RNP(N) suppressed tumor growth in vivo, which is due to the increased bio-availability and significant ROS scavenging at tumor sites. These results demonstrated that RNP(N) is a promising drug carrier with unique ROS-scavenging abilities, and it is able to overcome the crucial hurdle of curcumin's limitations to enhance its therapeutic potential.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Ceramides; Curcumin; Drug Liberation; Drug Stability; Humans; Male; Mice, Nude; Nanoparticles; NF-kappa B; Oxidation-Reduction; Polymers; Prostatic Neoplasms; Reactive Oxygen Species; Tumor Burden

Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner-Wadsworth-Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities toward both androgen-insensitive and androgen-sensitive prostate cancer cell lines and an aggressive cervical cancer cell line. Most of the synthesized compounds showed distinctly better in vitro potency than curcumin in the four cancer cell lines. The structure-activity data acquired from the study validated (1E,4E)-1,5-dihereroaryl-1,4-pentadien-3-ones as an excellent scaffold for in-depth development for clinical treatment of prostate and cervical cancers. 1-Alkyl-1H-imidazol-2-yl, ortho pyridyl, 1-alkyl-1H-benzo[d]imidazole-2-yl, 4-bromo-1-methyl-1H-pyrazol-3-yl, thiazol-2-yl, and 2-methyl-4-(trifluoromethyl)thiazol-5-yl were identified as optimal heteroaromatic rings for the promising in vitro potency. (1E,4E)-1,5-Bis(2-methyl-4-(trifluoromethyl)thiazol-5-yl)penta-1,4-dien-3-one, featuring thiazole rings and trifluoromethyl groups, was established as the optimal lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Chromatography, High Pressure Liquid; Curcumin; Drug Design; Female; Humans; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular Structure; Pentanones; Prostatic Neoplasms; Structure-Activity Relationship; Tandem Mass Spectrometry; Thiazoles; Tissue Distribution; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Prostate cancer is one of the most common malignancies in men. The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features, resulting in a poor outcome. However, the functional role for MUC1 C-terminal domain (MUC1-C) in androgen-independent prostate cancer occurrence and development has remained unclear.. Cell viability was measured by MTT assays. Western blot analysis was performed to measure the phosphorylation and protein expression of SAPK/JNK and ERK1/2, and MUC1-C, NF-κB subunit p65 and p50. Exogenous expression of MUC1-C, NF-κB subunit p65 was carried out by transient and electroporated transfection assays.. We showed that curcumin inhibited the growth of androgen-independent prostate cancer cells and a synergy was observed in the presence of curcumin and bicalutamide, the androgen receptor antagonist. To further explore the potential mechanism underlining this, we found that curcumin increased the phosphorylation of ERK1/2 and SAPK/JNK, which was enhanced by bicalutamide. In addition, curcumin reduced the protein expression of MUC1-C and NF-κB subunit p65, which were abrogated in the presence of the inhibitors of MEK/ERK1/2 (PD98059) and SAPK/JNK (SP60015). A further reduction was observed in the combination of curcumin with bicalutamide. Moreover, while exogenous expression of MUC1-C had little effect on curcumin-reduced p65, the overexpression of p65 reversed the effect of curcumin on MUC1-C protein expression suggesting that p65 is upstream of MUC1-C. Intriguingly, we showed that exogenous expression of MUC1-C feedback diminished the effect of curcumin on phosphorylation of ERK1/2 and SAPK/JNK, and antagonized the effect of curcumin on cell growth.. Our results show that curcumin inhibits the growth of androgen-independent prostate cancer cells through ERK1/2- and SAPK/JNK-mediated inhibition of p65, followed by reducing expression of MUC1-C protein. More importantly, there are synergistic effects of curcumin and bicalutamide. The negative feedback regulatory loop of MUC1-C to ERK1/2 and SAPK/JNK further demonstrates the role of MUC1-C that contributes to the overall responses of curcumin. This study unveils the potential molecular mechanism by which combination of curcumin with bicalutamide enhances the growth inhibition of androgen-independent prostate cancer cells.

Topics: Androgens; Anilides; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Mucin-1; Nitriles; Phosphorylation; Prostatic Neoplasms; Signal Transduction; Tosyl Compounds; Transcription Factor RelA

The antiapoptotic and antiautophagic abilities of cancer cells constitute a major challenge for anticancer drug treatment. Strategies for triggering nonapoptotic or nonautophagic cell death may improve therapeutic efficacy against cancer. Curcumin has been reported to exhibit cancer chemopreventive properties. Herein, we report that curcumin induced apoptosis in LNCaP, DU145, and PC-3 cells but triggered extensive cytoplasmic vacuolation in PC-3M cells. Electron microscopic images showed that the vacuoles lacked intracellular organelles and were derived from the endoplasmic reticulum (ER). Moreover, curcumin-induced vacuolation was not reversed by an apoptosis- or autophagy-related inhibitor, suggesting that vacuolation-mediated cell death differs from classical apoptotic and autophagic cell death. Mechanistic investigations revealed that curcumin treatment upregulated the ER stress markers CHOP and Bip/GRP78 and the autophagic marker LC3-II. In addition, curcumin induced ER stress by triggering ROS generation, which was supported by the finding that treating cells with the antioxidant NAC alleviated curcumin-mediated ER stress and vacuolation-mediated death. An in vivo PC-3M orthotopic prostate cancer model revealed that curcumin reduced tumor growth by inducing ROS production followed by vacuolation-mediated cell death. Overall, our results indicated that curcumin acts as an inducer of ROS production, which leads to nonapoptotic and nonautophagic cell death via increased ER stress.

Topics: Acetylcysteine; Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Cycloheximide; Disease Models, Animal; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Humans; Immunohistochemistry; Male; Mice; Mice, SCID; Microtubule-Associated Proteins; Prostatic Neoplasms; Reactive Oxygen Species; RNA Interference; RNA, Small Interfering; Transcription Factor CHOP; Transplantation, Heterologous; Vacuoles

Prostate cancer (PC) is a prevalent cancer in aged men. Curcumin is an active ingredient that has been extracted from the rhizome of the plant Curcuma longa. Recently, a potential of Curcumin against PC has been reported in PC, whereas the underlying molecular mechanisms are not completely understood. Here, we studied the effects of low-dose Curcumin on PC cell growth. Curcumin (from 0.2 to 0.8 μmol/l) dose-dependently inhibited the proliferation of PC cells, without affecting cell apoptosis. Further analyses showed that Curcumin dose-dependently increased a cell cycle suppressor CDKN1A at protein levels, but not mRNA levels, in PC cells, suggesting that Curcumin may regulate the translation of CDKN1A, as well as a possible involvement of miRNA intervention. From all CDKN1A-3'-UTR-binding miRNAs, we found that miR-208 was specifically inhibited in PC cells dose-dependently by Curcumin. Moreover, miR-208 was found to bind CDKN1A to suppress its expression. In a loss-of-function experiment, PC cells that overexpressed miR-208 failed to decrease cell proliferation in response to Curcumin. Together, these data suggest that Curcumin inhibits growth of PC via miR-208-mediated CDKN1A activation.

Topics: Apoptosis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Gene Expression Regulation, Neoplastic; Humans; Male; MicroRNAs; Prostatic Neoplasms; Protein Binding

Curcumin is a nontoxic, chemopreventive agent possessing multifaceted functions. Our previous study showed that curcumin inhibits androgen receptor (AR) through modulation of Wnt/β-catenin signaling in LNCaP cells. Therefore, we investigated the in vivo effects of curcumin by using LNCaP xenografts.. LNCaP cells were subcutaneously inoculated in Balb/c nude mice. When the tumor volume reached greater than 100 mm(3), either curcumin (500 mg/kg body weight) or vehicle was administered through oral gavage three times weekly for 4 weeks. The expression of AR and intermediate products of Wnt/β-catenin were assessed.. Curcumin had an inhibitory effect on tumor growth during the early period, which was followed by a slow increase in growth over time. Tumor growth was delayed about 27% in the curcumin group. The mean prostate-specific antigen (PSA) doubling time in the curcumin group was approximately twice that in the untreated group. Curcumin significantly decreased AR expression at both the mRNA and protein level. The PSA levels tended to be reduced in the curcumin group. However, there were no significant changes in expression of Wnt/β-catenin pathway intermediates.. This study revealed that curcumin initially interferes with prostate cancer growth by inhibiting AR activity and possibly by reducing PSA expression. Further research is needed to investigate the plausible mechanism of the antiandrogenic action of curcumin.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; beta Catenin; Curcumin; Cyclin D1; Heterografts; Humans; Male; Mice, Inbred BALB C; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; RNA, Messenger; Wnt Signaling Pathway

Prostate cancer is a common malignant tumor in urinary system. Curcumin has curative effect on many kinds of cancers and can inhibit prostate cancer (PC)-3 cells proliferation. This study aimed to explore the curcumin induced prostate cancer cell apoptosis and apoptosis related proteins Bcl-2 and Bax expression. PC-3 cells were injected subcutaneously to the nude mice to establish the tumor model. The nude mice were randomly divided into group C (normal saline), group B (6% polyethylene glycol and 6% anhydrous ethanol), group H, M, L (100 mg/kg, 50 mg/kg, and 25 mg/kg curcumin). The tumor volume was measured every 6 days to draw the tumor growth curve. The mice were killed at the 30(th) day after injection to weight the tumor. TUNEL assay was applied to determine cell apoptosis. Immunohistochemistry was used to detect Bcl-2 and Bax expression. The tumor volume and weight in group H, M, L were significantly lower than the control group (C, B) (P<0.05), and the inhibitory rate increased following the curcumin dose increase. Compared with the control group, Bcl-2 expression in group H, M, L gradually decreased, while Bax protein expression increased (P<0.05). The cell apoptosis rate showed no statistical difference between group B and C, while it increased in curcumin group H, M, and L (P<0.05). Curcumin could inhibit PC-3 growth, decrease tumor volume, reduce tumor weight, and induce cell apoptosis under the skin of nude mice by up-regulating Bax and down-regulating Bcl-2.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Curcumin; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2

Cancer-associated fibroblasts (CAFs) are key determinants in the malignant progression of cancer, supporting tumorigenesis and metastasis. CAFs also mediate epithelial to mesenchymal transition (EMT) in tumor cells and their achievement of stem cell traits. Curcumin has recently been found to possess anticancer activities via its effect on a variety of biological pathways involved in cancer progression. In this study, we found that CAFs could induce prostate cancer cell EMT and invasion through a monoamine oxidase A (MAOA)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway, which exploits reactive oxygen species (ROS) to drive a migratory and aggressive phenotype of prostate carcinoma cells. Moreover, CAFs was able to increase CXC chemokine receptor 4 (CXCR4) and interleukin-6 (IL-6) receptor expression in prostate cancer cells. However, curcumin abrogated CAF-induced invasion and EMT, and inhibited ROS production and CXCR4 and IL-6 receptor expression in prostate cancer cells through inhibiting MAOA/mTOR/HIF-1α signaling, thereby supporting the therapeutic effect of curcumin in prostate cancer.

Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Curcumin; Epithelial-Mesenchymal Transition; Fibroblasts; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Microscopy, Fluorescence; Monoamine Oxidase; Neoplasm Invasiveness; Prostatic Neoplasms; Real-Time Polymerase Chain Reaction; Signal Transduction; TOR Serine-Threonine Kinases

Prostate cancer is the most commonly diagnosed malignancy among men. The Discovery of new agents for the treatment of prostate cancer is urgently needed. Compound WZ35, a novel analog of the natural product curcumin, exhibited good anti-prostate cancer activity, with an IC50 of 2.2 μM in PC-3 cells. However, the underlying mechanism of WZ35 against prostate cancer cells is still unclear.. Human prostate cancer PC-3 cells and DU145 cells were treated with WZ35 for further proliferation, apoptosis, cell cycle, and mechanism analyses. NAC and CHOP siRNA were used to validate the role of ROS and ER stress, respectively, in the anti-cancer actions of WZ35.. Our results show that WZ35 exhibited much higher cell growth inhibition than curcumin by inducing ER stress-dependent cell apoptosis in human prostate cells. The reduction of CHOP expression by siRNA partially abrogated WZ35-induced cell apoptosis. WZ35 also dose-dependently induced cell cycle arrest in the G2/M phase. Furthermore, we found that WZ35 treatment for 30 min significantly induced reactive oxygen species (ROS) production in PC-3 cells. Co-treatment with the ROS scavenger NAC completely abrogated the induction of WZ35 on cell apoptosis, ER stress activation, and cell cycle arrest, indicating an upstream role of ROS generation in mediating the anti-cancer effect of WZ35.. Taken together, this work presents the novel anticancer candidate WZ35 for the treatment of prostate cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human prostate cancer treatment.

Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Endoplasmic Reticulum Stress; G2 Phase Cell Cycle Checkpoints; Gene Expression; Humans; Male; Prostatic Neoplasms; Reactive Oxygen Species; Transcription Factor CHOP

α-Tomatine is a glycoalkaloid found in tomatoes and curcumin is a major yellow pigment of turmeric. In the present study, the combined effect of these two compounds on prostate cancer cells was studied. Treatment of different prostate cancer cells with curcumin or α-tomatine alone resulted in growth inhibition and apoptosis in a concentration-dependent manner. Combinations of α-tomatine and curcumin synergistically inhibited the growth and induced apoptosis in prostate cancer PC-3 cells. Effects of the α-tomatine and curcumin combination were associated with synergistic inhibition of NF-κB activity and a potent decrease in the expression of its downstream gene Bcl-2 in the cells. Moreover, strong decreases in the levels of phospho-Akt and phosphor-ERK1/2 were found in PC-3 cells treated with α-tomatine and curcumin in combination. In animal experiment, SCID mice with PC-3 xenograft tumors were treated with α-tomatine and curcumin. Combination of α-tomatine and curcumin more potently inhibited the growth of PC-3 tumors than either agent alone. Results from the present study indicate that α-tomatine in combination with curcumin may be an effective strategy for inhibiting the growth of prostate cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Male; MAP Kinase Signaling System; Mice; Mice, SCID; NF-kappa B; Phosphorylation; Prostate; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tomatine

In the initial stages, human prostate cancer (PC) is an androgen-sensitive disease, which can be pharmacologically controlled by androgen blockade. This therapy often induces selection of androgen-independent PC cells with increased invasiveness. We recently demonstrated, both in cells and mice, that a testosterone metabolite locally synthetized in prostate, the 5α-androstane-3β, 17β-diol (3β-Adiol), inhibits PC cell proliferation, migration and invasion, acting as an anti-proliferative/anti-metastatic agent. 3β-Adiol is unable to bind androgen receptor (AR), but exerts its protection against PC by specifically interacting with estrogen receptor beta (ERβ). Because of its potential retro-conversion to androgenic steroids, 3β-Adiol cannot be used "in vivo", thus, the aims of this study were to investigate the capability of four ligands of ERβ (raloxifen, tamoxifen, genistein and curcumin) to counteract PC progression by mimicking the 3β-Adiol activity. Our results demonstrated that raloxifen, tamoxifen, genistein and curcumin decreased DU145 and PC3 cell proliferation in a dose-dependent manner; in addition, all four compounds significantly decreased the detachment of cells seeded on laminin or fibronectin. Moreover, raloxifen, tamoxifen, genistein and curcumin-treated DU145 and PC3 cells showed a significant decrease in cell migration. Notably, all these effects were reversed by the anti-estrogen, ICI 182,780, suggesting that their actions are mediated by the estrogenic pathway, via the ERβ, the only isoform present in these PCs. In conclusion, these data demonstrate that by selectively activating the ERβ, raloxifen, tamoxifen, genistein and curcumin inhibit human PC cells proliferation and migration favoring cell adesion. These synthetic and natural modulators of ER action may exert a potent protective activity against the progression of PC even in its androgen-independent status.

Topics: Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Estradiol; Estrogen Receptor beta; Estrogen Receptor Modulators; Fulvestrant; Genistein; Humans; Male; Prostatic Neoplasms; Raloxifene Hydrochloride; Tamoxifen

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

Inhibitor of DNA binding 1 (Id1) plays an important role in genesis and metastatic progression of prostate cancer. We previously reported that down regulation of Id1 by small interfering RNA could inhibit the proliferation of PC3 cells and growth of its xenografted tumors. Curcumin, the active ingredient of turmeric, has shown anti-cancer properties via modulation of a number of different molecular regulators. Here we investigated whether Id1 might be involved in the anti-cancer effects of curcumin in vivo and in vitro. We firstly confirmed that curcumin inhibited cell viability in a dose-dependent fashion, and induced apoptosis in PC3 cells, associated with significant decrease in the mRNA and protein expression of Id1. Similar effects of curcumin were observed in tumors of the PC3 xenografted mouse model with introperitoneal injection of curcumin once a day for one month. Tumor growth in mice was obviously suppressed by curcumin during the period of 24 to 30 days. Both mRNA and protein levels of Id1 were significantly down-regulated in xenografted tumors. Our findings point to a novel molecular pathway for curcumin anti-cancer effects. Curcumin may be used as an Id1 inhibitor to modulate Id1 expression.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Humans; Inhibitor of Differentiation Protein 1; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Prostatic Neoplasms; RNA Interference; RNA, Small Interfering; Signal Transduction; Transplantation, Heterologous

Four curcumin analogues ((2E,6E)-2,6-bis(thiophen-3-methylene) cyclohexanone (AS), (2E,5E)-2,5-bis(thiophen-3-methylene) cyclopentanone (BS), (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydropyran-4-one (ES) and (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydrothiopyran-4-one (FS) as shown in Fig. 1) with different linker groups were investigated for their effects in human prostate cancer CWR-22Rv1 and PC-3 cells. Compounds FS and ES had stronger inhibitory effects than curcumin, AS and BS on the growth of cultured CWR-22Rv1 and PC-3 cells, as well as on the androgen receptor (AR) and nuclear factor kappa B (NF-κB) activity. The strong activities of ES and FS may be correlated with a heteroatom linker. In animal studies, severe combined immunodeficient (SCID) mice were injected subcutaneously (s.c.) with PC-3 cells in Matrigel. After 4 to 6 weeks, mice with PC-3 tumors (about 0.6 cm wide and 0.6 cm long) received daily intraperitoneal (i.p.) injections of vehicle, ES and FS (10 µg/g body weight) for 31 d. FS had a potent effect in inhibiting the growth and progression of PC-3 tumors. Our results indicate that FS may be useful for inhibiting human prostate tumors growth.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Gene Expression; Genes, Reporter; Humans; Male; Mice, SCID; Molecular Structure; NF-kappa B; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship; Testosterone; Xenograft Model Antitumor Assays

Prostate cancer is the most commonly diagnosed cancer disease in men in the Unites States and its management remains a challenge in everyday oncology practice. Thus, advanced therapeutic strategies are required to treat prostate cancer patients. Curcumin (CUR) is a promising anticancer agent for various cancer types. The objective of this study was to evaluate therapeutic potential of novel poly(lactic-co-glycolic acid)- CUR nanoparticles (PLGA-CUR NPs) for prostate cancer treatment. Our results indicate that PLGA-CUR NPs efficiently internalize in prostate cancer cells and release biologically active CUR in cytosolic compartment of cells for effective therapeutic activity. Cell proliferation (MTS), clonogenic, and Western blot analyses reveal that PLGA-CUR NPs can effectively inhibit proliferation and colony formation ability of prostate cancer cells than free CUR. PLGA-CUR NPs showed superior tumor regression compared to CUR in xenograft mice. Further investigations reveal that PLGA-CUR NPs inhibit nuclear β-catenin and AR expression in cells and in tumor xenograft tissues. It also suppresses STAT3 and AKT phosphorylation and leads to apoptosis via inhibition of key anti-apoptotic proteins, Mcl-1, Bcl-xL and caused induction of PARP cleavage. Additionally, significant downregulation of oncogenic miR21 and up-regulation of miR-205 was observed with PLGA-CUR NPs treatment as determined by RT-PCR and in situ hybridization analyses. A superior anti-cancer potential was attained with PSMA antibody conjugated PLGA-CUR NPs in prostate cancer cells and a significant tumor targeting of (131)I labeled PSMA antibody was achieved with PLGA-CUR NPs in prostate cancer xenograft mice model. In conclusion, PLGA-CUR NPs can significantly accumulate and exhibit superior anticancer activity in prostate cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Cell Line, Tumor; Cell Proliferation; Curcumin; Endocytosis; Humans; Male; Mice, Nude; MicroRNAs; Nanoparticles; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Tumor Microenvironment; Xenograft Model Antitumor Assays

The androgen receptor (AR) has a critical role in prostate cancer development and progression. Several curcumin analogues (A10, B10, C10, E10 and F10) with different linker groups were investigated for their effects in human prostate cancer CWR‑22Rv1 and LNCaP cell lines. The ability of these compounds to inhibit testosterone (TT)‑ or dihydrotestosterone (DHT)‑induced AR activity was determined by an AR‑linked luciferase assay and by TT‑ or DHT‑induced expression of prostate specific antigen. Compounds F10 and E10 had stronger inhibitory effects on the growth of cultured CWR‑22Rv1 and LNCaP cell lines, and they also had enhanced stimulatory effects on apoptosis compared with curcumin and other curcumin analogues (A10, B10, C10) in CWR‑22Rv1 cells. E10 and F10 were more potent inhibitors of AR activity than curcumin, A10 and B10. The higher activities of E10 and F10 may be correlated with a heteroatom linker. The results indicate that one of the potential mechanisms for the anticancer effect of the curcumin analogues was inhibition of AR pathways in human prostate cancer cells.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Dihydrotestosterone; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Testosterone

An attempt has been made to use curcumin (CUR) in combination with Etoposide (ETP) by encapsulating in nanoemulsion, as two tier approach i.e., to evaluate improvement in efficacy of ETP on prostate cancer cells (PC3 and DU145) and to assess their effect on cross-talk between osteoblast and tumor cells leading to metastatic cascade in bones. Nanoemulsion was developed and evaluated for size, charge, in-vitro drug release and anticancer activity, effect on cross talk between osteoblast and prostate cancer cells and pharmacokinetics in rats. The entrapment efficiency of both ETP and CUR in nanoemulsion was more than 98% while the globule size was less than 150 nm with zeta potential - 29.8 mV. The percent inhibition in case of ETP and ETP: CUR (1:3 w/w) was 55.92 ± 1.2 and 41.13 ± 2.4% (at 5 μM) respectively when tested in PC3 cells. DU-145 seemed to be less responsive in comparison to PC3 cells both in respect of ETP and their mixture (ETP+ CUR). Our data shows that CUR and ETP after encapsulation in nanoemulsion (F5) were effectively delivered intracellularly in PC3 cells and the cytotoxicity of F5 was enhanced by 1.5 fold as compared to ETP + CUR at 5 μM concentration. It has also been observed that mice calvarial osteoblasts cultured and incubated with PC-3 and DU-145 cells conditioned media induces inhibition of osteoblast differentiation event. While this inhibition was significantly reversed by F5 at 5 μM concentration over other treated groups, the pharmacokinetic profile of both ETP and CUR was also significantly improved when administered in nanoemulsion.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cell Communication; Cell Line, Tumor; Curcumin; Drug Combinations; Emulsions; Etoposide; Humans; Male; Mice; Nanocapsules; Osteoblasts; Prostatic Neoplasms; Rats, Sprague-Dawley; Treatment Outcome

Curcumin has been shown to possess potent chemopreventive and antitumor effects on prostate cancer. However, the molecular mechanism involved in curcumin's ability to suppress prostate cancer cell invasion, tumor growth, and metastasis is not yet well understood. In this study, we have shown that curcumin can suppress epidermal growth factor (EGF)- stimulated and heregulin-stimulated PC-3 cell invasion, as well as androgen-induced LNCaP cell invasion. Curcumin treatment significantly resulted in reduced matrix metalloproteinase 9 activity and downregulation of cellular matriptase, a membrane-anchored serine protease with oncogenic roles in tumor formation and invasion. Our data further show that curcumin is able to inhibit the induction effects of androgens and EGF on matriptase activation, as well as to reduce the activated levels of matriptase after its overexpression, thus suggesting that curcumin may interrupt diverse signal pathways to block the protease. Furthermore, the reduction of activated matriptase in cells by curcumin was also partly due to curcumin's effect on promoting the shedding of matriptase into an extracellular environment, but not via altering matriptase gene expression. In addition, curcumin significantly suppressed the invasive ability of prostate cancer cells induced by matriptase overexpression. In xenograft model, curcumin not only inhibits prostate cancer tumor growth and metastasis but also downregulates matriptase activity in vivo. Overall, the data indicate that curcumin exhibits a suppressive effect on prostate cancer cell invasion, tumor growth, and metastasis, at least in part via downregulating matriptase function.

Topics: Androgens; Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Movement; Cell Proliferation; Curcumin; Dihydrotestosterone; Epidermal Growth Factor; Heterografts; Humans; Lymphatic Metastasis; Male; Neoplasm Invasiveness; Prostatic Neoplasms; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serine Endopeptidases; Tumor Cells, Cultured

Twelve pyridine analogs of curcumin were studied for their effects on growth and apoptosis in human prostate cancer PC-3 cells. The ability of these compounds to inhibit the transcriptional activity of nuclear factor-kappa B (NF-κB) and the level of phosphorylated extracellular signal-regulated kinases (phospho-ERK1/2) in PC-3 cells was also determined. Treatment of PC-3 cells with the pyridine analogs of curcumin resulted in concentration-dependent growth inhibition and apoptosis stimulation. Only pyridine analogs of curcumin with a tetrahydrothiopyrane-4-one linker (FN compounds) exhibited a strong inhibitory effect on growth and a strong stimulatory effect on apoptosis at low concentrations (≤ 1 μM). Mechanistic studies showed that NF-κB transcriptional activity in PC-3 cells was strongly inhibited by treatment with group FN compounds. Treatment of PC-3 cells with 1 μM FN1 resulted in a decrease of activated ERK1/2. Results from the present study indicate that FN compounds warrant further in vivo studies using suitable animal models of prostate cancer.

Topics: Apoptosis; Blotting, Western; Cell Proliferation; Curcumin; Enzyme Inhibitors; Humans; Luciferases; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Phosphorylation; Prostatic Neoplasms; Pyridines; Signal Transduction; Transcription, Genetic; Tumor Cells, Cultured

This study aims at modifying the synthesis method of preparing N-isopropylacrylamide (NIPAAM)/N-vinyl-2-pyrrolidone (VP)/Polyethylene glycol monoacrylate (PEG-A) polymeric nanoparticles encapsulating curcumin as a model drug. The optimal concentration of nanoparticle reagents was determined using Fourier Transform Infrared Spectroscopy. Curcumin nanoparticles mean hydrodynamic size was found to be 104 nm with zeta potential of 3 ± 13 mV. The release kinetic study of curcumin nanoparticles indicates that a maximum release of curcumin at 24 h positively correlates with increase in temperature; however, change in pH did not produce any substantial drug release. In vitro cell viability assay performed on cancer cells exposed to various concentrations of model compound displayed the IC50 ranging between 100 and 200 μg/mL for human prostate cancer cells (PC3 cells) and 50 and 200 μg/mL for epidermoid carcinoma (A431 cell line). The Hoechst staining and phase contrast micrographs for 48 h exposure of curcumin nanoparticles at a concentration of 400 μg/mL resulted in almost 92% of cells death in both cell lines. This study concludes that the physiochemical characteristics of NIPAAM/VP/PEG-A polymer with key features of water solubility, sustained drug release, small particle size make these nanoparticles a prominent drug delivery device.

Topics: Acrylamides; Acrylates; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Curcumin; Delayed-Action Preparations; Humans; Male; Nanoparticles; Polyethylene Glycols; Prostate; Prostatic Neoplasms; Pyrrolidinones

Curcumin possesses chemopreventive properties against several types of cancer, but the molecular mechanisms by which it induces apoptosis of cancer cells and inhibits cancer cell proliferation are not clearly understood. To evaluate the antitumor activity of curcumin for prostate cancer, we used an androgen dependent LNCaP prostate cancer cell line and an androgen independent PC-3 prostate cancer cell line as experimental models. We treated these cells with curcumin and then evaluated the effects of curcumin on cell cycle profiling and apoptosis, as well as the activation of NF-kaapaB and c-jun in these cells. The results showed that the ratios of apoptosis in LNCaP and PC-3 cells were significantly elevated in a dose dependent manner after exposure to curcumin. In addition, curcumin induces the G2/M cell cycle arrest of LNCaP and PC-3 cells in a dose dependent manner. Mechanistically, we found that curcumin upregulated the protein level of NF-kappaB inhibitor IkappaBalpha and downregulated protein levels of c-Jun and AR. These data suggest that curcumin is a promising agent for the treatment of both androgen-dependent and androgen-independent prostate cancer.

Topics: Analysis of Variance; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Curcumin; Flow Cytometry; G2 Phase; Humans; I-kappa B Proteins; Male; NF-kappa B; Prostatic Neoplasms; Proto-Oncogene Proteins c-jun; Receptors, Androgen; Signal Transduction

Infiltrating macrophages are a key component of inflammation during tumorigenesis, but the direct evidence of such linkage remains unclear. We report here that persistent coculturing of immortalized prostate epithelial cells with macrophages, without adding any carcinogens, induces prostate tumorigenesis and that induction involves the alteration of signaling of macrophage androgen receptor (AR)-inflammatory chemokine CCL4-STAT3 activation as well as epithelial-to-mesenchymal transition and downregulation of p53/PTEN tumor suppressors. In vivo studies further showed that PTEN(+/-) mice lacking macrophage AR developed far fewer prostatic intraepithelial neoplasia (PIN) lesions, supporting an in vivo role for macrophage AR during prostate tumorigenesis. CCL4-neutralizing antibody effectively blocked macrophage-induced prostate tumorigenic signaling and targeting AR via an AR-degradation enhancer, ASC-J9, reduced CCL4 expression, and xenografted tumor growth in vivo. Importantly, CCL4 upregulation was associated with increased Snail expression and downregulation of p53/PTEN in high-grade PIN and prostate cancer. Together, our results identify the AR-CCL4-STAT3 axis as key regulators during prostate tumor initiation and highlight the important roles of infiltrating macrophages and inflammatory cytokines for the prostate tumorigenesis.

Topics: Animals; Antibodies, Monoclonal; Cell Transformation, Neoplastic; Cells, Cultured; Chemokine CCL4; Curcumin; Cytokines; Enzyme-Linked Immunosorbent Assay; Epithelial-Mesenchymal Transition; Humans; Immunoenzyme Techniques; Macrophages; Male; Mice; Mice, Knockout; Prostate; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; PTEN Phosphohydrolase; Receptors, Androgen; Signal Transduction; STAT3 Transcription Factor

Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells-macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion. Mechanism dissection showed that Casodex/MDV3100 reduced the AR-mediated PIAS3 expression and enhanced the pSTAT3-CCL2 pathway. Addition of CCR2 antagonist reversed the Casodex/MDV3100-induced macrophage migration and PCa cell invasion. In contrast, ASC-J9 could regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation. These findings were confirmed in the in vivo mouse model with orthotopically injected TRAMP-C1 cells. Together, these results may raise the potential concern about the currently used ADT with anti-androgens that promotes PCa metastasis and may provide some new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Anilides; Animals; Antineoplastic Agents; Benzamides; Cell Movement; Chemokine CCL3; Coculture Techniques; Curcumin; Humans; Macrophages; Male; Mice; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Signal Transduction; STAT3 Transcription Factor; Tosyl Compounds

Prostate cancer is the second leading cause of cancer death among men. Multiple evidence suggests that a population of tumor-initiating, or cancer stem cells (CSCs) is responsible for cancer development and exceptional drug resistance, representing a highly important therapeutic target. The present study evaluated CSC-specific alterations induced by new-generation taxoid SBT-1214 and a novel polyenolic zinc-binding curcuminoid, CMC2.24, in prostate CSCs.. The CD133(high)/CD44(high) phenotype was isolated from spontaneously immortalized patient-derived PPT2 cells and highly metastatic PC3MM2 cells. Weekly treatment of the NOD/SCID mice bearing PPT2- and PC3MM3-induced tumors with the SBT-1214 led to dramatic suppression of tumor growth. Four of six PPT2 and 3 of 6 PC3MM2 tumors have shown the absence of viable cells in residual tumors. In vitro, SBT-1214 (100 nM-1 µM; for 72 hr) induced about 60% cell death in CD133(high)/CD44(+/high) cells cultured on collagen I in stem cell medium (in contrast, the same doses of paclitaxel increased proliferation of these cells). The cytotoxic effects were increased when SBT-1214 was combined with the CMC2.24. A stem cell-specific PCR array assay revealed that this drug combination mediated massive inhibition of multiple constitutively up-regulated stem cell-related genes, including key pluripotency transcription factors. Importantly, this drug combination induced expression of p21 and p53, which were absent in CD133(high)/CD44(high) cells. Viable cells that survived this treatment regimen were no longer able to induce secondary spheroids, exhibited significant morphological abnormalities and died in 2-5 days.. We report here that the SBT-1214 alone, or in combination with CMC2.24, possesses significant activity against prostate CD133(high)/CD44(+/high) tumor-initiating cells. This drug combination efficiently inhibits expression of the majority of stem cell-related genes and pluripotency transcription factors. In addition, it induces a previously absent expression of p21 and p53 ("gene wake-up"), which can potentially reverse drug resistance by increasing sensitivity to anti-cancer drugs.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Gene Expression Profiling; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Prostatic Neoplasms; Taxoids; Xenograft Model Antitumor Assays

Diamide linked γ-cyclodextrin (γ-CD) dimers are proposed as molecular-scale delivery agents for the anticancer agent curcumin. N,N'-Bis(6(A)-deoxy-γ-cyclodextrin-6(A)-yl)succinamide (66γCD2su) and N,N'-bis(6(A)-deoxy-γ-cyclodextrin-6(A)-yl)urea (66γCD2ur) markedly suppress the degradation of curcumin by forming a strong 1:1 cooperative binding complexes. The results presented in this study describe the potential efficacy of 66γCD2su and 66γCD2ur for intracellular curcumin delivery to cancer cells. Cellular viability assays demonstrated a dose-dependent antiproliferative effect of curcumin in human prostate cancer (PC-3) cells that was preserved by the curcumin-66γCD2su complex. In contrast, delivery of curcumin by 66γCD2ur significantly delayed the antiproliferative effect. We observed similar patterns of gene regulation in PC-3 cells for curcumin complexed with either 66γCD2su or 66γCD2ur in comparison to curcumin alone, although curcumin delivered by either 66γCD2su or 66γCD2ur induces a slightly higher up-regulation of heme oxygenase-1. Highlighting their nontoxic nature, neither 66γCD2su nor 66γCD2ur carriers alone had any measurable effect on cell proliferation or candidate gene expression in PC-3 cells. Finally, confocal fluorescence imaging and uptake studies were used to demonstrate the intracellular delivery of curcumin by 66γCD2su and 66γCD2ur. Overall, these results demonstrate effective intracellular delivery and action of curcumin when complexed with 66γCD2su and 66γCD2ur, providing further evidence of their potential applications to deliver curcumin effectively in cancer and other treatment settings.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Diamide; gamma-Cyclodextrins; Gene Expression; Heme Oxygenase-1; Humans; Male; Prostatic Neoplasms; Up-Regulation

Curcumin and methylseleninic acid (MSeA) are well-documented dietary chemopreventive agents. Apoptosis appears to be a major mechanism for both agents to exert anti-cancer activity. The purpose of the present study was designed to determine whether the apoptotic effect on human cancer cells can be enhanced by combining curcumin with MSeA. Apoptosis was evaluated by Annexin V staining of externalized phosphatidylserine by flow cytometry. Expression of protein was analyzed by Western blotting. Localization of apoptosis-inducing factor (AIF) was detected by immunocytochemistry. RNA interference was employed to inhibit expression of specific protein. We found here that combining curcumin with MSeA led to a significantly enhanced apoptosis in both MDA-MB-231 breast cancer cells and DU145 prostate cancer cells. Further mechanistic investigations revealed that curcumin treatment alone caused a concentration dependent upregulation of Mcl-1, which can be overcome by combining it with MSeA. In line with the Mcl-1 reduction, an enhanced mitochondrial permeability transition and AIF nuclear translocation by the combination were achieved. In addition, an increased suppression of focal adhesion kinase activity was observed in the combination-treated cells which were associated with cell detachment-induced apoptosis by the combination. Our findings suggest that curcumin/MSeA combination holds excellent potential for improving their efficacy against human breast and prostate cancer through enhanced apoptosis induction.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Inducing Factor; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Focal Adhesion Kinase 1; Humans; Male; Myeloid Cell Leukemia Sequence 1 Protein; Organoselenium Compounds; Prostatic Neoplasms; Reactive Oxygen Species; Up-Regulation

The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex, or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9 and targeting PCa stem/progenitor cells with 5-azathioprine and γ-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages.

Topics: Animals; Azacitidine; Curcumin; Decitabine; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Neoplastic Stem Cells; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Xenograft Model Antitumor Assays

Using androgen receptor (AR) knockout mice to determine AR functions in selective prostate cancer (PCa) cells, we determined that AR might play differential roles in various cell types, either to promote or suppress PCa development/progression. These observations partially explain the failure of current androgen deprivation therapy (ADT) to reduce/prevent androgen binding to AR in every cell. Herein, we identified the AR degradation enhancer ASC-J9, which selectively degrades AR protein via interruption of the AR-AR selective coregulator interaction. Such selective interruption could, therefore, suppress AR-mediated PCa growth in the androgen-sensitive stage before ADT and in the castration-resistant stage after ADT. Mechanistic dissection suggested that ASC-J9 could activate the proteasome-dependent pathway to promote AR degradation through the enhanced association of AR-Mdm2 complex. The consequences of ASC-J9-promoted AR degradation included reduced androgen binding to AR, AR N-C terminal interaction, and AR nuclear translocation. Such inhibitory regulation could then result in suppression of AR transactivation and AR-mediated cell growth in eight different mouse models, including intact or castrated nude mice xenografted with androgen-sensitive LNCaP cells or androgen-insensitive C81 cells and castrated nude mice xenografted with castration-resistant C4-2 and CWR22Rv1 cells, and TRAMP and Pten(+/-) mice. These results demonstrate that ASC-J9 could serve as an AR degradation enhancer that effectively suppresses PCa development/progression in the androgen-sensitive and castration-resistant stages.

Topics: Animals; Antineoplastic Agents; Castration; Cell Line, Tumor; Chemoprevention; Curcumin; Disease Models, Animal; Epithelial Cells; Humans; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Male; Mice; Mice, Nude; Nuclear Receptor Coactivators; Prostate; Prostatic Neoplasms; Proteolysis; PTEN Phosphohydrolase; Receptors, Androgen; Transcription, Genetic; Xenograft Model Antitumor Assays

To increase the oral bioavailability of curcumin and genistein, we fabricated nanostructured lipid carriers (NLCs), and the impact of these carriers on bioaccessibility of curcumin and genistein was studied. Entrapment efficiency was more than 75% for curcumin and/or genistein-loaded NLCs. Solubility of curcumin and/or genistein in simulated intestinal medium (SIM) was >75% after encapsulating within NLCs which otherwise was <20%. Both curcumin and genistein have shown good stability (≥85%) in SIM and simulated gastric medium (SGM) up to 6 h. Coloading of curcumin and genistein had no adverse effect on solubility and stability of each molecule. Instead, coloading increased loading efficiency and the cell growth inhibition in prostate cancer cells. Collectively, these results have shown that coloaded lipid based carriers are promising vehicles for oral delivery of poorly bioaccessible molecules like curcumin and genistein.

Topics: Biological Availability; Cell Proliferation; Curcumin; Digestion; Drug Carriers; Genistein; Humans; Lipids; Male; Nanostructures; Prostatic Neoplasms; Solubility

The androgen receptor (AR) plays a critical role in prostate cancer development and progression. Therefore, the inhibition of AR function is an established therapeutic intervention. Since the expression of the AR is retained and often increased in progressive disease, AR protein down-regulation is a promising therapeutic approach against prostate cancer. We show here that the curcumin analog 27 (ca27) down-regulates AR expression in several prostate cancer cell lines.. ca27 at low micromolar concentrations was tested for its effect on AR expression, AR activation, and induction of oxidative stress in human LNCaP, C4-2, and LAPC-4 prostate cancer cells.. ca27 induced the down-regulation of AR protein expression in LNCaP, C4-2, and LAPC-4 cells within 12 hr. Further, ca27 led to the rapid induction of reactive oxygen species (ROS). To further support this finding, ca27 treatment led to the activation of the cellular redox sensor NF-E2-related factor 2 (Nrf2) and the induction of the Nrf2-regulated genes NAD(P)H quinone oxidoreductase 1 and aldoketoreductase 1C1. We show that ROS production preceded AR protein loss and that ca27-mediated down-regulation of the AR was attenuated by the antioxidant, N-acetyl cysteine.. ca27 induces ROS and mediates AR protein down-regulation through an oxidative stress mechanism of action. Our results suggest that ca27 represents a novel agent for the elucidation of mechanisms of AR down-regulation, which could lead to effective new anti-androgenic strategies for the treatment of advanced prostate cancer.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Down-Regulation; Humans; Male; Oxidative Stress; Prostatic Neoplasms; Reactive Oxygen Species; Receptors, Androgen; Signal Transduction

Prostate cancer (PC) is the most frequently diagnosed disease in men in the United States. Curcumin (CUR), a natural diphenol, has shown potent anti-cancer efficacy in various types of cancers. However, suboptimal pharmacokinetics and poor bioavailability limit its effective use in cancer therapeutics. Several successful CUR nanoformulations have recently been reported which improve upon these features; however, there is no personalized safe nanoformulation for prostate cancer. This study contributes two important scientific aspects of prostate cancer therapeutics. The first objective was to investigate the comparative cellular uptake and cytotoxicity evaluation of β-cyclodextrin (CD), hydroxypropyl methylcellulose (cellulose), poly(lactic-co-glycolic acid) (PLGA), magnetic nanoparticles (MNP), and dendrimer based CUR nanoformulations in prostate cancer cells. Curcumin loaded cellulose nanoparticles (cellulose-CUR) formulation exhibited the highest cellular uptake and caused maximum ultrastructural changes related to apoptosis (presence of vacuoles) in prostate cancer cells. Secondly, the anti-cancer potential of the cellulose-CUR formulation was evaluated in cell culture models using cell proliferation, colony formation and apoptosis (7-AAD staining) assays. In these assays, the cellulose-CUR formulation showed improved anti-cancer efficacy compared to free curcumin. Our study shows, for the first time, the feasibility of cellulose-CUR formulation and its potential use in prostate cancer therapy.

Topics: Apoptosis; beta-Cyclodextrins; Cell Line, Tumor; Cell Proliferation; Cellulose; Chemistry, Pharmaceutical; Curcumin; Humans; Lactic Acid; Magnetics; Male; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostatic Neoplasms; Tumor Stem Cell Assay

Nuclear receptors and pioneer factors drive the development and progression of prostate cancer. In this disease, aggressive disease phenotypes and hormone therapy failures result from resurgent activity of androgen receptor (AR) and the upregulation of coactivator protein p300 and pioneer factors (e.g., GATA2 and FOXA1). Thus, a major emphasis in the field is to identify mechanisms by which castrate-resistant AR activity and pioneer factor function can be combinatorially suppressed. Here we show that the turmeric spice isoflavone curcumin suppresses p300 and CBP occupancy at sites of AR function. Curcumin reduced the association of histone acetylation and pioneer factors, thereby suppressing AR residence and downstream target gene expression. Histone deacetylase inhibitors reversed the effects of curcumin on AR activity, further underscoring the impact of curcumin on altering the chromatin landscape. These functions precluded pioneer factor occupancy, leading ultimately to a suppression of ligand-dependent and ligand-independent AR residence on chromatin. Moreover, these functions were conserved even in cells with heightened pioneer factor activity, thus identifying a potential strategy to manage this subclass of tumors. Biological relevance was further identified using in vivo xenograft models mimicking disease progression. Curcumin cooperated in vivo with androgen deprivation as indicated by a reduction in tumor growth and delay to the onset of castrate-resistant disease. Together, our results show the combinatorial impact of targeting AR and histone modification in prostate cancer, thus setting the stage for further development of curcumin as a novel agent to target AR signaling.

Topics: Animals; Cell Line, Tumor; Cell Survival; Chromatin; Curcumin; Disease Progression; GATA2 Transcription Factor; Hepatocyte Nuclear Factor 3-alpha; Histone Deacetylase Inhibitors; Humans; Male; Mice; p300-CBP Transcription Factors; Prostatic Neoplasms; Receptors, Androgen

Early studies suggested androgen receptor (AR) splice variants might contribute to the progression of prostate cancer (PCa) into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR) and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown) cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

Topics: Androgen Antagonists; Anilides; Animals; Antineoplastic Agents; Blotting, Western; Castration; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Nitriles; Prostatic Neoplasms; Protein Isoforms; Real-Time Polymerase Chain Reaction; Receptors, Androgen; Tosyl Compounds

Due to high prevalence and slow progression of prostate cancer, primary prevention appears to be attractive strategy for its eradication. During the last decade, curcumin (diferuloylmethane), a natural compound from the root of turmeric (Curcuma longa), was described as a potent chemopreventive agent. Curcumin exhibits anti-inflammatory, anticarcinogenic, antiproliferative, antiangiogenic, and antioxidant properties in various cancer cell models. This study was designed to identify proteins involved in the anticancer activity of curcumin in androgen-dependent (22Rv1) and -independent (PC-3) human prostate cancer cell lines using two-dimensional difference in gel electrophoresis (2D-DIGE). Out of 425 differentially expressed spots, we describe here the MALDI-TOF-MS analysis of 192 spots of interest, selected by their expression profile. This approach allowed the identification of 60 differentially expressed proteins (32 in 22Rv1 cells and 47 in PC-3 cells). Nineteen proteins are regulated in both cell lines. Further bioinformatic analysis shows that proteins modulated by curcumin are implicated in protein folding (such as heat-shock protein PPP2R1A; RNA splicing proteins RBM17, DDX39; cell death proteins HMGB1 and NPM1; proteins involved in androgen receptor signaling, NPM1 and FKBP4/FKBP52), and that this compound could have an impact on miR-141, miR-152, and miR-183 expression. Taken together, these data support the hypothesis that curcumin is an interesting chemopreventive agent as it modulates the expression of proteins that potentially contribute to prostate carcinogenesis.

Topics: Anticarcinogenic Agents; Base Sequence; Blotting, Western; Cell Line, Tumor; Curcumin; DNA Primers; Electrophoresis, Gel, Two-Dimensional; Humans; Male; Neoplasm Proteins; Nucleophosmin; Prostatic Neoplasms; Real-Time Polymerase Chain Reaction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Prostate cancer is the most commonly diagnosed cancer affecting 1 in 6 males in the US. Understanding the molecular basis of prostate cancer progression can serve as a tool for early diagnosis and development of novel treatment strategies for this disease. Protein Kinase D1 (PKD1) is a multifunctional kinase that is highly expressed in normal prostate. The decreased expression of PKD1 has been associated with the progression of prostate cancer. Therefore, synthetic or natural products that regulate this signaling pathway can serve as novel therapeutic modalities for prostate cancer prevention and treatment. Curcumin, the active ingredient of turmeric, has shown anti-cancer properties via modulation of a number of different molecular pathways. Herein, we have demonstrated that curcumin activates PKD1, resulting in changes in β-catenin signaling by inhibiting nuclear β-catenin transcription activity and enhancing the levels of membrane β-catenin in prostate cancer cells. Modulation of these cellular events by curcumin correlated with decreased cell proliferation, colony formation and cell motility and enhanced cell-cell aggregation in prostate cancer cells. In addition, we have also revealed that inhibition of cell motility by curcumin is mediated by decreasing the levels of active cofilin, a downstream target of PKD1. The potent anti-cancer effects of curcumin in vitro were also reflected in a prostate cancer xenograft mouse model. The in vivo inhibition of tumor growth also correlated with enhanced membrane localization of β-catenin. Overall, our findings herein have revealed a novel molecular mechanism of curcumin action via the activation of PKD1 in prostate cancer cells.

Topics: Animals; beta Catenin; Cell Adhesion; Cofilin 1; Curcumin; Humans; Male; Mice; Neoplasm Transplantation; Prostate; Prostatic Neoplasms; Protein Kinase C; RNA, Small Interfering; Signal Transduction; Transplantation, Heterologous

Curcumin (CUR) is a natural agent that has been demonstrated to effectively inhibit prostate cancer growth. However, natural CUR is relatively unstable and can be easily degraded in vivo. Therefore, it is essential to develop other stable curcuminoids. Demethoxycurcumin (DMC) is a candidate that has been verified in several tumor types and has potential for the treatment of prostate cancer. In the present study, we investigated the effects of DMC on proliferation, apoptosis and migration of PC-3 cells. MTT assay results indicated that DMC inhibited PC-3 cell viability in a dose- and time-dependent manner, and DMC induced G2/M phase arrest. Furthermore, PC-3 cells in DMC-treated groups had a higher apoptotic rate compared with DMSO-treated control. This effect may be due to the activation of the caspase-3 pathway. In DMC-treated groups, migrating and invasive cells were dramatically reduced (P<0.05). The activity of MMP-2, which is correlated with migration and invasion was also suppressed by DMC. These results indicated that DMC may inhibit PC-3 cell migration and invasion partially by affecting MMP-2 activity. In conclusion, DMC significantly inhibits proliferation, migration and invasion of cultured PC-3 cells, and this study may provide evidence for future in vivo studies and clinical use.

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Diarylheptanoids; Enzyme Activation; Humans; M Phase Cell Cycle Checkpoints; Male; Matrix Metalloproteinase 2; Proliferating Cell Nuclear Antigen; Prostatic Neoplasms

In our continuing study of curcumin analogs as potential anti-prostate cancer drug candidates, 15 new curcumin analogs were designed, synthesized and evaluated for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Twelve analogs (5-12, 15, 16, 19, and 20) are conjugates of curcumin (1) or methyl curcumin (2) with a flutamide- or bicalutamide-like moiety. Two compounds (22 and 23) are C4-mono- and difluoro-substituted analogs of dimethyl curcumin (DMC, 21). Among the newly synthesized conjugates compound 15, a conjugate of 2 with a partial bicalutamide moiety, was more potent than bicalutamide alone and essentially equipotent with 1 and 2 against both prostate tumor cell lines with IC(50) values of 41.8 μM (for LNCaP) and 39.1 μM (for PC-3). A cell morphology study revealed that the cytotoxicity of curcumin analogs or curcumin-anti-androgen conjugates detected from both prostate cancer cell lines might be due to the suppression of pseudopodia formation. A molecular intrinsic fluorescence experiment showed that 1 accumulated mainly in the nuclei, while conjugate 6 was distributed in the cytosol. At the tested conditions, anti-androgens suppressed pseudopodia formation in PC-3 cells, but not in LNCaP cells. The evidence suggests that distinguishable target proteins are involved, resulting in the different outcomes toward pseudopodia suppression.

Topics: Androgen Antagonists; Anilides; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Drug Design; Flutamide; Humans; Male; Nitriles; Prostatic Neoplasms; Pseudopodia; Structure-Activity Relationship; Tosyl Compounds

Androgen receptor antagonists have been proved to be effective anti-prostate cancer agents. 3D-QSAR and Molecular docking methods were performed on curcumin derivatives as androgen receptor antagonists. The bioactive conformation was explored by docking the potent compound 29 into the binding site of AR. The constructed Comparative Molecular Field Analysis (CoMFA) and Comparative Similarity Indices Analysis (CoMSIA) models produced statistically significant results with the cross-validated correlation coefficients q(2) of 0.658 and 0.567, non-cross-validated correlation coefficients r(2) of 0.988 and 0.978, and predicted correction coefficients r(2) (pred) of 0.715 and 0.793, respectively. These results ensure the CoMFA and CoMSIA models as a tool to guide the design of novel potent AR antagonists. A set of 30 new analogs were proposed by utilizing the results revealed in the present study, and were predicted with potential activities in the developed models.

Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Design; Humans; Male; Molecular Docking Simulation; Prostatic Neoplasms; Quantitative Structure-Activity Relationship

Acquired chemotherapy resistance is a major contributor to treatment failure in oncology. For example, the efficacy of the common anticancer agent doxorubicin (DOX) is limited by the emergence of multidrug resistance (MDR) phenotype in cancer cells. While dose escalation of DOX can circumvent such resistance to a degree, this is precluded by the appearance of cardiotoxicity, a particularly debilitating condition in children. In vitro studies have established the ability of the natural phytochemical curcumin to overcome MDR; however, its widespread clinical application is restricted by poor solubility and low bioavailability. Building upon our recently developed polymer nanoparticle of curcumin (NanoCurc or NC) that significantly enhances the systemic bioavailability of curcumin, we synthesized a doxorubicin-curcumin composite nanoparticle formulation called NanoDoxCurc (NDC) for overcoming DOX resistance. Compared to DOX alone, NDC inhibited the MDR phenotype and caused striking growth inhibition both in vitro and in vivo in several models of DOX-resistant cancers (multiple myeloma, acute leukemia, prostate and ovarian cancers, respectively). Notably, NDC-treated mice also demonstrated complete absence of cardiac toxicity, as assessed by echocardiography, or any bone marrow suppression, even at cumulative dosages where free DOX and pegylated liposomal DOX (Doxil®) resulted in demonstrable attenuation of cardiac function and hematological toxicities. This improvement in safety profile was achieved through a reduction of DOX-induced intracellular oxidative stress, as indicated by total glutathione levels and glutathione peroxidase activity in cardiac tissue. A composite DOX-curcumin nanoparticle that overcomes both MDR-based DOX chemoresistance and DOX-induced cardiotoxicity holds promise for providing lasting and safe anticancer therapy.

Topics: Animals; Antibiotics, Antineoplastic; Cardiomyopathies; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Resistance, Neoplasm; Glutathione; Humans; Male; Mice; Mice, Nude; Multiple Myeloma; Nanoparticles; Prostatic Neoplasms; Random Allocation; Xenograft Model Antitumor Assays

Curcumin (Cur), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) are major forms of curcuminoids found in the rhizomes of turmeric. This study examined the effects of three curcuminoid analogues on prostate cancer cells. The results revealed that DMC demonstrated the most efficient cytotoxic effects on prostate cancer PC3 cells. DMC activated AMPK and in turn decreased the activity and/or expression of lipogenic enzymes, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). AICAR, an AMPK activator, and DMC down-regulated heat shock protein (HSP) 70 and increased the activity of the pro-apoptotic effector, caspase-3. In addition, DMC sustained epidermal growth factor receptor (EGFR) activation by suppressing the phosphatases PP2a and SHP-2. DMC also increased the interaction between EGFR and Cbl and induced the tyrosine phosphorylation of Cbl. The results suggest that DMC may have antitumor effects on prostate cancer cells via AMPK-induced down-regulation of HSP70 and EGFR.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Antineoplastic Agents, Phytogenic; Caspase 3; Cell Line, Tumor; Cell Proliferation; Curcuma; Curcumin; Diarylheptanoids; Down-Regulation; ErbB Receptors; Fatty Acid Synthase, Type I; HSP70 Heat-Shock Proteins; Humans; Male; Phosphorylation; Prostatic Neoplasms; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins c-cbl; Ribonucleotides

Tumor hypoxia with deregulated expression of hypoxia inducing factor (HIF) and its biological consequence leads to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors. Emerging evidence also suggest that hypoxia and HIF signaling pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation, all of which contribute to radiation therapy and chemotherapy resistance. However, the detailed mechanisms by which hypoxia/HIF drive these events are not fully understood. Here, we have shown that hypoxia leads to increased expression of VEGF, IL-6, and CSC marker genes such as Nanog, Oct4 and EZH2, and also increased the expression of miR-21, an oncogenic miRNA, in prostate cancer (PCa) cells (PC-3 and LNCaP). The treatment of PCa cells with CDF, a novel Curcumin-derived synthetic analogue previously showed anti-tumor activity in vivo, inhibited the productions of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 under hypoxic condition. Moreover, CDF treatment of PCa cells led to decreased cell migration under hypoxic condition. Taken together, these results suggest that the anti-tumor effect of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become useful for cancer therapy.

Topics: 3' Untranslated Regions; Animals; Antigens, Neoplasm; Antineoplastic Agents; Biomarkers, Tumor; Cell Adhesion Molecules; Cell Dedifferentiation; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Endothelial Cells; Epithelial Cell Adhesion Molecule; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Male; MicroRNAs; Neoplasm Invasiveness; Neoplastic Stem Cells; Neovascularization, Physiologic; Prostatic Neoplasms; Rabbits; Spheroids, Cellular; Vascular Endothelial Growth Factor A

In America and Western Europe, prostate cancer is the second leading cause of death in men. Emerging evidence suggests that chronic inflammation is a major risk factor for the development and metastatic progression of prostate cancer. We previously reported that the chemopreventive polyphenol curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. In this study, we analyze the effects of curcumin on prostate carcinoma growth, apoptosis and metastasis. We show that curcumin inhibits translocation of NFκB to the nucleus through the inhibition of the IκB-kinase (IKKβ, leading to stabilization of the inhibitor of NFκB, IκBα, in PC-3 prostate carcinoma cells. Inhibition of NFκB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NFκB. The combination of curcumin with the synthetic IKKβ inhibitor, SC-541, shows no additive or synergistic effects indicating that the two compounds share the target. Treatment of the cells with curcumin and siRNA-based knockdown of CXCL1 and -2 induce apoptosis, inhibit proliferation and downregulate several important metastasis-promoting factors like COX2, SPARC and EFEMP. In an orthotopic mouse model of hematogenous metastasis, treatment with curcumin inhibits statistically significantly formation of lung metastases. In conclusion, chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive proinflammatory and prometastatic feedback loop between NFκB and CXCL1/-2. Curcumin disrupts this feedback loop by the inhibition of NFκB signaling leading to reduced metastasis formation in vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chemokine CXCL1; Chemokine CXCL2; Curcumin; Humans; Male; Mice; Neoplasm Metastasis; NF-kappa B; Prostatic Neoplasms; Signal Transduction; Xenograft Model Antitumor Assays

Turmeric (Curcuma longa) has been shown to possess anti-inflammatory, antioxidant and antitumor properties. However, despite the progress in research with C. longa, there is still a big lacuna in the information on the active principles and their molecular targets. More particularly very little is known about the role of cell cycle genes p57(kip2) and Rad9 during chemoprevention by turmeric and its derivatives especially in prostate cancer cell lines.. Accordingly, in this study, we have examined the antitumor effect of several extracts of C. longa rhizomes by successive fractionation in clonogenic assays using highly metastatic PC-3M prostate cancer cell line.. A mixture of isopropyl alcohol: acetone: water: chloroform: and methanol extract of C. longa showed significant bioactivity. Further partition of this extract showed that bioactivity resides in the dichloromethane soluble fraction. Column chromatography of this fraction showed presence of biological activity only in ethyl acetate eluted fraction. HPLC, UV-Vis and Mass spectra studies showed presence three curcuminoids in this fraction besides few unidentified components.. From these observations it was concluded that the ethyl acetate fraction showed not only inhibition of colony forming ability of PC-3M cells but also up-regulated cell cycle genes p57(kip2) and Rad9 and further reduced the migration and invasive ability of prostate cancer cells.

Topics: Antioxidants; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Chemical Fractionation; Curcuma; Cyclin-Dependent Kinase Inhibitor p57; Humans; Male; Neoplasm Invasiveness; Phytotherapy; Plant Extracts; Prostatic Neoplasms

Many plant-derived products exhibit potent chemopreventive activity against animal tumor models as well as rodent and human cancer cell lines. They have low side effects and toxicity and presumably modulate the factors that are critical for cell proliferation, differentiation, senescence and apoptosis. The present study investigates the effects of some medicinal plant extracts from generally recognized as safe plants that may be useful in the prevention and treatment of cancer.. Clonogenic assays using logarithmically-growing cells were performed to test the effect. The cytotoxic effects of Curcuma longa and Zingiber officinale were studied using sulforhodamine B assay, tetrazolium dye assay, colony morphology and microscopic analysis.. Out of the 13 lyophilized plant-derived extracts evaluated for growth-inhibitory effects on the PC-3M prostate cancer cell line, two extracts derived from C. longa and Z. officinale showed significant inhibitory effects on colony-forming ability. The individual and augmentative effects of these two extracts were tested for their narrow range effective lower concentration on PC-3M in clonogenic assays. At relatively lower concentrations, C. longa showed significant inhibition of colony formation in clonogenic assays; whereas at same concentrations Z. officinale showed only moderate inhibitory effects. However, when both the agents were tested together at the same concentrations, the combined effects were much more significant than their individual ones. On normal prostate epithelial cells both C. longa and Z. officinale had similar effects but at a lower magnitude. These observations were confirmed by several cytotoxicity assays involving the morphological appearance of the colonies, microscopic observations, per cent inhibition in comparison to control by sulforhodamine B and tetrazolium dye assay.. From these observations, it was concluded that the combined effects of C. longa and Z. officinale are much greater than their individual effects, suggesting the role of multiple components and their synergistic mode of actions to elicit stronger beneficial effects.

Topics: Cell Line, Tumor; Cell Survival; Curcuma; Drug Synergism; Humans; Male; Phytotherapy; Plant Extracts; Prostatic Neoplasms; Zingiber officinale

Recently, we reported that combined ingestion of soy isoflavones and curcumin significantly decreased the serum level of prostate-specific antigen based on a randomized placebo-controlled double-blind clinical study. We investigated whether these polyphenols inhibited the proliferation of prostate cancer cells by activating a DNA damage response. The effects of isoflavones and curcumin on the expression and phosphorylation of ataxia-telangiectasia-mutated kinase (ATM), histone H2AX variant (H2AX) and checkpoint kinase2 (Chk2) were examined in LNCaP cells. The induction of apoptosis in LNCaP cells was evaluated by poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the effects of a testosterone supplement on modulation of the DNA damage response were examined. Combined treatment of isoflavones and curcumin additively suppressed cellular proliferation and induced phosphorylation of ATM, histone H2AX, Chk2 and p53. Testosterone augmented the activation of the DNA damage response and PARP cleavage induced by curcumin. Our results indicate that activation of the DNA damage response by polyphenols might suppress the malignant transformation of prostate cancer. In addition, testosterone, when combined with curcumin, may have suppressive effects on the progression of prostate cancer.

Topics: Antineoplastic Agents; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 2; Curcumin; DNA Damage; DNA-Binding Proteins; Flavonoids; Glycine max; Histones; Humans; Immunoblotting; Isoflavones; Male; Phenols; Poly(ADP-ribose) Polymerases; Polyphenols; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Testosterone; Tumor Suppressor Proteins

Activation of the Wingless (Wnt)/ß-catenin signaling pathway contributes to prostate tumorigenesis and metastasis. Depending of the stage of prostate cancer development, current drug therapies are of limited efficiency, so that prevention with natural compounds appears as an attractive strategy especially due to the slow progressive development of prostate cancer. We report here that the chemopreventive agent curcumin from the rhizome of Curcuma longa was able to affect cell proliferation of androgen-dependent prostate cancer through the induction of cell cycle arrest in G2 and modulation of Wnt signaling. Curcumin decreases the level of Tcf-4, CBP and p300 proteins implicated in the Wnt transcriptional complex that leads to the decrease of ß-catenin/Tcf-4 transcriptional activity and of the expression of ß-catenin target genes (cyclin D1 and c-myc). Subsequent cell death induction is linked to autophagy. Interestingly, in androgen-independent prostate cancer cells, curcumin does not affect Wnt/ß-catenin transcriptional activity. Altogether our results suggest that curcumin is an interesting chemopreventive agent for early stage prostate cancer.

Topics: Androgens; Antineoplastic Agents, Phytogenic; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Humans; Male; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Signal Transduction; Wnt Proteins

Prostate cancer (PCa) is one of the most deadly malignancies among men in the United States. Although localized prostate cancer can be effectively treated via surgery or radiation, metastatic disease is usually lethal. Recent evidence suggests that the development and progression of human prostate cancer involves complex interplay between epigenetic alterations and genetic defects. We have recently demonstrated that Nrf2, a master regulator of cellular antioxidant defense systems, was epigenetically silenced during the progression of prostate tumorigenesis in TRAMP mice. The aim of this study is to investigate the potential of curcumin (CUR), a dietary compound that we have reported to be able to prevent the development of prostate cancer in TRAMP mice, as a DNA hypomethylation agent. Using bisulfite genomic sequencing (BGS), treatment of TRAMP C1 cells we showed that CUR reversed the methylation status of the first 5 CpGs in the promoter region of the Nrf2 gene. Methylation DNA immunoprecipitation (MeDIP) analysis revealed that CUR significantly reduced the anti-mecyt antibody binding to the first 5 CpGs of the Nrf2 promoter, corroborated the BGS results. Demethylation of Nrf2 was found to be associated with the re-expression of Nrf2 and one of its downstream target gene, NQO-1, one of the major anti-oxidative stress enzymes, both at the mRNA and protein levels. Taken together, our current study suggests that CUR can elicit its prostate cancer chemopreventive effect, potentially at least in part, through epigenetic modification of the Nrf2 gene with its subsequent induction of the Nrf2-mediated anti-oxidative stress cellular defense pathway.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cells, Cultured; CpG Islands; Curcumin; DNA; DNA Methylation; Gene Expression Regulation, Neoplastic; Male; Mice; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Oxidative Stress; Promoter Regions, Genetic; Prostatic Neoplasms

The anti-tumor activity of curcumin against androgen-independent prostate cancer cells in vitro and the possible mechanism were investigated. After curcumin treatment, the effect of curcumin on the proliferation of prostate cancer PC-3 cells was assessed by CFSE staining. Flow cytometery (FCM) was performed to analyze the cell cycle and the induction of apoptosis of tumor cells. A luciferase reporter gene assay was used to determine the effects of curcumin on the activities of intracellular NF-κB and AP-1 signaling pathways. The results showed curcumin could effectively inhibit the proliferation of PC-3 cells in vitro (P<0.05). Cells were arrested at G(2)/M phase. After curcumin treatment, the percentage of apoptotic cells was significantly higher than in control group (P<0.05). The results of the luciferase assay revealed that curcumin selectively inhibited the activities of the NF-κB and AP-1 signaling pathways in PC-3 cells significantly. It was suggested that curcumin could exert anti-tumor activity against androgen-independent prostate cancer cells in vitro by inhibiting cellular proliferation and inducing apoptosis, which was probably contributed to the inhibition of transcription factors NF-κB and AP-1.

Topics: Androgens; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Humans; Male; NF-kappa B; Prostatic Neoplasms; Signal Transduction; Transcription Factor AP-1

In this work we prepared and evaluated the curcumin loaded fibrinogen nanoparticles (CRC-FNPs) as a novel drug delivery system for cancer therapy. These novel CRC-FNPs were prepared by a two-step co-acervation method using calcium chloride as the cross-linker. The prepared nanoparticles were characterized using dynamic light scattering (DLS), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FT-IR), thermogravimetry (TG), differential thermal analysis (DTA) and X-ray diffraction (XRD) studies. DLS studies showed that the particle size of CRC-FNPs was in the range of 150-200 nm. The loading efficiency (LE) and in vitro drug release were studied using UV spectrophotometer. The LE was found to be 90%. The cytotoxicity was studied using L929 (mouse fibroblast), PC3 (prostate) and MCF7 (breast) cancer cell lines by MTT assay, which confirmed that CRC-FNPs were comparatively non toxic to L929 cell line while toxic to PC3 and MCF7 cancer cells. Cellular uptake of CRC-FNPs studied using L929, MCF-7 and PC3 cells monitored by fluorescent microscopy, demonstrated significant internalization and retention of nanoparticles inside the cells. The preferential accumulation of curcumin within the cancer cells were also confirmed by flowcytometry based uptake studies. The apoptosis assay showed increased apoptosis on MCF-7 compared to L929 cells. The blood compatibility of CRC-FNPs throws light on the fact that it is possible to administer the prepared nanoformulation intravenously. The results indicated that CRC-FNPs could be a promising therapeutic agent for cancer treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Female; Fibrinogen; Hemolysis; Humans; In Vitro Techniques; Male; Materials Testing; Mice; Nanocapsules; Nanotechnology; Particle Size; Prostatic Neoplasms

Prostate-specific antigen (PSA) is a well-known marker for diagnosing and monitoring prostate cancer. Curcumin, a yellow curry pigment, has been reported to enhance androgen receptor (AR) degradation. We examined the effects of curcumin on increasing PSA expression by hypoxia and prolyl hydroxylase inhibitors, L-mimosine and dimethyloxalylglycine (DMOG), in human prostate carcinoma LNCaP cells.. The 3H-thymidine incorporation assay revealed that either L-mimosine or DMOG treatments attenuated cell proliferation. Immunoblot and enzyme-linked immunosorbent assays (ELISA) indicated that both L-mimosine and DMOG have an effect similar to hypoxia, which stabilized hypoxia-inducible factor-1α (HIF-1α) and induced PSA gene expression. The results of the immunoblot and transient gene expression assays indicated that induction of the PSA expression by hypoxia is both HIF-1α- and AR-dependent. Immunoblot assays revealed that a curcumin treatment (10 μM) decreased the protein abundance of AR but did not significantly affect the protein levels of HIF-1α and vascular endothelial growth factor, which were induced by hypoxia. ELISA and transient gene expression assays indicated that curcumin blocked the activation of L-mimosine or DMOG treatment on PSA expression.. These results indicate that curcumin blocked the enhanced effect of PSA expression by L-mimosine and DMOG that induce hypoxia condition.

Topics: Amino Acids, Dicarboxylic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Carcinoma; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Curcumin; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Iron Chelating Agents; Male; Mimosine; Neoplasm Proteins; Procollagen-Proline Dioxygenase; Prostate-Specific Antigen; Prostatic Neoplasms; Recombinant Proteins

Prostate cancer is a polyfactorial molecular anomaly that is offering refractoriness against a broad range of therapeutic drugs. Growth factor receptors are actively implicated in oncogenesis. PDGFR/EGFR mediated exacerbated signaling has a central participation and is contributory in fueling the signal transductions that gear up prostate cancer progression.. In this particular study, androgen sensitive, Prostate cancer cell line (LNCaP) was used. Pretreatment of cell line with PDGF resulted in an enhanced proliferation of cells which was evaluated by MTT assay. Treatment of cell line with either alone Curcumin, EGCG, sulforaphane or in combination was evaluated. PDGFR/EGFR activation (phosphorylation) was studied using western blot.. Results indicated that phosphorylation was gradually downregulated after treatment with individual compound. However there was a remarkable decrease in cellular proliferation after a combinatorial approach which is indicative of the fact that PDGFR phosphorylation was decreased outstandingly as evaluated by MTT assay. That also gave a prominent decline in the expression and subsequent decrease in proliferation pattern of cells.. Despite the fact that little is still known regarding the mechanistic insights by which phytonutrients act as barrier to cancer, and attempts to translate the studies from benchtop to bedside are in progress. A detailed analysis of nutraceuticals will help a lot in identifying the stumbling blocks in the standardization of therapeutic interventions.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Catechin; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Synergism; ErbB Receptors; Humans; Isothiocyanates; Male; Phosphorylation; Prostatic Neoplasms; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Sulfoxides; Thiocyanates

Curcumin, the principal curcuminoid of tumeric, has potent anticancer activity. To determine the mechanism of curcumin-induced cytotoxicity in prostate cancer cells, we exposed PC3 prostate carcinoma cells to 25 to 100 microM curcumin for 24 to 72 h. Curcumin treatment of PC3 cells caused time- and dose-dependent induction of apoptosis and depletion of cellular reduced glutathione (GSH). Exogenous GSH and its precursor N-acetyl-cysteine, but not ascorbic acid (AA) or ebselen, decreased curcumin accumulation in PC3 cells and also prevented curcumin-induced DNA fragmentation. The failure of AA and ebselen to protect PC3 cells from curcumin-induced apoptosis argued against the involvement of reactive oxygen species; rather, GSH-mediated inhibition of curcumin-induced cytotoxicity was due to reduced curcumin accumulation in PC3 cells. Curcumin-treated PC3 cells showed apoptosis-inducing cellular ceramide accumulation and activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK). Caspase-3, caspase-8, and caspase-9 were activated, and cytochrome c and apoptosis-inducing factor (AIF) were released from mitochondria following curcumin treatment. Interestingly, curcumin-induced apoptosis was not prevented by p38 MAPK, JNK, or caspase inhibition. We conclude that curcumin-induced cytotoxicity was due to cellular ceramide accumulation and damage to mitochondria that resulted in apoptosis mediated by AIF and other caspase-independent processes.

Topics: Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Ceramides; Curcumin; Glutathione; Humans; JNK Mitogen-Activated Protein Kinases; Male; Mitochondria; p38 Mitogen-Activated Protein Kinases; Prostatic Neoplasms; Reactive Oxygen Species

Curcumin, a hydrophobic polyphenolic compound derived from the rhizome of the herb Curcuma longa, possesses a wide range of biological applications including cancer therapy. However, its prominent application in cancer treatment is limited due to sub-optimal pharmacokinetics and poor bioavailability at the tumor site. In order to improve its hydrophilic and drug delivery characteristics, we have developed a beta-cyclodextrin (CD) mediated curcumin drug delivery system via encapsulation technique. Curcumin encapsulation into the CD cavity was achieved by inclusion complex mechanism. Curcumin encapsulation efficiency was improved by increasing the ratio of curcumin to CD. The formations of CD-curcumin complexes were characterized by Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), thermo-gravimetric analysis (TGA), scanning electron microscope (SEM), and transmission electron microscope (TEM) analyses. An optimized CD-curcumin complex (CD30) was evaluated for intracellular uptake and anti-cancer activity. Cell proliferation and clonogenic assays demonstrated that beta-cyclodextrin-curcumin self-assembly enhanced curcumin delivery and improved its therapeutic efficacy in prostate cancer cells compared to free curcumin.

Topics: Antineoplastic Agents; beta-Cyclodextrins; Calorimetry, Differential Scanning; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Drug Compounding; Drug Delivery Systems; Humans; Male; Microscopy, Electron; Prostatic Neoplasms; Spectroscopy, Fourier Transform Infrared; Thermogravimetry; Tumor Stem Cell Assay; X-Ray Diffraction

A novel PCD/CUR self-assembly approach for improved curcumin delivery to prostate cancer cells is described. The formation of PCD/CUR was confirmed using FTIR, DSC, TGA, and SEM/TEM, and their stability and solubility under physiological conditions was demonstrated. A mechanism for self-assembly is proposed. Intracellular uptake of the self-assemblies was studied by flow cytometry and immunofluorescence microscopy. The therapeutic efficacy was determined by cell proliferation and colony formation assays using C4-2, DU145 and PC3 prostate cancer cells. The results suggest that the PCD/CUR formulation could be a useful system for improving curcumin delivery and its therapeutic efficacy in prostate cancer.

Topics: Antineoplastic Agents; beta-Cyclodextrins; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Humans; Male; Models, Molecular; Propylene Glycols; Prostatic Neoplasms

Recently, studies have investigated the significance of the Wnt/β-catenin pathway in prostate cancer. The transcriptional activity of the androgen receptor (AR) is modulated by interaction with coregulators, one of which is β-catenin. Curcumin, a dietary yellow pigment of Curcuma longa, has emerged as having a chemopreventive role. Although curcumin has been shown to inhibit AR expression, its molecular mechanism has not been fully elucidated. In this study, whether curcumin mediates the Wnt/β-catenin signaling pathway with regard to AR/β-catenin interactions was studied. Curcumin was shown to induce significant inhibition of AR expression in a dose-dependent manner. Marked curcumin-induced suppression of β-catenin was shown in the nuclear and cytoplasmic extracts as well as whole cell lysates. Further analysis revealed that phosphorylation of Akt and glycogen synthase kinase-3β were attenuated, but phosphorylated β-catenin was increased after curcumin treatment. Finally, cyclin D1 and c-myc, the target gene of the β-catenin/T-cell factor transcriptional complex, were also decreased. These findings suggest that curcumin modulates the Wnt/β-catenin signaling pathway and might have a significant role in mediating inhibitory effects on LNCaP prostate cancer cells.

Topics: Adenocarcinoma; Antineoplastic Agents; beta Catenin; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Male; Prostatic Neoplasms; Protein Binding; Receptors, Androgen; Signal Transduction; Wnt1 Protein

The oxidizing anticancer system of vitamin C and vitamin K₃ (VC:VK₃, producing hydrogen peroxide via superoxide) was combined individually with melatonin, curcumin, quercetin, or cholecalciferol (VD₃) to determine interactions. Substrates were LNCaP and PC-3 prostate cancer cell lines. Three of the tested antioxidants displayed differences in cell line cytotoxicity. Melatonin combined with VC:VK₃ quenched the oxidizing effect, while VC:VK₃ applied 24 hours after melatonin showed no quenching. With increasing curcumin concentrations, an apparent combined effect of VC:VK₃ and curcumin occurred in LNCaP cells, but not PC-3 cells. Quercetin alone was cytotoxic on both cell lines, but demonstrated an additional 50-percent cytotoxicity on PC-3 cells when combined with VC:VK₃. VD₃ was effective against both cell lines, with more effect on PC-3. This effect was negated on LNCaP cells with the addition of VC:VK₃. In conclusion, a natural antioxidant can enhance or decrease the cytotoxicity of an oxidizing anticancer system in vitro, but generalizations about antioxidants cannot be made.

Topics: Antineoplastic Agents; Antioxidants; Ascorbic Acid; Cell Cycle; Cholecalciferol; Curcumin; Cytotoxins; Drug Interactions; Drug Therapy, Combination; Humans; Male; Melatonin; Oxidative Stress; Prostatic Neoplasms; Quercetin; Tumor Cells, Cultured; Vitamin K 3

A new ionic Pd(II) complex, [(bipy)Pd(Pcurc)][CF(3)SO(3)], 1, with the metal center coordinated to two different chelating ligands, the pure curcumin (Pcurc) and the 4,4'-dinonyl-2,2'-bipyridine (bipy), has been synthesized, fully characterized, and its antitumoral mechanism and oxidant property have been investigated. The Pd(II) complex induces both cell growth inhibition and apoptosis of human prostate cancer cells, (LnCaP, PC3, and DU145) through the production of ROS and JNK phosphorylation associated with GSTp1 down-regulation. ROS production induced by complex 1 treatment activated apoptosis through mitochondrial membrane depolarization in all prostate cancer cells, with up-regulation of Bax and down-regulation of Bcl-2 proteins. In addition, while curcumin determines DNA damage and PARP cleavage, complex 1 does not elicit any activation of PARP enzyme. Taken together, these data validate the significance of curcumin complexation to a metal center and its conjugation to another functionalized bioactive ligand in the apoptosis signal transduction and enhancement of cell death in prostate cancer cell lines and suggest the potential of this design strategy in the improvement of the metal-based drugs cytotoxicity.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Curcumin; DNA Damage; Humans; Male; MAP Kinase Kinase 4; Oxidants; Palladium; Prostatic Neoplasms; Reactive Oxygen Species; Signal Transduction; Spectrophotometry, Ultraviolet

There is little known on the involvement of vasoactive intestinal peptide (VIP) in the metastatic cascade of human prostate cancer, that is, cell proliferation, cell-cell adhesion, extracellular-matrix degradation, and migration/invasion. Here we evaluated the expression of related biomarker proteins (cyclin D1, metalloproteinases MMP-2 and MMP-9, and E-cadherin) in human androgen-dependent (LNCaP) and independent (PC3) prostate cancer cells.. Reverse transcriptase (RT)-polymerase chain reaction (PCR), gelatin zymography, Western blotting, confocal immunofluorescence microscopy, and assays on cell proliferation, adhesion, wound-healing, migration and random homing were performed.. VIP increased cell proliferation and cyclin D1 expression whereas it decreased cell adhesion and E-cadherin expression in LNCaP and PC3 cells. VIP enhanced the gelatinolytic activity of MMP-2 and MMP-9. Semiquantitative RT-PCR assays showed that VIP stimulated mRNA levels of these MMPs and suppressed mRNA levels of its inhibitory protein RECK. VIP promoted cell invasion and migration, and the responses were faster according to the most aggressive status in cancer progression (androgen-independence). The involvement of nuclear factor-kappaB (NF-kappaB) was demonstrated since the anti-inflammatory agent curcumin blocked VIP effects on the above biomarkers in both cell lines.. Taken together, these results and the presence of kappaB sites on gene promoter of cyclin D1, MMPs and, possibly, E-cadherin suggest that VIP may act as a cytokine in an early metastatic stage of human prostate cancer through the NF-kappaB/MMPs-RECK/E-cadherin system. Our findings may help to define novel targets and agents with potential usefulness in prostate cancer therapy.

Topics: Anti-Inflammatory Agents; Biomarkers, Tumor; Cadherins; Cell Adhesion; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Curcumin; Cyclin D1; Extracellular Matrix; GPI-Linked Proteins; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Membrane Glycoproteins; Microscopy, Confocal; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; Vasoactive Intestinal Peptide

Increasing interest in the use of phytochemicals to reduce prostate cancer led us to investigate 2 potential agents, curcumin and resveratrol as preventive agents. However, there is concern about the bioavailability of these agents pertinent to the poor absorption and thereby limiting its clinical use. With the view to improve their bioavailability, we used the liposome encapsulated curcumin, and resveratrol individually and in combination in male B6C3F1/J mice. Further, we examined the chemopreventive effect of liposome encapsulated curcumin and resveratrol in combination in prostate-specific PTEN knockout mice. In vitro assays using PTEN-CaP8 cancer cells were performed to investigate the combined effects curcumin with resveratrol on (i) cell growth, apoptosis and cell cycle (ii) impact on activated p-Akt, cyclin D1, m-TOR and androgen receptor (AR) proteins involved in tumor progression. HPLC analysis of serum and prostate tissues showed a significant increase in curcumin level when liposome encapsulated curcumin coadministered with liposomal resveratrol (p < 0.001). Combination of liposomal forms of curcumin and resveratrol significantly decreased prostatic adenocarcinoma in vivo (p < 0.001). In vitro studies revealed that curcumin plus resveratrol effectively inhibit cell growth and induced apoptosis. Molecular targets activated due to the loss of phosphatase and tensin homolog (PTEN) including p-Akt, cyclin D1, mammalian target of rapamycin and AR were downregulated by these agents in combination. Findings from this study for the first time provide evidence on phytochemicals in combination to enhance chemopreventive efficacy in prostate cancer. These findings clearly suggest that phytochemicals in combination may reduce prostate cancer incidence due to the loss of the tumor suppressor gene PTEN.

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carrier Proteins; Cell Cycle; Cell Proliferation; Curcumin; Cyclin D1; Disease Progression; Drug Carriers; Drug Delivery Systems; Incidence; Liposomes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptors, Androgen; Resveratrol; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases

Expression and activity of CC motif ligand 2 (CCL2) is down-regulated by curcumin, the active phytochemical ingredient of turmeric (Curcuma longa), a dietary supplement often self-prescribed to promote prostate health. CCL2 is a potent chemotactic factor of prostate cancer (PCa) with important roles in development of bone metastasis. The relationship between CCL2 and curcumin, however, has not been studied in PCa. Adhesion, invasion and motility of PC-3 cells were measured in response to exposure to curcumin (30 microM; 18 h), CCL2 (100 ng/ml; 18 h) or PMA (100 ng/ml; 18 h). CCL2 mRNA expression and protein secretion levels were measured by real-time PCR and ELISA respectively. Curcumin significantly blocked CCL2 induced adhesion, invasion and motility. Curcumin also significantly suppressed the mRNA expression and secreted CCL2 protein levels. The addition of PMA, a protein kinase C (PKC) activator, blocked the effects of curcumin, leading to an increase in CCL2 expression as well as an increase in PC-3 cell adhesion, invasion and motility. The introduction of a PKC inhibitor, however, blocked the effects of CCL2. We also found that curcumin, CCL2 and PMA, in part, function through the differential regulation of the proteolytic protein matrix metalloproteinase (MMP)-9. These data indicate a potential mechanism; by which curcumin can block the chemotactic effects of CCL2 on PCa. Curcumin exerts potential anti-metastatic effects in bone-derived PCa cells by blocking CCL2 mediated actions on invasion, adhesion and motility, in part through differential regulation of PKC and MMP-9 signaling.

Topics: Cell Adhesion; Cell Movement; Chemokine CCL2; Curcumin; Down-Regulation; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Humans; Male; Matrix Metalloproteinase 9; Models, Biological; Neoplasm Invasiveness; Prostatic Neoplasms; Protein Kinase C; Protein Processing, Post-Translational; Tumor Cells, Cultured

Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development in cancer. To enhance its potency, we tested the efficacy of synthetic curcumin analogues, known as FLLL11 and FLLL12, in cancer cells. We examined the impact of FLLL11 and FLLL12 on cell viability in eight different breast and prostate cancer cell lines. FLLL11 and FLLL12 (IC(50) values 0.3-5.7 and 0.3-3.8 micromol/L, respectively) were substantially more potent than curcumin (IC(50) values between 14.4-50 micromol/L). FLLL11 and FLLL12 were also found to inhibit AKT phosphorylation and downregulate the expression of HER2/neu. In addition, we demonstrate for the first time that FLLL11 and FLLL12 inhibit phosphorylation of signal transducer and activator of transcription (STAT) 3, an oncogene frequently found to be persistently active in many cancer types. The inhibition of STAT3 signaling was confirmed by the inhibition of STAT3 DNA binding and STAT3 transcriptional activity. Furthermore, FLLL11 and FLLL12 were more effective than curcumin in inhibiting cell migration and colony formation in soft agar as well as inducing apoptosis in cancer cells. These results indicate that FLLL11 and FLLL12 exhibit more potent activities than curcumin on the inhibition of STAT3, AKT, and HER-2/neu, as well as inhibit cancer cell growth and migration, and may thus have translational potential as chemopreventive or therapeutic agents for breast and prostate cancers.

Topics: Blotting, Western; Breast Neoplasms; Cell Adhesion; Cell Movement; Cell Proliferation; Colony-Forming Units Assay; Curcumin; Female; Growth Inhibitors; Humans; Male; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor

Topics: Curcumin; Humans; Male; Prostatic Neoplasms; Receptors, Androgen

We used an in vivo model of human experimental prostate cancer in order to shed a new light on the effects of vasoactive intestinal peptide (VIP) on tumor growth as well as its pro-metastatic potential in this disease. We used nude mice subcutaneously injected with prostate cancer androgen-independent PC3 cells for 30 days. The regulatory role of VIP on cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) expression as well as on matrix metalloproteinase-2 and 9 (MMP-2 and 9) activities was examined. A selective COX-2 inhibitor, NS-398, and curcumin were used to block VIP effects. Xenografts of VIP-treated PC3 prostate cancer cells in nude mice gave tumors that grew significantly faster than those in the untreated group. It is conceivably a result of both the trophic effect of VIP on prostate cancer cells and the proangiogenic action of the neuropeptide in the growing tumor. We show the overexpression at mRNA and/or protein levels of VIP, its main receptor VPAC(1), the major angiogenic factor VEGF, and the pro-inflammatory enzyme COX-2 as well as the increased activity of MMP-2 and 9 in tumors derived from VIP-treated PC3 cells as compared with control group. The overexpression of the above biomarkers was suppressed in tumors derived from VIP-treated PC3 cells that had been previously incubated with curcumin or NS-398. Thus, the potential therapeutic role of curcumin and selective COX-2 inhibitors in combination with available VIP antagonists should be considered in prostate cancer therapy as supported by their inhibitory activities on tumor cell growth.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclooxygenase 2; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase 2; Mice; Mice, Nude; Nitrobenzenes; Polymerase Chain Reaction; Prostatic Neoplasms; Sulfonamides; Vasoactive Intestinal Peptide; Xenograft Model Antitumor Assays

Phosphatase of regenerating liver-3 (PRL-3) has been suggested as a potential target for anticancer drugs based on its involvement in tumor metastasis. However, little is known about a small-molecule inhibitor against PRL-3. In this study, we report that curcumin, the component of the spice turmeric, shows its antitumor effect by selectively down-regulating the expression of PRL-3 but not its family members PRL-1 and -2 in a p53-independent way. Curcumin inhibited the phosphorylation of Src and stat3 partly through PRL-3 down-regulation. Cells with PRL-3 stably knocked down show less sensitivity to curcumin treatment, which reveals that PRL-3 is the much further upstream target of curcumin. Curcumin treatment also remarkably prevented B16BL6 from invading the draining lymph nodes in the spontaneous metastatic tumor model, which is probably of relevance to PRL-3 down-regulation. Our results reveal a novel capacity of curcumin to down-regulate oncogene PRL-3, raising its possibility in therapeutic regimen against malignant tumor.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Immediate-Early Proteins; Male; Melanoma; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Prostatic Neoplasms; Protein Tyrosine Phosphatases; Proto-Oncogene Proteins pp60(c-src); Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Transcription, Genetic; Tumor Suppressor Protein p53

Among the potent anticancer agents, curcumin has been found to be very efficacious against many different types of cancer cells. However, the major disadvantage associated with the use of curcumin is its low systemic bioavailability when administered orally due to its poor aqueous solubility. Our present work investigated the efficiency of encapsulation of curcumin in poly (lactic-coglycolic acid) (PLGA) nanospheres using solid/oil/water emulsion solvent evaporation method.. The nanospheres were formulated and then characterized for percent yield, encapsulation efficiency, surface morphology, particle size, drug distribution studies, drug polymer interaction studies and in vitro drug release profiles.. Our studies showed the successful formation of smooth and spherical curcumin-loaded PLGA nanospheres, with an encapsulation efficiency of 90.88+/-0.14%. The particle size distribution showed a range of 35 nm to 100 nm, with the mean particle size being 45 nm. Evaluation of these curcumin-loaded nanospheres was carried out in prostate cancer cell lines. Results showed robust intracellular uptake of the nanospheres in the cells. Cell viability studies revealed that the curcumin-loaded nanospheres were able to exert a more pronounced effect on the cancer cells as compared to free curcumin.. Our studies achieved successful formulation of curcumin loaded PLGA nanospheres, thus indicating that nanoparticle-based formulation of curcumin has high potential as an adjuvant therapy for clinical application in prostate cancer.

Topics: Antineoplastic Agents; Calorimetry, Differential Scanning; Cell Line, Tumor; Cell Survival; Curcumin; Drug Delivery Systems; Humans; Lactic Acid; Male; Microscopy, Confocal; Nanospheres; NF-kappa B; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostatic Neoplasms

Curcumin (diferuloylmethane) is the major active component of turmeric and is being actively investigated for its anti-cancer properties. To better understand the biological mechanisms of the chemopreventive potential of curcumin in prostate cancer, we have evaluated curcumin regulated transcriptome in prostate cancer cells. Hierarchical clustering methods and functional classification of the Curcumin-Gene Expression Response (Cu-GER) showed temporal co-regulation of genes involved in oxidative stress response and growth signaling pathways. Interestingly, C4-2B, androgen independent metastatic prostate cancer cells exhibited attenuated Cu-GER response in comparison to parental androgen dependent and less aggressive LNCaP cells. Androgen Receptor (AR) regulated genes which play critical roles in normal growth and differentiation of the prostate gland, as well as in prostate cancer, were also a part of the Cu-GER. Of note, curcumin downregulated transcript encoded by the potentially causal TMPRSS2-ERG gene fusion, a common oncogenic alteration noted in 50-70% of prostate cancer patients. Further more, expression of EGFR and ERBB2 receptor were found to be downregulated in curcumin treated LNCaP and C4-2B cells. This report for the first time establishes novel features of Cu-GER in prostate cancer cells of varying tumorigenic phenotypes and provides potentially novel read-outs for assessing effectiveness of curcumin in prostate cancer and likely in other cancers. Importantly, new gene-networks identified here further delineate molecular mechanism(s) of action of curcumin in prostate cancer cells.

Topics: Androgens; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Formazans; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heme Oxygenase (Decyclizing); Humans; Male; Models, Biological; Neoplasms, Hormone-Dependent; Oxidative Stress; Prostatic Neoplasms; Tetrazolium Salts; Time Factors

Topics: Androgens; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Gene Expression Regulation, Neoplastic; Humans; India; Male; Neoplasms, Hormone-Dependent; North America; Prostatic Neoplasms; Signal Transduction; Spices

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a highly toxic environmental contaminant. When exposed to TCDD, mammalian cells undergo malignant transformation via abnormal intracellular signaling cascades, and the robust inductions of cytochrome P450 (CYP) enzymes are considered to mediate carcinogenesis by producing genotoxic metabolites. We here examined whether curcumin has preventive activity against TCDD-induced CYP production and cell transformation. Initially, the cellular levels of cytochrome P450 (CYP) 1A1 and 1B1 were examined, because these are known to generate estrogen metabolites that mediate genotoxic stress. Curcumin inhibited CYP1A1 and 1B1 induction by TCDD at the mRNA and protein levels. Notably, the nuclear levels of arylhydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) were decreased by curcumin, but those in the cytoplasm were not. It was also found that oxidative stress mediated the curcumin-induced degradations of AhR and ARNT. Furthermore, in vitro transformation assays showed that in normal human embryonic kidney cells and normal prostate cells curcumin prevents the anchorage-independent growth induced by TCDD. In conclusion, curcumin attenuates AhR/ARNT-mediated CYP induction by dioxin and presumably this mode-of-action may be responsible for the curcumin prevention of malignant transformation. The findings of this study should be found helpful in the design stage of pharmacodynamic studies for developing curcumin as a chemopreventive or anticancer agent.

Topics: Antigens, Polyomavirus Transforming; Aryl Hydrocarbon Receptor Nuclear Translocator; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Cell Transformation, Viral; Curcumin; Cytochrome P-450 Enzyme System; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Liver Neoplasms; Male; Polychlorinated Dibenzodioxins; Prostatic Neoplasms; Reactive Oxygen Species; RNA, Small Interfering

Because of lack of effective treatment options for hormone-refractory prostate cancer at the present time, the need for developing novel therapeutic strategies and targets to treat and prevent the progression of hormone-sensitive prostate cancer to the hormone-refractory stage is paramount. Our previous in vitro studies have shown that curcumin sensitizes both hormone-sensitive and hormone-resistant prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and that combined curcumin/TRAIL treatment induces apoptosis in cancer cells by inhibiting antiapoptotic p-Akt and nuclear factor-kappaB (NF-kappaB). In the present study, we demonstrate that curcumin and TRAIL combination regimen is also the most effective treatment for inhibiting the growth of PC3 xenografts compared to curcumin or TRAIL monotherpy. The inhibition of PC3 tumors by combined treatment correlated with significant reduction in expression of p-Akt and NF-kappaB in tumor tissue. Furthermore, tumor growth inhibition by curcumin/TRAIL combination regimen was associated with significant decrease in cell proliferation and an increase in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the tumors without significant change in microvessel density. Based on the significant efficacy in this preclinical model, combined curcumin/TRAIL regimen may be an effective adjuvant therapy for hormone-refractory prostate cancer.

Topics: Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Resistance, Neoplasm; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; TNF-Related Apoptosis-Inducing Ligand; Treatment Outcome; Xenograft Model Antitumor Assays

To study the effects of curcumin on the expression of the vascular endothelial growth factor (VEGF) and androgen-independent prostate cancer cell line PC-3, and to explore its anticarcinogenic mechanism.. PC-3 cells were treated with curcumin at the concentration of 0, 6.25, 12.5, 25 and 50 micromol/L respectively. Then the cell activity was assayed by dyed rate of Typan blue and MTT at 12, 24, 36, 48, 72 and 96 hours, the cell cycle and morphological changes observed by flow cytometry (FCM) and electronic microscopy at 24 hours, the VEGF mRNA expression measured by semi-quantitative RT-PCR, and the secreting protein levels of VEGF in the supernatants determined by enzyme-linked immunosorbent assay (ELISA).. The growth of PC-3 cells was suppressed obviously by curcumin in a dose- and time-dependent manner in vitro. There were significant differences in inhibition rate among different concentration and time groups (P < 0.01). Furthermore, curcumin arrested the cell cycle of PC-3 cells in the G2/M phase in a dose-dependent manner (P < 0.01). The percentages of apoptotic cells were significantly higher in different concentration groups than in the controls (P < 0.01). Apoptosis-associated morphological changes were observed in PC-3 cells at 24 hours, and a marked decline in the expression of VEGF was noted after the exposure to different concentrations of curcumin within 24 hours.. Curcumin can suppress the growth of PC-3 cells, promote their apoptosis and arrest their cell cycle in the G2/M phase, and reduce the expression of VEGF mRNA and proteins, which may sever to explain its inhibitory effect on tumor and angiogenesis.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Male; Microscopy, Electron, Transmission; Prostatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Vascular Endothelial Growth Factor A

We have initiated studies to enhance targeted delivery of an anticancer agent, curcumin, for prostate cancer treatment by incorporating this agent into the liposomes (nanodelivery vehicles primarily composed of phospholipids) coated with prostate membrane specific antigen specific antibodies. We prepared curcumin-loaded liposomes of various lipid compositions by sonication at an average size of 100-150 nm. Un-entrapped curcumin was removed by size exclusion chromatography. Data show that curcumin preferentially partitioned into liposomes prepared from dimyristoyl phosphatidyl choline (DMPC) and cholesterol among the various compositions tested. The anti-proliferative activity of liposomal curcumin was studied using two human prostate cancer cell lines (LNCaP and C4-2B) by a tetrazolium dye-based (MTT) assay. Treatment of cells with liposomal curcumin (5-10 microM) for 24-48 h at 37 degrees C resulted in at least 70-80% inhibition of cellular proliferation without affecting their viability. On the other hand, free curcumin exhibited similar inhibition only at 10-fold higher doses (>50 microM). We also observed that LNCaP cells were relatively more sensitive to liposomal curcumin mediated block of cellular proliferation than C4-2B cells. We are currently developing liposome formulations with targeting ability to further improve the efficacy of curcumin in vivo.

Topics: Antibodies; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemistry, Pharmaceutical; Curcumin; Dose-Response Relationship, Drug; Drug Compounding; Humans; Liposomes; Male; Nanotechnology; Phospholipids; Prostate-Specific Antigen; Prostatic Neoplasms; Technology, Pharmaceutical

Prior studies from our laboratory have demonstrated the efficacy of a combined treatment of low doses of dietary agents curcumin and phenylethylisothiocyanate in effectively suppressing prostate cancer in vitro in human prostate cancer PC3 cells as well as in vivo in immunodeficient mice implanted with PC3 cells. Hence, this study was undertaken to examine the potential chemopreventive properties of the two agents against transgenic adenocarcinoma of the mouse prostate.. The efficacy of AIN-76A diet supplemented with 2% curcumin or 0.05% PEITC or a combination of 1% curcumin and 0.025% PEITC for periods of 10 and 16 weeks was tested against adenocarcinoma of the mouse prostate. Immunohistochemistry and Western blot analysis were used to examine the expression of proliferation and apoptotic biomarkers. All statistical tests were two-sided.. Supplementing AIN-76A diet with dietary phytochemicals curcumin or PEITC either alone or in combination, significantly decreased incidence of prostate tumor formation (P = 0.0064). Immunohistochemistry revealed a significant inhibition of high-grade PIN (P = 0.0006, 0.000069, 0.00029 for a treatment period of 10 weeks and P = 0.02582, 0.022179, 0.0317 for a treatment period of 16 weeks) along with decreased proliferation and increased apoptotic index in the curcumin, PEITC or curcumin and PEITC treated animals, respectively. Furthermore, Western blot analysis revealed that downregulation of the Akt signaling pathway may in part play a role in decreasing cell proliferation ultimately retarding prostate tumor formation.. Our data lucidly evidence the chemopreventive merits of dietary phytochemicals curcumin and PEITC in suppressing prostate adenocarcinoma.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Apoptosis; bcl-Associated Death Protein; Caspase 3; Cell Proliferation; Curcumin; Diet; Disease Models, Animal; Drug Therapy, Combination; Forkhead Box Protein O1; Forkhead Transcription Factors; Isothiocyanates; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Signal Transduction; Time Factors

Our previous studies have shown that dietary pigment curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1-6-heptadine-3,5-dione; C21H20O6] sensitizes human prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L)-induced apoptosis by inhibiting nuclear factor (NF)-kappaB. In the present study, we demonstrate that activated (phosphorylated) Akt kinase plays a pivotal role in regulation of NF-kappaB and sensitization of LNCaP and PC3 prostate cancer cells to TRAIL by curcumin. Curcumin inhibited the expression of phospho-Akt (p-Akt), which was not due to activation of phosphatase and tensin homolog deleted on chromosome 10 phosphatase activity by curcumin. Because NF-kappaB is a downstream target of Akt, we investigated whether inhibition of NF-kappaB by curcumin is mediated through suppression of p-Akt. Data demonstrate that treatment of PC3 cells with SH-6 (JAm Chem Soc 125:1144-1145, 2003), a specific inhibitor of Akt, or transfection with small inhibitory RNA (siRNA)-Akt not only inhibited p-Akt but also abrogated the expression and transcriptional activity of NF-kappaB. Furthermore, overexpression of constitutively active Akt1 in cancer cells prevented the inhibition of NF-kappaB by curcumin. In addition, treatment with SH-6 or transfection with siRNA-Akt sensitized PC3 cells to TRAIL-induced cytotoxicity. On the other hand, SH-6 does not inhibit NF-kappaB or sensitize DU145 cancer cells to TRAIL because these cells do not express p-Akt. Because expression of antiapoptotic Bcl-2, Bcl-xL, and X-chromosome-linked inhibitor of apoptosis protein (XIAP) is regulated by NF-kappaB, both curcumin and SH-6 decreased the levels of these proteins in PC3 cells through inhibition of NF-kappaB. Furthermore, gene silencing of Bcl-2 with siRNA-Bcl-2 sensitized PC3 cells to TRAIL. Collectively, these data define a pathway whereby curcumin sensitizes prostate cancer cells to TRAIL by inhibiting Akt-regulated NF-kappaB and NF-kappaB-dependent antiapoptotic Bcl-2, Bcl-xL, and XIAP.

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Humans; I-kappa B Proteins; Male; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphatidylinositols; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand

To elucidate the effect and the mechanisms of curcumin on the expression of the human homeobox gene NKX3.1 in the prostate cancer cell LNCaP.. The expression change of NKX3.1 in cells incubated with varying concentrations of curcumin was observed by Western blotting and RT-PCR. A dual luciferase reporter assay was used to test the effect of curcumin on the activity of the NKX3.1 1040 bp promoter. Curcumin-treated cells disposed to a designated amount of androgen analog R1881 and the androgen receptor (AR) antagonist flutamide, then the expression of NKX3.1 or the activity of the NKX3.1 promoter were investigated by Western blotting or reporter gene assay, respectively. Finally, Western blotting and electrophoretic mobility shift assay were performed to demonstrate the effect of curcumin on the expression of AR and its binding activity to the androgen response element (ARE).. Curcumin downregulated the expression of NKX3.1 and the activity of the NKX3.1 1040 bp promoter in LNCaP cells. R1881 increased the expression of NKX3.1, and the AR antagonist flutamide decreased the expression of NKX3.1 in LNCaP cells, while curcumin could inhibit androgen-AR mediated induction of NKX3.1 expression. Curcumin decreased the expression of AR and the binding activity to ARE directly.. Curcumin could downregulate NKX3.1 expression in LNCaP cells. It could also inhibit the androgen-AR mediated induction of NKX3.1 expression by downregulating AR expression and blocking its DNA binding activity.

Topics: Androgens; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Curcumin; Down-Regulation; Homeodomain Proteins; Humans; Male; Metribolone; Prostatic Neoplasms; Receptors, Androgen; Transcription Factors; Transfection

The oncoprotein MDM2, a major ubiquitin E3 ligase of tumor suppressor p53, has been suggested as a novel target for human cancer therapy based on its p53-dependent and p53-independent activities. We have identified curcumin, which has previously been shown to have anticancer activity, as an inhibitor of MDM2 expression. Curcumin down-regulates MDM2, independent of p53. In a human prostate cancer cell lines PC3 (p53(null)), curcumin reduced MDM2 protein and mRNA in a dose- and time-dependent manner, and enhanced the expression of the tumor suppressor p21(Waf1/CIP1). The inhibitory effects occur at the transcriptional level and seem to involve the phosphatidylinositol 3-kinase/mammalian target of rapamycin/erythroblastosis virus transcription factor 2 pathway. Curcumin induced apoptosis and inhibited proliferation of PC3 cells in culture, but both MDM2 overexpression and knockdown reduced these effects. Curcumin also inhibited the growth of these cells and enhanced the cytotoxic effects of gemcitabine. When it was administered to tumor-bearing nude mice, curcumin inhibited growth of PC3 xenografts and enhanced the antitumor effects of gemcitabine and radiation. In these tumors, curcumin reduced the expression of MDM2. Down-regulation of the MDM2 oncogene by curcumin is a novel mechanism of action that may be essential for its chemopreventive and chemotherapeutic effects. Our observations help to elucidate the process by which mitogens up-regulate MDM2, independent of p53, and identify a mechanism by which curcumin functions as an anticancer agent.

Topics: Animals; Curcumin; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Protein Kinases; Proto-Oncogene Protein c-ets-2; Proto-Oncogene Proteins c-mdm2; Radiation-Sensitizing Agents; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Curcumin (diferulolylmethane), an active ingredient derived from the rhizome of the plant Curcuma longa, has anticancer activity in vitro and in vivo. Although curcumin possesses chemopreventive properties against several types of cancer, the molecular mechanisms by which it inhibits cell growth and induces apoptosis are not clearly understood. Our data revealed that curcumin inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells. Curcumin downregulated the expression of Bcl-2, and Bcl-XL and upregulated the expression of p53, Bax, Bak, PUMA, Noxa, and Bim. Curcumin upregulated the expression of p53 as well as its phosphorylation at serine 15, and acetylation in a concentration-dependent manner. Acetylation of histone H3 and H4 was increased in cells treated with curcumin, suggesting histone modification may regulate gene expression. Treatment of LNCaP cells with curcumin resulted in translocation of Bax and p53 to mitochondria, production of reactive oxygen species, drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and induction of apoptosis. Furthermore, curcumin inhibited expression of phosphatidyl-inositol-3 kinase (PI3K) p110 and p85 subunits, and phosphorylation of Ser 473 AKT/PKB. Downregulation of AKT by inhibitors of PI3K (Wortmannin and LY294002) and AKT, or by dominant negative AKT increased curcumin-induced apoptosis, whereas transfection of constitutively active AKT attenuated this effect. Similarly, wild-type phosphatase and tensin homolog deleted from chromosome 10 (PTEN) enhanced curcumin-induced apoptosis and, in contrast, inactive PTEN (G129E and G129R) inhibited curcumin-induced apoptosis. Overexpression of constitutively active AKT inhibited curcumin-induced p53 translocation to mitochondria, and Smac release to cytoplasm, whereas inhibition of AKT by dominant negative AKT enhanced curcumin-induced p53 translocation to mitochondria and Smac release. Our study establishes a role for AKT in modulating the direct action of p53 on the caspase-dependent mitochondrial death pathway and suggests that these important biological molecules interact at the level of the mitochondria to influence curcumin sensitivity. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.

Topics: Antineoplastic Agents; Apoptosis; Caspase 1; Curcumin; Histones; Humans; Male; Mitochondria; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; PTEN Phosphohydrolase; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Up-Regulation

The effect of vasoactive intestinal peptide (VIP) on cyclooxygenase-2 (COX-2) expression was analyzed in human prostate non-neoplastic (RWPE-1) as well as cancer androgen-dependent (LNCaP) and independent (PC3) cells. The three cell lines expressed VIP mRNA and VIP peptide, as measured by RT-PCR and immunochemistry, which supports an autocrine/paracrine action of VIP in the prostate gland. VIP levels were progressively higher from non-neoplastic to androgen-dependent and independent cells. Real-time RT-PCR and Western-blotting showed that VIP stimulated both COX-2 mRNA and protein expression in a faster manner as prostate cancer stage progressed (i.e. RWPE1

Topics: Cell Line, Tumor; Curcumin; Cyclooxygenase 2; Disease Progression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Membrane Proteins; NF-kappa B; Prostatic Neoplasms; Protein Transport; RNA, Messenger; Time Factors; Vasoactive Intestinal Peptide

We have recently shown that curcumin induces apoptosis in prostate cancer cells through Bax translocation to mitochondria and caspase activation, and enhances the therapeutic potential of TRAIL. However, the molecular mechanisms by which it causes growth arrest are not well-understood. We studied the molecular mechanism of curcumin-induced cell cycle arrest in prostate cancer androgen-sensitive LNCaP and androgen-insensitive PC-3 cells. Treatment of both cell lines with curcumin resulted in cell cycle arrest at G1/S phase and that this cell cycle arrest is followed by the induction of apoptosis. Curcumin induced the expression of cyclin-dependent kinase (CDK) inhibitors p16(/INK4a), p21(/WAF1/CIP1) and p27(/KIP1), and inhibited the expression of cyclin E and cyclin D1, and hyperphosphorylation of retinoblastoma (Rb) protein. Lactacystin, an inhibitor of 26 proteasome, blocks curcumin-induced down-regulation of cyclin D1 and cyclin E proteins, suggesting their regulation at level of posttranslation. The suppression of cyclin D1 and cyclin E by curcumin may inhibit CDK-mediated phosphorylation of pRb protein. The inhibition of p21(/WAF1/CIP1) by siRNA blocks curcumin-induced apoptosis, thus establishing a link between cell cycle and apoptosis. These effects of curcumin result in the proliferation arrest and disruption of cell cycle control leading to apoptosis. Our study suggests that curcumin can be developed as a chemopreventive agent for human prostate cancer.

Topics: Apoptosis; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; G1 Phase; Gene Expression Regulation; Humans; Male; Prostatic Neoplasms

Many naturally occurring compounds, including beta-phenylethyl isothiocyanate (PEITC) and curcumin, exhibit significant anti-cancer chemopreventive effects. In this study, we investigated the combined effects of PEITC and curcumin in PC-3 human prostate cancer cells and in PC-3 cells that were stably transfected with an NF-kappaB luciferase plasmid (PC-3 C4). We found an additive effect of PEITC and curcumin for the induction of apoptosis. To elucidate the potential mechanisms of this effect, we studied several critical cellular signaling pathways, including the critical NF-kappaB cell survival signal that is hyper-activated in PC-3 cells and many other cancers. PEITC and curcumin additively inhibited NF-kappaB luciferase activity. Furthermore, the combined treatment significantly increased the activity of poly(ADP-Ribose) polymerase and cleavage of caspase-3 in correlation with apoptotic cell death. Studying upstream signaling events, we found that the phosphorylations of IkappaBalpha and Akt (Ser473, Thr308) were significantly attenuated by the combination of PEITC and curcumin. As these events can be downstream of the activation of epidermal growth factor receptor (EGFR), we pretreated PC-3 cells with PEITC and curcumin and then stimulated them with EGF. EGFR phosphorylations (Y845 and Y1068) were dramatically suppressed by PEITC or curcumin, and more so by the combination. Importantly, the degree of Akt and PI3K phosphorylations induced by EGF were also significantly suppressed. We conclude that the simultaneous targeting of EGFR, Akt and NF-kappaB signaling pathways by PEITC and curcumin could be the molecular targets by which PEITC and curcumin exert their additive inhibitory effects on cell proliferation and ultimately lead to programmed cell death of tumor cells.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Drug Interactions; ErbB Receptors; Humans; Isothiocyanates; Luciferases; Male; NF-kappa B; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; Transfection; Tumor Cells, Cultured

Curcumin has become a focus of interest with regard to its antitumor effects in prostate cancer; however, the effects of this agent on invasion and metastasis remain less well understood. Matrix metalloproteinases (MMPs) are important prerequisite for tumor invasion and metastasis. In this study, we evaluated the effects of curcumin on prostate cancer cells (DU-145) invasion in both in vitro and in vivo. We utilized zymography and ELISA in order to determine the MMP-2 and MMP-9 activity. Matrigel invasion assay was performed to assess cellular invasion. We developed a xenograft model to examine tumorigenicity. Curcumin treatment resulted not only in a significant reduction in the expression of MMP-2 and MMP-9, but also effected the inhibition of invasive ability in vitro. Curcumin was shown to induce a marked reduction of tumor volume, MMP-2, and MMP-9 activity in the tumor-bearing site. The metastatic nodules in vivo were significantly fewer in the curcumin-treated group than untreated group. Curcumin appears to constitute a potential agent for the prevention of cancer progression, or at least of the initial phase of metastasis, in prostate cancer.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Caspase 3; Caspases; Cell Proliferation; Curcumin; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; In Vitro Techniques; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Neoplasm Invasiveness; Neoplasms, Experimental; Probability; Prostatic Neoplasms; Sensitivity and Specificity; Statistics, Nonparametric; Transplantation, Heterologous; Tumor Cells, Cultured

The anti-tumor potential of components from Chinese herbal medicines has been greatly concerned. Alisol B acetate, a triterpene from Alismatis rhizoma, induced apoptotic cell death in human hormone-resistant prostate cancer PC-3 cells in a time- and concentration-dependent manner. A good correlation between loss of mitochondrial membrane potential and apoptotic cell death was apparent indicating the participation of mitochondria-related mechanism. Alisol B acetate induced Bax up-regulation and nuclear translocation; it also induced the activation of initiator caspase-8 and caspase-9, and executor caspase-3, suggesting the involvement of both extrinsic and intrinsic apoptosis pathways. Taken together, it is suggested that alisol B acetate induces apoptosis in PC-3 cells via a mitochondria-mediated mechanism with activation of caspase-8, -9 and -3. Furthermore, the Bax activation and translocation from the cytosol to nucleus might be a crucial response to the apoptotic effect.

Topics: Alismataceae; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspases; Cell Nucleus; Cholestenones; Curcumin; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Male; Membrane Potentials; Mitochondria; Neoplasms, Hormone-Dependent; Nitric Oxide Synthase; Paclitaxel; Prostatic Neoplasms; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Triterpenes; Tumor Cells, Cultured

Earlier studies using prostate cancer cells in culture showed that phenethyl isothiocyanate (PEITC) and curcumin have significant chemopreventive and possibly chemotherapeutic effects. However, their in vivo effects are still lacking. Hence, this study was undertaken to determine the possible in vivo efficacy of prostate cancer-prevention as well as cancer-therapeutic treatment by PEITC and curcumin alone or in combination. We evaluated the effects on tumor growth in vivo, using NCr immunodeficient (nu/nu) mice bearing s.c. xenografts of PC-3 human prostate cancer cells. Molecular biomarkers representing proliferation and apoptosis were determined. Continued i.p. injection of curcumin or PEITC (6 and 5 mumol; thrice a week for 28 days), beginning a day before tumor implantation significantly retarded the growth of PC-3 xenografts. Combination of i.p. administration of PEITC (2.5 mumol) and curcumin (3 mumol) showed stronger growth-inhibitory effects. Next, we evaluated the cancer-therapeutic potential of curcumin and PEITC in mice with well-established tumors, and the results showed that PEITC or curcumin alone had little effect, whereas combination of curcumin and PEITC significantly reduced the growth of PC-3 xenografts. Immunohistochemistry staining and Western blot analysis revealed that the inhibition of Akt and nuclear factor-kappaB signaling pathways could contribute to the inhibition of cell proliferation and induction of apoptosis. Taken together, our results show that PEITC and curcumin alone or in combination possess significant cancer-preventive activities in the PC-3 prostate tumor xenografts. Furthermore, we found that combination of PEITC and curcumin could be effective in the cancer-therapeutic treatment of prostate cancers.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Curcumin; Immunocompromised Host; Immunohistochemistry; Infusions, Parenteral; Isothiocyanates; Male; Mice; Prostatic Neoplasms; Transplantation, Heterologous

4-Ethoxycarbonylethyl curcumin (ECECur) (3) is a current drug candidate for the treatment of prostate cancer. Due to problems inherent in the tautomerism of ECECur, 4-fluoro-4-ethoxycarbonylethyl curcumin (4) and 4-ethoxycarbonylethylenyl curcumin (5) were designed and synthesized. These two target compounds and their synthetic intermediates (4-9) were evaluated for their inhibitory activity against androgen receptor transcription in LNCaP and PC-3 prostate cancer cell lines. While the enol-keto analogs showed varying anti-androgen potencies, the di-keto analogs showed no activity. Tetrahydropyranylation of the phenoxy groups had a positive impact on the anti-AR activity of 4-ethoxycarbonylethylenyl curcumin, but a negative impact on the activity of ECECur. With potent anti-AR activity, di-tetrapyranylated 4-ethoxycarbonylethylenyl curcumin (9), which exists in only one form, is a good drug lead for further structural modification. Based on the SAR information obtained from the above study, five new compounds were designed and subsequently synthesized. Among them, compound 10 was found to be the most potent anti-AR agent and is considered to be a promising drug candidate for the treatment of prostate cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Humans; Magnetic Resonance Spectroscopy; Male; Prostatic Neoplasms; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship

To explore the apoptosis induction by curcumin in androgen-dependent prostate cancer cell line LNCaP).. After LNCaP cells were induced by 10, 25, 50, 75, 100 micromol/L curcumin respectively, the cell activity was assayed by MTT at 5, 12 and 24 hours. Flow cytometry and electronic microscopy were adopted to observe cell cycle and morphological changes of LNCaP cells at 24 hours. After 5 hours, the expression of IkappaBalpha in LNCaP cells was detected by Western blotting.. The growth of LNCaP cells was suppressed obviously by curcumin in dose-dependent and time-dependent manners in vitro. There were significant differences in inhibition rate among different concentrations and time groups (P < 0.05). Furthermore, curcumin could arrest the cell cycle of LNCaP cells at G2/M phase in a dose-dependent manner (P <0.01). The ratios of apoptosis were significantly higher than those of controls (P < 0. 5). Curcumin could lead to characteristic morphological changes of apoptosis in LNCaP cells after 24 hours. The expression of IkappaBalpha in LNCaP cell did not show marked changes after the exposure to different concentrations of curcumin within 5 hours.. Curcumin can suppress the growth of LNCaP, and promotes their apoptosis.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Humans; I-kappa B Proteins; Male; Neoplasms, Hormone-Dependent; NF-KappaB Inhibitor alpha; Prostatic Neoplasms

Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant molecular targets for drug development. In this study, we demonstrate that the small molecule natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that alpha, beta unsaturated carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degradation of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addition to inducing p300 degradation curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent association with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compound for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.

Topics: Antineoplastic Agents; Benzamides; Cell Cycle Proteins; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Histone Acetyltransferases; Humans; Isotope Labeling; Lymphocytes; Male; p300-CBP Transcription Factors; Prostatic Neoplasms; Proteasome Endopeptidase Complex; Pyridines; Transcription Factors; Tumor Cells, Cultured

In a continuing study of curcumin analogues as potential drug candidates to treat prostate cancer at both androgen-dependent and androgen-refractory stages, we designed and synthesized over 40 new analogues classified into four series: monophenyl analogues (series A), heterocycle-containing analogues (series B), analogues bearing various substituents on the phenyl rings (series C), and analogues with various linkers (series D). These new compounds were tested for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Antiandrogenic activity was also evaluated in LNCaP cells and PC-3 cells transfected with wild-type androgen receptor. Ten compounds possessed potent cytotoxicity against both LNCaP and PC-3 cells, seven only against LNCaP, and one solely against PC-3. This study established an advanced structure-activity relationship (SAR), and these correlations will guide the further design of new curcumin analogues with better anti-prostate cancer activity.

Topics: Androgen Antagonists; Antineoplastic Agents; Cell Line, Tumor; Curcumin; Drug Design; Drug Screening Assays, Antitumor; Genes, Reporter; Humans; Luciferases; Male; Mutation; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Receptors, Androgen; Structure-Activity Relationship; Transcriptional Activation; Transfection

To investigate the curcumin-induced the expression of IkappaBalpha in androgen-dependent (LNCaP) and androgen-independent (PC3) prostate cancer cells, and to study the mechanisms of curcumin on the proliferative inhibition of prostate cancer cells.. After LNCaP and PC3 cells were affected by 10, 25, 50, 75, 100 micromol/L curcumin respectively, the cell activity was assayed with methyl thiazolyl tetrazolium (MTT) method at 5, 12 and 24 hours; Flow cytometry was adopted to observe the cell cycle of LNCaP and PC3 cells at 24 hours. After 5 hours, the expression of IkappaBalpha in LNCaP and PC3 cells was observed with Western blotting.. Curcumin obviously suppressed the proliferation of LNCaP and PC3 cells in does-dependent and time-dependent manners. Curcumin could arrest the cell cycle of LNCaP and PC3 cells at G(2), M phase and then induce cell apoptosis. The expression of IkappaBalpha in LNCaP cells had no significant difference after using curcumin (F = 0.129, P > 0.05). However, the expression of IkappaBalpha in PC3 cells increased gradually with the inducement of concentration-increased curcumin (F = 31.618, P < 0.05).. IkappaBalpha may play a role in the curcumin inducing apoptosis of PC3 cell, while the curcumin inducing apoptosis of LNCaP cells is by antioxidation and inhibiting metabolites formation in LNCaP cells.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Humans; I-kappa B Proteins; Male; NF-KappaB Inhibitor alpha; Prostatic Neoplasms

To study the effect of curcumin on the apoptosis of prostate cancer cell line LNCaP and regulation of expression of maspin gene.. MTT and DNA electrophoresis were used to examine the cell growth and apoptosis of prostate cancer cell line LNCaP after treated with different doses of curcumin. The expression of maspin gene at transcription level and translation level was also detected by RT-PCR and Western blotting. pGL3-maspin luciferase expression vector, containing 847 bp (- 764 -/+ 83) DNA of maspin gene 5' promoter region, was transient transfected into LNCaP cell. Through detecting the activity of luciferase, the effect of curcumin on the promoter of maspin was studied.. Curcumin inhibited cell growth, induced the apoptosis and enhanced the expression of maspin gene in LNCaP cells.. Curcumin up-regulated expression of maspin gene in LNCaP cells through enhancing the transcription activity of promoter of maspin gene.

Topics: Androgen Receptor Antagonists; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Male; Promoter Regions, Genetic; Prostatic Neoplasms; Receptors, Androgen; RNA, Messenger; Serpins

In this study, we show that the novel synthetic curcumin analog, EF24, induces cell cycle arrest and apoptosis by means of a redox-dependent mechanism in MDA-MB-231 human breast cancer cells and DU-145 human prostate cancer cells. Cell cycle analysis demonstrated that EF24 causes a G2/M arrest in both cell lines, and that this cell cycle arrest is followed by the induction of apoptosis as evidenced by caspase-3 activation, phosphatidylserine externalization and an increased number of cells with a sub-G1 DNA fraction. In addition, we demonstrate that EF24 induces a depolarization of the mitochondrial membrane potential, suggesting that the compound may also induce apoptosis by altering mitochondrial function. EF24, like curcumin, serves as a Michael acceptor reacting with glutathione (GSH) and thioredoxin 1. Reaction of EF24 with these agents in vivo significantly reduced intracellular GSH as well as oxidized GSH in both the wild-type and Bcl-xL overexpressing HT29 human colon cancer cells. We therefore propose that the anticancer effect of a novel curcumin analog, EF24, is mediated in part by redox-mediated induction of apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspase 3; Caspases; Cell Cycle; Colonic Neoplasms; Curcumin; Female; Humans; Male; Oxidation-Reduction; Prostatic Neoplasms; Reactive Oxygen Species; Tumor Cells, Cultured

It is becoming increasingly recognized that hydrogen peroxide (HP) plays a role in cell proliferation and migration. In the present study we found that exogenous HP significantly induced human prostate cancer LNCaP cell proliferation and migration. Heparin affin regulatory peptide (HARP) seems to be involved in the stimulatory effect of HP, because the latter had no effect on stably transfected LNCaP cells that did not express HARP. Moreover, HP significantly increased HARP mRNA and protein amounts in a concentration- and time-dependent manner. Curcumin and activator protein-1 (AP-1) decoy oligonucleotides abrogated both HP-induced HARP expression and LNCaP cell proliferation and migration. HP increased luciferase activity of the 5'-flanking region of the HARP gene introduced in a reporter gene vector, an effect that was abolished when even one of the two putative AP-1 binding sites of the HARP promoter was mutated. The effect of HP seems to be due to the binding of Fra-1, JunD, and phospho-c-Jun to the HARP promoter. These results support the notion that HARP is important for human prostate cancer cell proliferation and migration, establish the role of AP-1 in the up-regulation of HARP expression by low concentrations of HP, and characterize the AP-1 dimers involved.

Topics: Base Sequence; Carrier Proteins; Cell Division; Cell Line, Tumor; Cell Movement; Curcumin; Cytokines; DNA; Gene Expression Regulation; Humans; Hydrogen Peroxide; Luciferases; Male; Molecular Sequence Data; Mutagenesis, Site-Directed; Oligodeoxyribonucleotides; Oligonucleotides, Antisense; Promoter Regions, Genetic; Prostatic Neoplasms; Protein Subunits; Recombinant Fusion Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription Factor AP-1; Transfection

Cyclooxygenase (COX) inhibitors have suppressive effects on several types of cancer cells including prostate cancer. In this study, we considered the potential COX-inhibitory activity of a unique anti-inflammatory herbal preparation (Zyflamend; New Chapter, Inc., Brattleboro, VT) and analyzed its effects on the human prostate cancer cell line LNCaP. COX inhibitory activity of Zyflamend was determined by a spectrophotometric-based assay using purified ovine COX-1 and COX-2 enzymes. Effects of Zyflamend on LNCaP cell growth and apoptosis in vitro were assessed by cell counting, Western blot detection of poly ADP-ribose polymerase (PARP) cleavage, and measurement of caspase-3 activity in treated and control cell extracts. Western blotting techniques were conducted to determine the effects of this herbal preparation on the expression of the cell signaling proteins, p21, androgen receptor (AR), phospho-protein kinase C (pPKC)(alpha/beta), and phospho (p)Stat3. The phospohorylation status of several signal transduction phosphoproteins was profiled using a high-throughput phosphoprotein screening assay in treated cells and compared to controls. Zyflamend dramatically decreased COX-1 and COX-2 enzymatic activity. Elevated p21 expression coincided with attenuated cell growth following treatment of LNCaP cells with Zyflamend. PARP cleavage fragments were evident, and caspase-3 activity was upregulated over the control indicating the ability of Zyflamend to induce apoptosis of these cells. Androgen receptor expression levels declined by 40%, and decreases were observed in the active forms of Stat3 and PKC(alpha/beta) in Zyflamend-treated LNCaP cells. Zyflamend inhibited both COX-1 and COX-2 enzymatic activities, suppressed cell growth, and induced apoptosis in LNCaP cells. However, our data suggests that the effects are likely due to COX-independent mechanisms potentially involving enhanced expression of p21 and reduced expression of AR, pStat3, and pPKC(alpha/beta).

Topics: Apoptosis; Blotting, Western; Caspase 3; Caspases; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Male; Plant Extracts; Prostatic Neoplasms

To study the effect of curcumin on the expression of prostate specific antigen (PSA).. AXSYM system-chemical luciferase method was used to examine the content of PSA in prostate cancer cell lines, LNCap after treated with different doses of curcumin. pGL3-PSA luciferase expression vector, containing 640 bp DNA of PSA gene 5' promoter region was constructed and transfected into LNCap cell with lipofectin. Through detecting the activity of luciferase, the effect of curcumin on the promoter of PSA was studied. Western blotting was used to detect expression of androgen receptor (AR) in LNCap cell with different concentrations of curcumin.. The expression of PSA was inhibited and activity of luciferase was reduced by curcumin. There was also significant difference in AR expression as shown by Western blotting experiment after treatment of different doses of curcumin.. Through inhibiting AR expression, curcumin reduced the function of PSA promoter and inhibited PSA protein expression.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Humans; Luciferases; Male; Promoter Regions, Genetic; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen

Failure to undergo apoptosis has been implicated in the resistance of tumor cells to anticancer therapies. Promotion of apoptosis in tumor cells could potentially increase the efficacy of conventional treatment regimens and improve prognosis. Prostate cancer cells are generally resistant to induction of apoptosis by anticancer agents and death ligands. We investigated the sensitization of prostate cancer cell lines by curcumin (diferuloyl-methane) to TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. Prostate cancer cells treated with curcumin or TRAIL or curcumin and TRAIL together were assessed for induction of apoptosis and pathway of apoptosis was determined from the activation of procaspases and release of cytochrome c from mitochondria. Curcumin sensitized LNCaP, DU145 and PC3 tumor cell lines to TRAIL. Combined curcumin and TRAIL treatment produced the most loss of viable cells by inducing apoptosis as revealed by accumulation of hypodiploid cells in sub-G1 phase, enhanced annexin V binding, DNA fragmentation, cleavage of procaspases-3, -8, and 9, truncation of proapoptotic Bid, and release of cytochrome c from mitochondria. Tumor cells expressed constitutively active NF-kappaB and sensitization to TRAIL involved inhibition of NF-kappaB by curcumin. These findings suggest that combined curcumin/TRAIL chemo-immunotherapy may be a beneficial adjunct to the standard therapeutic regimens for prostate cancer.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Caspase 3; Caspase 8; Caspases; Cell Line, Tumor; Curcumin; Drug Synergism; G1 Phase; Humans; Male; Membrane Glycoproteins; NF-kappa B; Prostatic Neoplasms; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

Curcumin (Diferuloylmethane) is a major chemical component of turmeric (curcuma longa) and is used as a spice to give a specific flavor and yellow color in Asian food. Curcumin exhibits growth inhibitory effects in a broad range of tumors as well as in TPA-induced skin tumors in mice. This study was undertaken to investigate the radiosensitizing effects of curcumin in p53 mutant prostate cancer cell line PC-3. Compared to cells that were irradiated alone (SF(2)=0.635; D(0)=231 cGy), curcumin at 2 and 4 microM concentrations in combination with radiation showed significant enhancement to radiation-induced clonogenic inhibition (SF(2)=0.224: D(0)=97 cGy and SF(2)=0.080: D(0)=38 cGy) and apoptosis. It has been reported that curcumin inhibits TNF-alpha-induced NFkappaB activity that is essential for Bcl-2 protein induction. In PC-3 cells, radiation upregulated TNF-alpha protein leading to an increase in NFkappaB activity resulting in the induction of Bcl-2 protein. However, curcumin in combination with radiation treated showed inhibition of TNF-alpha-mediated NFkappaB activity resulting in bcl-2 protein downregulation. Bax protein levels remained constant in these cells after radiation or curcumin plus radiation treatments. However, the downregulation of Bcl-2 and no changes in Bax protein levels in curcumin plus radiation-treated PC-3 cells, together, altered the Bcl2 : Bax ratio and this caused the enhanced radiosensitization effect. In addition, significant activation of cytochrome c and caspase-9 and -3 were observed in curcumin plus radiation treatments. Together, these mechanisms strongly suggest that the natural compound curcumin is a potent radiosesitizer, and it acts by overcoming the effects of radiation-induced prosurvival gene expression in prostate cancer.

Topics: Apoptosis; Caspases; Cell Line, Tumor; Combined Modality Therapy; Curcumin; Cyclin D1; Cytochromes c; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Gene Expression Regulation, Neoplastic; Humans; Male; NF-kappa B; Prostatic Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Radiation, Ionizing; Tumor Necrosis Factor-alpha

There is increasing evidence that the stringent selective pressure imposed by androgen ablation therapy on the residual prostate cancer cells may actually accelerate the development of the hormone refractory and bone metastatic phenotype. The propensity of prostate cancer to establish osseous metastases is very likely mediated by the osteomimetic properties of the prostate cancer cells. Prostate cancer cells acquire these "bone-like" properties in order to survive in the bony microenvironment. This process is facilitated by common growth factor trophisms between the bone stromal cells, osteoblasts, and the prostate cancer cells wherein a number of growth factors and their receptors are involved. Thus, a general inhibition of the tyrosine kinase signaling pathways may have a therapeutic advantage in interfering with the metastatic potential of these prostate cancer cells. This study focuses on the potential of curcumin, a plant based non-toxic tyrosine kinase inhibitor in interfering with the development of bone like properties of C4-2B, a highly metastatic derivative of LNCaP prostate cancer cell line.. C4-2B prostate cancer cells were analyzed for their constitutive expression and ligand inducible activation of growth factor receptors such as EGF-R and CSF1-R. Expression of bone-specific transcription factors such as Cbfa-1 and the production of PTHRP were followed. The ability of the C4-2B cells to mineralize under specific conditions was analyzed. The activation status of the transcription factor NF-kappa B was also followed.. Curcumin inhibited the ligand-stimulated autophosphorylation of EGF-R and CSF1-R that were crucially involved in the development of osteomimetic properties of C4-2B cells. When C4-2B cells were grown under promineralization conditions, curcumin prevented the formation of the mineralized nodules. It also inhibited the expression of the core-binding factor a-1 in C4-2B cells which was responsible for the expression of several bone-specific proteins. The IKK activity was severely impaired, showing marked NF-kappa B inhibition. The experiments indicate that curcumin can also interfere with the development of the osteoblast and the osteoclast-like properties by these prostate cancer cells.. The highly metastatic C4-2B prostate cancer cell line is already "programmed" to exhibit the bone-like properties that would at least in part explain its affinity to set up osseous metastases. Curcumin is able to interfere with the osteoblastic component as well as the osteoclastic component of this phenotype, by interfering with the growth factor receptor pathways and by inhibiting the NF-kappa B activation process. It is concluded that curcumin may inhibit the growth factor collaboration between the prostate cancer cells and the osteoblast/stromal cells, thus exhibiting a potential to prevent the establishment of bony metastases.

Topics: Antineoplastic Agents; Bone Neoplasms; Cell Communication; Cell Survival; Curcumin; ErbB Receptors; Humans; Male; Osteoblasts; Phenotype; Prostatic Neoplasms; Receptor, Macrophage Colony-Stimulating Factor; Tumor Cells, Cultured

Curcumin is a dietary phytochemical associated with anti-tumorigenic effects, but the mechanisms by which it inhibits cancer cell growth and metastasis are not completely understood. For example, little information is available regarding the effects of curcumin on cytoskeletal organization and function. In this study, time-lapse video and immunofluorescence labeling methods were used to demonstrate that curcumin significantly alters microfilament organization and cell motility in PC-3 and LNCaP human prostate cancer cells in vitro. Curcumin rapidly arrests cell movements and subsequently alters cell shape in the highly motile PC-3 cell line, but has a less noticeable effect on the relatively immobile LNCaP cell line. Stress fibers are augmented, and the overall quantity of f-actin appears to increase in both types of cells following curcumin treatment. Cytochalasin B (CB) disrupts microfilament organization in both cell lines, and causes vigorous membrane blebbing in PC-3 cells, but not LNCaP cells. Pre-treatment of cells with curcumin suppresses changes in microfilament organization caused by CB, and blocks PC-3 membrane blebbing. At least some of the effects of curcumin appear to be mediated by protein kinase C (PKC), as treatment with the PKC inhibitor bisindolylmaleimide inhibits the ability of curcumin to block CB-induced membrane blebbing. These findings demonstrate that curcumin exerts significant effects on the actin cytoskeleton in prostate cancer cells, including altering microfilament organization and function. This is a novel observation that may represent an important mechanism by which curcumin functions as a chemopreventative agent, and as an inhibitor of angiogenesis and metastasis.

Topics: Actin Cytoskeleton; Antineoplastic Agents; Cell Culture Techniques; Cell Line, Tumor; Cell Movement; Curcumin; Humans; Male; Microscopy, Interference; Prostatic Neoplasms; Time Factors

Epidemiologic studies suggest that diet rich in plant-derived foods plays an important role in the prevention of prostate cancer. Curcumin, the yellow pigment in the spice turmeric, has been shown to exhibit chemopreventive and growth inhibitory activities against multiple tumor cell lines. We have shown previously that curcumin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L interact to induce cytotoxicity in the LNCaP prostate cancer cell line. In this study, we investigated the mechanism by which curcumin augments TRAIL-induced cytotoxicity in LNCaP cells. Subtoxic concentrations of the curcumin-TRAIL combination induced strong apoptotic response in LNCaP cells as demonstrated by the binding of Annexin V-FITC and cleavage of procaspase-3. Furthermore, LNCaP cells express constitutively active nuclear factor-kappaB (NF-kappaB), which is inhibited by curcumin. Because NF-kappaB has been shown to mediate resistance to TRAIL-induced apoptosis in tumor cells, we investigated whether there is a relationship between NF-kappaB activation and resistance to TRAIL in LNCaP prostate cancer cells. Pretreatment with curcumin inhibited the activation of NF-kappaB and sensitized LNCaP cells to TRAIL. A similar increase in the sensitivity of LNCaP cells to TRAIL-induced apoptosis was observed following inhibition of NF-kappaB by dominant negative mutant IkappaBalpha, an inhibitor of NF-kappaB. Finally, curcumin was found to inhibit NF-kappaB by blocking phosphorylation of IkappaBalpha. We conclude that NF-kappaB mediates resistance of LNCaP cells to TRAIL and that curcumin enhances the sensitivity of these tumor cells to TRAIL by inhibiting NF-kappaB activation by blocking phosphorylation of IkappaBalpha and its degradation.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Nucleus; Curcumin; Drug Resistance, Neoplasm; Humans; I-kappa B Proteins; Male; Membrane Glycoproteins; Mutation; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Prostatic Neoplasms; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

Prostate cancer is an important public health problem in the United States. Seven phytoestrogens found in common herbal products were screened for estrogen receptor binding and growth inhibition of androgen-insensitive (PC-3) and androgen-sensitive (LNCaP) human prostate tumor cells. In a competitive 3H-estradiol ligand binding assay using mouse uterine cytosol, 2.5 M quercetin, baicalein, genistein, epigallocatechin gallate (EGCG), and curcumin displaced > 85% of estradiol binding, whereas apigenin and resveratrol displaced > 40%. From growth inhibition studies in LNCaP cells, apigenin and curcumin were the most potent inhibitors of cell growth, and EGCG and baicalein were the least potent. In PC-3 cells, curcumin was the most potent inhibitor of cell growth, and EGCG was the least potent. In both cell lines, significant arrest of the cell cycle in S phase was induced by resveratrol and EGCG and in G2M phase by quercetin, baicalein, apigenin, genistein, and curcumin. Induction of apoptosis was induced by all of the 7 compounds in the 2 cell lines as shown by TUNEL and DNA fragmentation assays. Androgen responsiveness of the cell lines did not correlate with cellular response to the phytoestrogens. In conclusion, these 7 phytoestrogens, through different mechanisms, are effective inhibitors of prostate tumor cell growth.

Topics: Antineoplastic Agents, Hormonal; Catechin; Cell Cycle; Cell Division; Curcumin; DNA Fragmentation; Humans; Male; Phytoestrogens; Prostatic Neoplasms; Quercetin; Receptors, Estrogen; Resveratrol; Stilbenes; Tumor Cells, Cultured

The role of natural food products in prevention of prostate cancer has been confirmed in recent epidemiological studies; however, the mechanism of chemoprevention by the dietary constituents largely remains unknown. Curcumin, the yellow pigment and active component of turmeric (Curcuma longa), exhibits chemopreventive and growth inhibitory activity against several tumor cell lines. The androgen-sensitive human prostate cancer cell line LNCaP is only slightly susceptible to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor family of cell death-inducing ligands. In this study, we investigated whether curcumin and TRAIL cooperatively interact to promote death of LNCaP cells. At low concentrations (10 micro M curcumin and 20 ng/ml TRAIL), neither of the two agents alone produced significant cytotoxicity (curcumin, <10%; TRAIL, approximately 15%) in LNCaP cells, as measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium dye reduction assay. On the other hand, cell death was markedly enhanced (2-3-fold) if tumor cells were treated with curcumin and TRAIL together. The combined curcumin and TRAIL treatment increased the number of hypodiploid cells and induced DNA fragmentation in LNCaP cells. The combined treatment induced cleavage of procaspase-3, procaspase-8, and procaspase-9, truncation of Bid, and release of cytochrome c from the mitochondria, indicating that both the extrinsic (receptor-mediated) and intrinsic (chemical-induced) pathways of apoptosis are triggered in prostate cancer cells treated with a combination of curcumin and TRAIL. These results define a potential use of curcumin to sensitize prostate cancer cells for TRAIL-mediated immunotherapy.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Caspase 3; Caspases; Cell Survival; Curcumin; Humans; Male; Membrane Glycoproteins; Prostatic Neoplasms; Resveratrol; Stilbenes; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in several human tumors both in vitro and in vivo, however, some tumors remain resistant for poorly understood reasons. Using a quantitative DNA fragmentation assay for apoptosis, we have shown that human prostate cancer cells are resistant to a wide range of TRAIL doses up to 500 ng/ml. However, translation inhibitors, such as anisomycin, cycloheximide, emetine, harringtonine, and puromycin, unlike several transcription inhibitors, significantly sensitized PC3-neomycin (PC3-neo) cells to TRAIL-induced apoptosis. These effects were inhibited in PC3 cells engineered to express bcl2 (PC3-bcl2). Translation inhibitors led to activation of c-Jun N-terminal kinase (JNK), which plays a role in this sensitization process because inhibition of JNK activation resulted in protection against TRAIL plus translation inhibitor-induced apoptosis. JNK activation may be required for this process, but it is not sufficient because activation of JNK using an MEKK2 expression vector did not mimic the sensitizing effect of translation inhibitors. Other stress-activated protein kinases, such as ERK and p38, play an insignificant role in determining the apoptotic sensitivity. We conclude that activation of JNK is required for sensitization of PC3 cells to TRAIL-induced apoptosis by translation inhibitors in cells that are otherwise TRAIL-resistant. However, in addition to JNK activation, other aspects of translation inhibition such as the suppressed activity of apoptosis-inhibitory proteins or activation of other signal transduction pathways must also be involved.

Topics: Activating Transcription Factor 2; Anisomycin; Apoptosis; Apoptosis Regulatory Proteins; Curcumin; Cyclic AMP Response Element-Binding Protein; Cycloheximide; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Genetic Vectors; Humans; Imidazoles; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Kinase Kinase 2; MAP Kinase Kinase Kinases; Membrane Glycoproteins; Mitogen-Activated Protein Kinases; Peptide Fragments; Prostatic Neoplasms; Protein Biosynthesis; Protein Synthesis Inhibitors; Pyridines; TNF-Related Apoptosis-Inducing Ligand; Transcription Factors; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Although curcumin has been shown to inhibit prostate tumor growth in animal models, its mechanism of action is not clear. To better understand the anti-cancer effects of curcumin, we investigated the effects of curcumin on cell survival factor Akt in human prostate cancer cell lines, LNCaP, PC-3, and DU-145. Our results demonstrated differential activation of Akt. Akt was constitutively activated in LNCaP and PC-3 cells. Curcumin inhibited completely Akt activation in both LNCaP and PC-3 cells. The presence of 10% serum decreased the inhibitory effect of curcumin in PC-3 cells whereas complete inhibition was observed in 0.5% serum. Very little or no activation of Akt was observed in serum starved DU-145 cells (0.5% serum). The presence of 10% serum activated Akt in DU-145 cells and was not inhibited by curcumin. Results suggest that one of the mechanisms of curcumin inhibition of prostate cancer may be via inhibition of Akt. To our knowledge this is the first report on the curcumin inhibition of Akt activation in LNCaP and PC-3 but not in DU-145 cells.

Topics: Antineoplastic Agents; Becaplermin; Cell Survival; Culture Media; Curcumin; Enzyme Activation; Enzyme Inhibitors; Fibroblast Growth Factor 2; Humans; Male; Platelet-Derived Growth Factor; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Signal Transduction; Tumor Cells, Cultured

Curcumin, traditionally used as a seasoning spice in Indian cuisine, has been reported to decrease the proliferation potential of prostate cancer cells, by a mechanism that is not fully understood. In the current study, we have evaluated the effects of curcumin in cell growth, activation of signal transduction, and transforming activities of both androgen-dependent and independent cell lines. Prostate cancer cell lines, LNCaP and PC-3, were treated with curcumin and its effects were further analyzed on signal transduction and expression of androgen receptor (AR) and AR-related cofactors using transient transfection assay and Western blotting. Our results show that curcumin down-regulates transactivation and expression of AR, activator protein-1 (AP-1), nuclear factor-kappaB (NF-kappaB), and CREB (cAMP response element-binding protein)-binding protein (CBP). Curcumin also inhibited the transforming activities of both cell lines as evidenced by the reduced colony forming ability in soft agar. The results obtained here demonstrate that curcumin has a potential therapeutic effect on prostate cancer cells through down-regulation of AR and AR-related cofactors (AP-1, NF-kappaB and CBP).

Topics: Antineoplastic Agents; Curcumin; Dose-Response Relationship, Drug; Down-Regulation; Humans; Male; NF-kappa B; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Transcription Factor AP-1; Transfection; Tumor Cells, Cultured

A number of curcumin analogues were prepared and evaluated as potential androgen receptor antagonists against two human prostate cancer cell lines, PC-3 and DU-145, in the presence of androgen receptor (AR) and androgen receptor coactivator, ARA70. Compounds 4 [5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one], 20 [5-hydroxy-1,7-bis[3-methoxy-4-(methoxycarbonylmethoxy)phenyl]-1,4,6-heptatrien-3-one], 22 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]-5-oxohepta-4,6-dienoic acid ethyl ester], 23 [7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-methoxyphenyl)acryloyl]5-oxohepta-4,6-dienoic acid], and 39 [bis(3,4-dimethoxyphenyl)-1,3-propanedione] showed potent antiandrogenic activities and were superior to hydroxyflutamide, which is the currently available antiandrogen for the treatment of prostate cancer. Structure-activity relationship (SAR) studies indicated that the bis(3,4-dimethoxyphenyl) moieties, the conjugated beta-diketone moiety, and the intramolecular symmetry of the molecules seem to be important factors related to antiandrogenic activity. The data further suggest that the coplanarity of the beta-diketone moiety and the presence of a strong hydrogen bond donor group were also crucial for the antiandrogenic activity, which is consistent with previous SAR results for hydroxyflutamide analogues. When the pharmacophoric elements of dihydrotestosterone (DHT) and compound 4 are superposed, the resulting construct implies that the curcumin analogues may function as a 17alpha-substituted DHT. Compounds 4, 20, 22, 23, and 39 have been identified as a new class of antiandrogen agents, and these compounds or their new synthetic analogues could be developed into clinical trial candidates to control androgen receptor-mediated prostate cancer growth.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Antineoplastic Agents; Curcumin; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Prostatic Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

The modulatory effects and molecular mechanisms of curcumin (CCM) on the cytotoxicity of chemotherapeutic agents to prostate cancer cells were explored.. The combined effects of CCM and chemotherapeutic agents were examined by three different administration schedules (one concurrent and two sequential treatments) in two androgen-independent prostate cancer (AIPC) cells (PC-3 and DU145). Alteration of cell cycle progression, protein levels, and transcriptional activation in PC-3 cells were assayed by flow cytometry, Western blotting, and gel shift assay, respectively.. The combined effects of CCM --> chemotherapeutic agent schedule showed the greatest synergistic cytotoxicity when compared to the other two schedules in both cells. CCM induced a significant G1 arrest in PC-3, which may be mediated by the induction of p21(WAF1/CIP1) and C/EBPbeta. Moreover, CCM was able to inhibit both the constitutional and TNF-alpha-induced NF-kappaB activation in a time-dependent manner.. The incorporation of CCM into cytotoxic therapies may be a promising strategy for the treatment of AIPC.

Topics: Antineoplastic Agents; CCAAT-Enhancer-Binding Protein-beta; Cell Cycle; Cell Nucleus; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; DNA; Drug Synergism; Humans; Male; NF-kappa B; Pregnancy-Specific beta 1-Glycoproteins; Prostatic Neoplasms; Sp1 Transcription Factor; Tumor Cells, Cultured; Up-Regulation

The chemopreventive efficacy of lycopene and curcumin with regard to prostate carcinogenesis was investigated using 3,2'-dimethyl-4-aminobiphenol (DMAB)- and 2-amino-1-methylimidazo[4,5-b]pyridine (PhIP)-induced rat ventral prostate cancer models. Three 60 week experiments with male F344 rats were carried out. In the first DMAB was given for the first 20 weeks and lycopene or curcumin were administered concomitantly or subsequently at dietary doses of 15 and 500 p.p.m., respectively. In the second experiment lycopene and curcumin were given to rats pretreated with DMAB at doses of 5, 15 or 45 p.p.m. or 100 or 500 p.p.m. In the third PhIP was selected as an initiator for prostate carcinogenesis and administered for 20 weeks. Rats were then fed a diet containing lycopene at a dose of 45 p.p.m. or curcumin at a dose of 500 p.p.m. or both together. Chemopreventive effects of lycopene and curcumin on development of DMAB-induced ventral prostate carcinomas were observed only in the first experiment and no confirmation of inhibition potential was obtained in the following studies. Neither summational nor synergistic chemoprevention was evident. It is concluded from the present data that, overall, neither lycopene nor curcumin can consistently prevent rat prostate carcinogenesis.

Topics: Aminobiphenyl Compounds; Animals; Anticarcinogenic Agents; Carcinogens; Carotenoids; Curcumin; Imidazoles; Lycopene; Male; Prostatic Neoplasms; Rats; Rats, Inbred F344

Earlier work from our laboratory highlighted the therapeutic potential of curcumin (turmeric), used as a dietary ingredient and as a natural anti-inflammatory agent in India and other Southeast Asian countries. This agent was shown to decrease the proliferative potential and induce the apoptosis potential of both androgen-dependent and androgen-independent prostate cancer cells in vitro, largely by modulating the apoptosis suppressor proteins and by interfering with the growth factor receptor signaling pathways as exemplified by the EGF-receptor. To extend these observations made in vitro and to study the efficacy of this potential anti-cancer agent in vivo, the growth of LNCaP cells as heterotopically implanted tumors in nude mice was followed.. The androgen-dependent LNCaP prostate cancer cells were grown, mixed with Matrigel and injected subcutaneously into nude mice. Experimental group received a synthetic diet containing 2% curcumin for up to 6 weeks. At the end point, sections taken from the excised tumors were evaluated for pathology, cell proliferation, apoptosis, and vascularity.. Curcumin causes a marked decrease in the extent of cell proliferation as measured by the BrdU incorporation assay and a significant increase in the extent of apoptosis as measured by an in situ cell death assay. Moreover, a significant decrease in the microvessel density as measured by the CD31 antigen staining was also seen.. Curcumin could be a potentially therapeutic anti-cancer agent, as it significantly inhibits prostate cancer growth, as exemplified by LNCaP in vivo, and has the potential to prevent the progression of this cancer to its hormone refractory state.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Division; Curcumin; Growth Inhibitors; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mice; Mice, Nude; Neovascularization, Pathologic; Prostatic Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

While the role of nuclear transcription factor activator protein-1 (AP-1) in cell proliferation, and of nuclear factor-kappaB (NF-kappaB) in the suppression of apoptosis are known, their role in survival of prostate cancer cells is not well understood. We investigated the role of NF-kappaB and AP-1 in the survival of human androgen-independent (DU145) and -dependent (LNCaP) prostate cancer cell lines. Our results show that the faster rate of proliferation of DU145 cells when compared to LNCaP cells correlated with the constitutive expression of activated NF-kappaB and AP-1 in DU-145 cells. The lack of constitutive expression of NF-kappaB and AP-1 in LNCaP cells also correlated with their sensitivity to the antiproliferative effects of tumor necrosis factor (TNF). TNF induced NF-kappaB activation but not AP-1 activation in LNCaP cells. In DU145 cells both c-Fos and c-Jun were expressed and treatment with TNF activated c-Jun NH2-terminal kinase (JNK), needed for AP-1 activation. In LNCaP cells, however, only low levels of c-Jun was expressed and treatment with TNF minimally activated JNK. Treatment of cells with curcumin, a chemopreventive agent, suppressed both constitutive (DU145) and inducible (LNCaP) NF-kappaB activation, and potentiated TNF-induced apoptosis. Curcumin alone induced apoptosis in both cell types, which correlated with the downregulation of the expression of Bcl-2 and Bcl-xL and the activation of procaspase-3 and procaspase-8. Overall, our results suggest that NF-kappaB and AP-1 may play a role in the survival of prostate cancer cells, and curcumin abrogates their survival mechanisms.

Topics: Antineoplastic Agents; Apoptosis; bcl-X Protein; Caspase 3; Caspase 8; Caspase 9; Caspases; Cell Division; Cell Survival; Curcumin; Down-Regulation; Enzyme Precursors; Humans; JNK Mitogen-Activated Protein Kinases; Male; Mitogen-Activated Protein Kinases; NF-kappa B; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Transcription Factor AP-1; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

In a search for alternative and preventive therapies for prostate cancer, attention was focused on the ways in which curcumin (Turmeric), used in food and medicine in India for centuries, could interfere with the growth factor signaling pathways in both androgen-dependent and androgen-independent prostate cancer cells, as exemplified by the epidermal growth factor receptor (EGF-R) signaling.. The androgen-sensitive LNCaP and androgen-insensitive PC-3 cell lines were grown in 5 to 50 microM curcumin and analyzed for EGF-R protein by Western blotting and for EGF-R tyrosine kinase activity.. Curcumin was a potent inhibitor of EGF-R signaling, and it accomplished this effect by three different means (1) down regulating the EGF-R protein; (2) inhibiting the intrinsic EGF-R tyrosine kinase activity; and (3) inhibiting the ligand-induced activation of the EGF-R.. These results, taken together with our previous results that curcumin can induce apoptosis in both androgen-dependent and androgen-independent prostate cancer cells, support our view that curcumin may be a novel modality by which one can interfere with the signal transduction pathways of the prostate cancer cell and prevent it from progressing to its hormone-refractory state.

Topics: Androgens; Antineoplastic Agents; Curcumin; ErbB Receptors; Humans; Male; Prostatic Neoplasms; Receptor Protein-Tyrosine Kinases; Signal Transduction; Tumor Cells, Cultured