curcumin and Lung-Neoplasms

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

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

Researchers have made crucial advances in understanding the pathogenesis and therapeutics of non-small cell lung cancer (NSCLC), improving our understanding of lung tumor biology and progression. Although the survival of NSCLC patients has improved due to chemoradiotherapy, targeted therapy, and immunotherapy, overall NSCLC recovery and survival rates remain low. Thus, there is an urgent need for the continued development of novel NSCLC drugs or combination therapies with less toxicity. Although the anticancer effectiveness of curcumin (Cur) and some Cur analogs has been reported in many studies, the results of clinical trials have been inconsistent. Therefore, in this review, we collected the latest related reports about the anti-NSCLC mechanisms of Cur, its analogs, and Cur in combination with other chemotherapeutic agents via the Pubmed database (accessed on 18 June 2022). Furthermore, we speculated on the interplay of Cur and various molecular targets relevant to NSCLC with discovery studio and collected clinical trials of Cur against NSCLC to clarify the role of Cur and its analogs in NSCLC treatment. Despite their challenges, Cur/Cur analogs may serve as promising therapeutic agents or adjuvants for lung carcinoma treatment.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Humans; Lung Neoplasms; Motivation

Lung cancer remains the most common cancer worldwide. Although significant advances in screening have been made and early diagnosis strategies and therapeutic regimens have been developed, the overall survival rate remains bleak. Curcumin is extracted from the rhizomes of turmeric and exhibits a wide range of biological activities. In lung cancer, evidence has shown that curcumin can markedly inhibit tumor growth, invasion and metastasis, overcome resistance to therapy, and even eliminate cancer stem cells (CSCs). Herein, the underlying molecular mechanisms of curcumin were summarized by distinct biological processes. To solve the limiting factors that curtail the clinical applications of curcumin, nanoformulations encapsulating curcumin were surveyed in detail. Nanoparticles, including liposomes, micelles, carbon nanotubes (CNTs), solid lipid nanoparticles (SLNs), nanosuspensions, and nanoemulsions, were explored as proper carriers of curcumin. Moreover, it was firmly verified that curcumin has the ability to sensitize lung cancer cells to chemotherapeutic drugs, such as cisplatin and docetaxel, and to various targeted therapies. Regarding the advantages and drawbacks of curcumin, we concluded that combination therapy based on nanoparticles would be the optimal approach to broaden the application of curcumin in the clinic in the near future.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemistry, Pharmaceutical; Curcuma; Curcumin; Drug Delivery Systems; Humans; Lung Neoplasms; Nanoparticles

Non-small-cell lung carcinoma (NSCLC) is one of the most lethal malignancies that include more than 80% of lung cancer cases worldwide. During the past decades, plants and plant-derived products have attracted great interest in the treatment of various human diseases. Curcumin, the turmeric isolated natural phenolic compound, has shown a promising chemo-preventive and anticancer agent. Numerous studies have shown that curcumin delays the initiation and progression of NSCLC by affecting a wide range of molecular targets and cell signalling pathways including NF-kB, Akt, MAPKS, BCL-2, ROS and microRNAs (miRNAs). However, the poor oral bioavailability and low chemical stability of curcumin remain as major challenges in the utilisation of this compound as a therapeutic agent. Different analogs of curcumin and new delivery systems (e.g., micelles, nanoparticles and liposomes) provided promising solutions to overcome these obstacles and improve curcumin pharmacokinetic profile. The present review focuses on current reported studies about anti-NSCLC effects of curcumin. NSCLC involved miRNAs whose expression is regulated by curcumin has also been discussed. Furthermore, recent researches on the use of curcumin analogs and delivery systems to enhance the curcumin benefits in NSCLC are also described.

Topics: Antineoplastic Agents, Phytogenic; Biological Availability; Carcinoma, Non-Small-Cell Lung; Curcumin; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; MicroRNAs; Nanoparticles; Signal Transduction

Lung cancer is a main cause of death all over the world with a high incidence rate. Metastasis into neighboring and distant tissues as well as resistance of cancer cells to chemotherapy demand novel strategies in lung cancer therapy. Curcumin is a naturally occurring nutraceutical compound derived from Curcuma longa (turmeric) that has great pharmacological effects, such as anti-inflammatory, neuroprotective, and antidiabetic. The excellent antitumor activity of curcumin has led to its extensive application in the treatment of various cancers. In the present review, we describe the antitumor activity of curcumin against lung cancer. Curcumin affects different molecular pathways such as vascular endothelial growth factors, nuclear factor-κB (NF-κB), mammalian target of rapamycin, PI3/Akt, microRNAs, and long noncoding RNAs in treatment of lung cancer. Curcumin also can induce autophagy, apoptosis, and cell cycle arrest to reduce the viability and proliferation of lung cancer cells. Notably, curcumin supplementation sensitizes cancer cells to chemotherapy and enhances chemotherapy-mediated apoptosis. Curcumin can elevate the efficacy of radiotherapy in lung cancer therapy by targeting various signaling pathways, such as epidermal growth factor receptor and NF-κB. Curcumin-loaded nanocarriers enhance the bioavailability, cellular uptake, and antitumor activity of curcumin. The aforementioned effects are comprehensively discussed in the current review to further direct studies for applying curcumin in lung cancer therapy.

Topics: Antineoplastic Agents; Apoptosis; Curcumin; Drug Synergism; ErbB Receptors; Humans; Lung Neoplasms

Topics: Alzheimer Disease; Animals; Curcuma; Curcumin; Disease Models, Animal; Heart Diseases; Humans; Liver Diseases; Lung Neoplasms; Medicine, Ayurvedic; Osteoarthritis; Phytotherapy

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biological Availability; Cell Proliferation; Clinical Trials as Topic; Curcumin; Humans; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Signal Transduction

Integrins are cell-matrix adhesion molecules providing both mechanical engagement of cell to extracellular matrix, and generation of cellular signals that are implicated in cancer malignancies. The concept that integrins play important roles in cell survival, proliferation, motility, differentiation, and ensuring appropriate cell localization, leads to the hypothesis that inhibition of certain integrins would benefit cancer therapy. In lung cancer, integrins αv, α5, β1, β3, and β5 have been shown to augment survival and metastatic potential of cancer cells. This review presents data suggesting integrins as molecular targets for anti-cancer approaches, and the mechanisms through which integrins confer resistance of lung cancer to chemotherapeutics and metastasis. The better understanding of these key molecules may benefit the discovery of anti-cancer drugs and strategies.

Topics: Antineoplastic Agents; Cell Adhesion; Cell Differentiation; Cell Proliferation; Cell Survival; Curcumin; Disease Progression; Extracellular Matrix; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Integrins; Lung Neoplasms; Neoplasm Metastasis; Ouabain; Phloretin; Xanthones

Lung cancer is one of the most common types of cancer worldwide and is characterized by a poor prognosis, related to both late diagnosis and lack of effective treatments. In the last years, microRNAs (miRNAs) have been demonstrated to have an important role in tumor microenvironment and immune regulation. These RNAs can be categorized into tumor-suppressor genes, such as let-7 family and miR-34, and oncogenes such as miR-221 and miR-222. Curcumin is a bioactive polyphenol that is documented to have promising anticancer activity, and to be well tolerated in humans.. The present review aims to gather available evidence on the involvement of mRNAs in the therapeutic effects of curcumin against lung cancer.. The anti-cancer properties of curcumin against lung cancer have been shown in both cellular and experimental models and are mediated by modulation of several molecular targets that regulate the expression of transcription factors, inflammatory cytokines, enzymes, growth factors, receptors, adhesion molecules, antiapoptotic proteins, and cell cycle proteins, leading to cell apoptosis, inhibition of cell proliferation and migration, and also chemo- and radio-sensitization of lung cancer cells. Recent studies have documented that pharmacological effects of curcumin in lung cancer are also mediated by modulation of several miRNAs, such as downregulation of oncogenic miR-21 and upregulation of oncosuppressive miR-192-5p and miR-215.. Further studies are necessary to explore this very promising field and the link between regulation of oncogenic and tumor-suppressive miRNAs and putative anti-cancer properties of curcumin.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Curcumin; Humans; Lung Neoplasms; MicroRNAs

Lung cancer is among the leading causes of cancer-related-death. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. More than 70% of NSCLC patients have locally advanced or metastatic disease in diagnosis stage, which are then being treated with platinum-based chemotherapy or epidermal-growthfactor- receptor (EGFR) inhibitors. Several molecules which target multiple ErbB receptors and EGFR have been developed, including gefitinib and erlotinib. Identification of novel agents with less toxicity is warranted. Several interesting data have been reported about the antitumor activity of curcumin in several tumors, including lung, breast and colorectal cancers. In particular, a recent phase I trial evaluated the activity of curcumin in combination with FOLFOX chemotherapy in patients with inoperable colorectal cancer. They showed that curcumin added benefit in subsets of patients when administered with FOLFOX and was well-tolerated chemotherapy adjunct. Another ongoing trial is now investigating the beneficial effects of curcumin plus gefitinib or erlotinib for EGFRmutant NSCLC. Improved understanding of molecular mechanisms behind resistance to EGFR tyrosine kinase inhibitors suggests the importance of a genotype-guided approach to therapy and inhibition of parallel and downstream pathways, using agents which target heat-shock-protein-90, poly (ADP-ribose) polymerase and PI3K/mTOR pathway. The aim of the current review is to give an overview of the possible molecular mechanisms of curcumin in the preclinical and clinical investigations in solid tumors, with particular emphasis on its combination with other chemotherapeutic agents in lung cancers.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Cell Survival; Curcumin; ErbB Receptors; Humans; Lung Neoplasms; Molecular Targeted Therapy

Lung cancer is the leading cause of cancer-related deaths worldwide with a 5-year overall survival rate of less than 20 %. Considering the treatments currently available, this statistics is shocking. A possible explanation for the disconnect between sophisticated treatments and the survival rate can be related to the post-treatment enrichment of Cancer Stem Cells (CSCs), which is one of a sub-set of drug resistant tumor cells with abilities of self-renewal, cancer initiation, and further maintenance of tumors. Lung CSCs have been associated with resistance to radiation and chemotherapeutic treatments. CSCs have also been implicated in tumor recurrence because CSCs are not typically killed after conventional therapy. Investigation of CSCs in determining their role in tumor recurrence and drug-resistance relied heavily on the use of specific markers present in CSCs, including CD133, ALDH, ABCG2, and Nanog. Yet another cell type that is also associated with increased resistance to treatment is epithelial-to-mesenchymal transition (EMT) phenotypic cells. Through the processes of EMT, epithelial cells lose their epithelial phenotype and gain mesenchymal properties, rendering EMT phenotypic cells acquire drug-resistance. In this chapter, we will further discuss the role of microRNAs (miRNAs) especially because miRNA-based therapies are becoming attractive target with respect to therapeutic resistance and CSCs. Finally, the potential role of the natural agents and synthetic derivatives of natural compounds with anti-cancer activity, e.g. curcumin, CDF, and BR-DIM is highlighted in overcoming therapeutic resistance, suggesting that the above mentioned agents could be important for better treatment of lung cancer in combination therapy.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Curcumin; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MicroRNAs; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Signal Transduction

Lung cancer is a prominent cause of cancer-associated mortality worldwide. The main reason for high mortality due to lung cancer is attributable to the fact that the diagnosis is generally made when it has spread beyond a curable stage and cannot be treated surgically or with radiation therapy. Therefore, new approaches like dietary modifications could be extremely useful in reducing lung cancer incidences. Several fruits and vegetables offer a variety of bioactive compounds to afford protection against several diseases, including lung cancer. A number of research studies involving dietary agents provide strong evidence for their role in the prevention and treatment of lung cancer, and have identified their molecular mechanisms of action and potential targets. In this review article, we summarize data from in-vitro and in-vivo studies and where available, in clinical trials, on the effects of some of the most promising dietary agents against lung cancer.

Topics: Adenocarcinoma; Administration, Oral; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Catechin; Curcumin; Flavonoids; Flavonols; Humans; Indoles; Isothiocyanates; Lung Neoplasms; Plant Extracts; Polyphenols

Curcumin (diferuloylmethane) is the most important component of the spice turmeric and is derived from the rhizome of the East Indian plant Curcuma longa. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including antioxidant, analgesic, anti-inflammatory, and antiseptic activities. Recently, curcumin has been widely studied for its anticancer properties via its effects on a variety of biological pathways involved in apoptosis, tumor proliferation, chemo- and radiotherapy sensitization, tumor invasion, and metastases. Curcumin can be an effective adjunct in treating solid organ tumors due to its properties of regulating oncogenes like p53, egr-1, c-myc, bcl-XL, etc.; transcription factors like NF-kB, STAT-3, and AP-1; protein kinases like MAPK; and enzymes like COX and LOX. Lung cancer is the most common malignancy worldwide and a leading cause of cancer-related deaths. Seventy-five percent of lung cancer presents at an advanced stage where the existing treatment is not very effective and may result in tremendous patient morbidity. As a result, there is a significant interest in developing adjunctive chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo studies of curcumin in lung cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Cell Adhesion Molecules; Curcumin; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Lung Neoplasms; Mice; Neoplasm Metastasis; Plant Extracts; Protein Kinases; Radiation-Sensitizing Agents; Rats; Transcription Factors; Tumor Necrosis Factor-alpha

Lung cancer is responsible for over one million deaths worldwide each year. Smoking cessation for lung cancer prevention remains key, but it is increasingly acknowledged that prevention strategies also need to focus on high-risk groups, including ex-smokers, and patients who have undergone resection of a primary tumor. Models for chemoprevention of lung cancer often present conflicting results, making rational design of lung cancer chemoprevention trials challenging. There has been much focus on use of dietary bioactive compounds in lung cancer prevention strategies, primarily due to their favorable toxicity profile and long history of use within the human populace. One such compound is curcumin, derived from the spice turmeric. This review summarizes and stratifies preclinical evidence for chemopreventive efficacy of curcumin in models of lung cancer, and adjudges the weight of evidence for use of curcumin in lung cancer chemoprevention strategies.

Topics: Acute Lung Injury; Animals; Cell Line, Tumor; Curcumin; Evidence-Based Medicine; Humans; Lung Neoplasms; Primary Prevention; Secondary Prevention; Smoking Cessation; Tertiary Prevention; Translational Research, Biomedical

Curcumin, a yellow pigment derived from Curcuma longa Linn, has attracted great interest in the research of cancer during the past decades. Extensive studies documented that curcumin attenuates cancer cell proliferation and promotes apoptosis in vivo and in vitro. Curcumin has been demonstrated to interact with multiple molecules and signal pathways, which makes it a potential adjuvant anti-cancer agent to chemotherapy. Previous investigations focus on the mechanisms of action for curcumin, which is shown to manipulate transcription factors and induce apoptosis in various kinds of human cancer. Apart from transcription factors and apoptosis, emerging studies shed light on latent targets of curcumin against epidermal growth factor receptor (EGFR), microRNAs (miRNA), autophagy and cancer stem cell. The present review predominantly discusses significance of EGFR, miRNA, autophagy and cancer stem cell in lung cancer therapy. Curcumin as a natural phytochemicals could communicate with these novel targets and show synergism to chemotherapy. Additionally, curcumin is well tolerated in humans. Therefore, EGFR-, miRNA-, autophagy- and cancer stem cell-based therapy in the presence of curcumin might be promising mechanisms and targets in the therapeutic strategy of lung cancer.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Curcumin; ErbB Receptors; Humans; Lung Neoplasms; MicroRNAs; Neoplastic Stem Cells; Signal Transduction; Transcription Factors

Carcinogens from cigarette smoke form the link between nicotine addiction and lung cancer, which is the leading cause of cancer-related mortality in the world. One of the most frequently studied chemopreventive agents is a curcumin, a natural compound extracted from turmeric that inhibits cell proliferation and induces apoptosis in human leukaemia, prostate cancer, and non-small cell lung cancer. Curcumin (diferuoylmethane) is a major yellow pigment in turmeric (Curcuma longa) and is widely used as a spice. Curcumin exhibits a variety of pharmacological effects, and has been reported to have anti-inflammatory and anti-tumor activities.

Topics: Curcumin; Humans; Lung Neoplasms; Phytotherapy

Curcumin is a polyphenolic compound derived from the plant turmeric and the structural instability of which limits its further clinical applications. In this study, 11 curcumin analogs with more stable scaffold were prepared and evaluated. The results indicated that the optimal compound

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Curcumin; Lung Neoplasms

Curcumin is a natural chemical component that has an anticancer effect. The aim of this study was to explore the potential molecular mechanism of curcumin regulating lung cancer (LC) progression.. The expression of circRUNX1, miR-760 and Ras-like GTPase 3D (RAB3D) was detected by qRT-PCR. Cell proliferation were determined by CCK8 assay and colony formation assay. Cell apoptosis, migration and invasion were detected by flow cytometry, wound healing and transwell assays. Protein levels were examined by western blot (WB) analysis. RNA interaction was confirmed by dual-luciferase reporter assay. LC xenograft tumors were constructed using BALB/c nude mice.. CircRUNX1 was upregulated in LC and its expression could be inhibited by curcumin. Curcumin reduced LC cell proliferation, metastasis, and accelerate apoptosis, while circRUNX1 overexpression reversed these effects. MiR-760 was confirmed to be a target of circRUNX1, which could reverse the effects of circRUNX1 on curcumin-treated LC cell functions. RAB3D was a target of miR-760, and its knockdown reversed the promotion effect of miR-760 inhibitor on the progression of curcumin-treated LC cells.. Curcumin suppressed LC progression via circRUNX1/miR-760/RAB3D axis.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Lung Neoplasms; Mice; Mice, Nude; MicroRNAs; rab3 GTP-Binding Proteins

In comparison with normal cells, cancer cells feature intrinsic oxidative stress, thereby being more vulnerable to further production of reactive oxygen species (ROS) by pro-oxidative anticancer agents (PAAs). However, PAAs also inevitably generate ROS in normal cells, resulting in their narrow therapeutic window and toxic side effects that greatly limit their clinical application. To develop PAAs that generate ROS selectively in cancer cells over in normal cells, we rationally designed three series of 21 dietary curcumin 5-carbon mono-carbonyl analogs differentiated by either placement of the cyclohexanone, piperidone, and methylpiperidone linkers, or introduction of electron-withdrawing trifluoromethyl and electron-donating methoxyl groups on its two aromatic rings in the ortho, meta, or para position to the linkers. From the designed molecules, 2c, characterized of the presence of the meta-CF

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Humans; Lung Neoplasms; Mice; Mice, Nude; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase

Curcumin, a natural phytochemical isolated from tumeric roots, represents a candidate for prevention and therapy of colorectal cancer/CRC. However, the exact mechanism of action and the downstream mediators of curcumin's tumor suppressive effects have remained largely unknown. Here we used a genetic approach to determine the role of the p53/miR-34 pathway as mediator of the effects of curcumin. Three isogenic CRC cell lines rendered deficient for the p53, miR-34a and/or miR-34b/c genes were exposed to curcumin and subjected to cell biological analyses. siRNA-mediated inhibition and ectopic expression of NRF2, as well as Western blot, qPCR and qChIP analyses of its target genes were performed. CRC cells were i.v. injected into NOD/SCID mice and lung-metastases formation was determined by longitudinal, non-invasive imaging. In CRC cells curcumin induced apoptosis and senescence, and suppressed migration and invasion in a p53-independent manner. Curcumin activated the KEAP1/NRF2/ARE pathway by inducing ROS. Notably, curcumin induced miR-34a and miR-34b/c expression in a ROS/NRF2-dependent and p53-independent manner. NRF2 directly induced miR-34a and miR-34b/c via occupying multiple ARE motifs in their promoter regions. Curcumin reverted repression of miR-34a and miR-34b/c induced by IL6 and hypoxia. Deletion of miR-34a and miR-34b/c significantly reduced curcumin-induced apoptosis and senescence, and prevented the inhibition of migration and invasion by curcumin or ectopic NRF2. In CRC cells curcumin induced MET and prevented the formation of lung-metastases in mice in a miR-34a-dependent manner. In addition, we found that curcumin may enhance the therapeutic effects of 5-FU on CRC cells deficient for p53 and miR-34a/b/c. Activation of the KEAP1/NRF2/miR-34a/b/c axis mediates the tumor suppressive activity of curcumin and suggests a new approach for activating miR-34 genes in tumors for therapeutic purposes.

Topics: Animals; Cell Line, Tumor; Colorectal Neoplasms; Curcumin; Gene Expression Regulation, Neoplastic; Kelch-Like ECH-Associated Protein 1; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs; NF-E2-Related Factor 2; Reactive Oxygen Species; Tumor Suppressor Protein p53

Rationally designed ∼ 100 nm sized curcumin (CRC) loaded exfoliated layered double hydroxide nanoparticles (X-LDH/CRC-NPs) have been tested for its suitability as nanomedicine in non-small cell lung cancer (NSCLC) cell lines (A549 and NCI-H460) resulting enhanced apoptosis. Preclinical evaluation on A549 tumor bearing nude mouse model confirmed that such a well-designed X-LDH/CRC NPs would be highly advantageous for treating lung cancers.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Hydroxides; Lung Neoplasms; Mice; Nanomedicine; Nanoparticles

Drug combination therapy is a key approach in cancer treatments, aiming to improve therapeutic efficacy and overcome drug resistance. Evaluation of intracellular response in cancer cells to drug treatment may disclose the underlying mechanism of drug resistance. In this study, we aimed to investigate the effect of osimertinib, a tyrosine kinase inhibitor (TKI), and a curcumin derivative, 35d, on HCC827 cells and tumors by analyzing alterations in metabolome and related regulations. HCC827 tumor-bearing SCID mice and cultured HCC827 cells were separately examined. The treatment comprised four conditions: vehicle-only, 35d-only, osimertinib-only, and a combination of 35d and osimertinib. The treated tumors/cells were subsequently subjected to metabolomics profiling, fatty acyl analysis, mitochondrial potential measurement, and cell viability assay. Osimertinib induced changes in the ratio of short-chain (SC) to long-chain (LC) fatty acyls, particularly acylcarnitines (ACs), in both tumors and cells. Furthermore, 35d enhanced this effect by further lowering the SC/LC ratio of most ACs. Osimertinib and 35d also exerted detrimental effects on mitochondria through distinct mechanisms. Osimertinib upregulated the expression of carnitine palmitoyltransferase I (CPTI), while 35d induced the expression of heat shock protein 60 (HSP60). The alterations in ACs and CPTI were correlated with mitochondrial dysfunction and inhibited cell growth. Our results suggest that osimertinib and 35d disrupted the fatty acyl metabolism and induced mitochondrial stress in cancer cells. This study provides insights into the potential application of fatty acyl metabolism inhibitors, such as osimertinib or other TKIs, and mitochondrial stress inducers, such as curcumin derivatives, as combination therapy for cancer.

Topics: Aniline Compounds; Animals; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; Lung Neoplasms; Mice; Mice, SCID; Mitochondria; Mutation; Protein Kinase Inhibitors

Curcumin, an anticancer natural compound with multiple pharmacological activities, has a weak pharmacokinetic and instability due to diketone moiety. Curcumin's stability challenges can be overcome by removing the diketone moiety and shortening the 7-carbon chain, resulting in mono-carbonyl analogs. Cancer proliferation is caused by the activation of Epidermal Growth Factor (EGFR) pathways. Current available EGFR inhibitors have an issue of resistance.. Thus, we aimed to design new mono-carbonyl curcumin derivatives and analyse their drug likeness properties. Further, to investigate them on three distinct crystal structures, namely two wild-type and L858R/T790M/C797S mutant generations for EGFR inhibitory activity.. Ten New Molecular Entities (NME's) were designed using literature survey. These molecules were subjected to comparative molecular docking, on the EGFR crystal structures viz. wild-type (PDB: 1M17 and 4I23) and L858R/T790M/C797S mutant (PDB: 6LUD) using Schrodinger software. The molecules were also tested for Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties. The docked complex of the hit molecule was studied for molecular simulation.. NME 1 and NME 2 have shown better binding against wild type of EGFR. NME 3 have shown comparable binding and more stability as compared to Osimertinib against L858R/T790M/C797S mutated protein structure. The hit compound can be further explored for its Molecular mechanics with generalised Born and surface area solvation (MM-GBSA) and discrete Fourier transform (DFT) studies to find out the energy and atomic level study. In the future, this molecule could be taken for wet lab studies and can be tested for mutated EGFR inhibitory activity.

Topics: Curcumin; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Molecular Docking Simulation; Mutation; Protein Kinase Inhibitors

Topics: Animals; Antineoplastic Agents; Antioxidants; Biphenyl Compounds; Cell Proliferation; Cell Survival; Cells, Cultured; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinases; Molecular Structure; Neoplasms, Experimental; NF-kappa B; Picrates; STAT3 Transcription Factor; Structure-Activity Relationship; Triazoles; Zebrafish

Drug resistance is a critical factor responsible for the recurrence of non-small cell lung cancer (NSCLC). Previous studies suggest that curcumin acts as a chemosensitizer and radiosensitizer in human malignancies, but the underlying mechanism remains elusive. In the present study, we explored how curcumin regulates the expression of miR-142-5p and sensitizes NSCLC cells to crizotinib. We found that miR-142-5p is significantly downregulated in NSCLC tissue samples and cell lines. Curcumin could increase crizotinib cytotoxicity by epigenetically restoring the expression of miR-142-5p. Furthermore, curcumin treatment suppressed the expression of DNA methylation-related enzymes, including DNMT1, DNMT3A, and DNMT3B, in NSCLC cells. In addition, the upregulation of miR-142-5p expression increased crizotinib cytotoxicity and induced apoptosis in tumor cells in a similar manner to that of curcumin. Strikingly, miR-142-5p overexpression suppressed crizotinib-induced autophagy in A549 and H460 cells. Mechanistically, miR-142-5p inhibited autophagy in lung cancer cells by targeting Ulk1. Overexpression of Ulk1 abrogated the miR-142-5p-induced elevation of crizotinib cytotoxicity in A549 and H460 cells. Collectively, our findings demonstrate that curcumin sensitizes NSCLC cells to crizotinib by inactivating autophagy through the regulation of miR-142-5p and its target Ulk1.

Topics: Apoptosis; Autophagy; Autophagy-Related Protein-1 Homolog; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Crizotinib; Curcumin; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; MicroRNAs

This study aimed to investigated whether Curcumin-mediated PDT can suppress EMT in lung cancer cells, and explore the roles of autophagy in the process of regulating EMT.. Lung cancer cell viability was assessed by CCK-8 assay. The expression of epithelial marker and mesenchymal markers, the conversion of LC3-I to LC3-II and the levels of p62 and beclin1 in A549 and SPCA1 cells were measured by Western blotting assay. The Wound healing and Transwell assays were used to detect the migration and invasion abilities of the A549 and SPCA1 cells. Autophagosome formation was detected via observing the colocalization of Lamp-2 with LC3 in A549 cells, and the autophagy ultrastructure was observed by TEM.. Curcumin-PDT inhibited EMT, migration and invasion and induced autophagy in lung cancer cells. Curcumin-PDT induced autophagy was involved in the process of PDT inhibiting EMT, but it presented a promoting effect of EMT in lung cancer cells. Curcumin-PDT combined with CQ further inhibited EMT, invasion and migration of lung cancer cells.. The role of PDT-induced autophagy in the regulation of EMT was determined to be a promoting effect in lung cancer. Therefore, Curcumin-mediated PDT combined with autophagy inhibitor further suppressed EMT of lung cancer cells, and may represent a potential strategy against invasion and migration of lung cancer.

Topics: Autophagy; Cell Line, Tumor; Cell Movement; Curcumin; Epithelial-Mesenchymal Transition; Humans; Lung Neoplasms; Photochemotherapy

Lung tumors express high levels of aromatase enzyme compared to surrounding normal tissue. Inhibition of aromatase has emerged as a recent therapeutic approach for the treatment of breast cancer. However, the role of aromatase inhibition in lung cancer treatment requires further investigation.. The anti-proliferative effects of aromatase inhibitors were evaluated by MTT assay. Cell migration was assessed using a wound healing assay. The mechanism of cell death was determined using the annexin VFITC/ propidium iodide staining flow cytometry method. The soft agar colony formation assay evaluated cells' capability to form colonies.. Exemestane and curcumin significantly inhibited the growth of lung cancer cell lines in a dose- and timedependent manner. The IC. Aromatase inhibition by exemestane or curcumin had significantly inhibited the growth of lung cancer cell lines, synergized with cisplatin, raloxifene, and celecoxib, suppressed lung cancer cell migratory potential, induced apoptosis, and reduced colony formation of lung cancer cells.

Topics: Agar; Annexins; Apoptosis; Aromatase; Aromatase Inhibitors; Celecoxib; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Humans; Lung Neoplasms; Propidium; Raloxifene Hydrochloride

The main aim of this study was to improve the therapeutic potential of a paclitaxel (PTX) and curcumin (CU) combination regimen using solid lipid nanoparticles (SLNs). PTX and CU were successfully co-encapsulated at a predetermined ratio in SLNs (PC-SLNs) with high encapsulation efficiency (CU: 97.6%, PTX: 95.8%), appropriate particle size (121.8 ± 1.69 nm), small PDI (0.267 ± 0.023), and negative zeta potential (-30.4 ± 1.25 mV). Compared with PTX or the combination of CU and PTX (CU + PTX), PC-SLNs can greatly reduce the dose of PTX while still achieving the same therapeutic effect on four cancer cell lines, among which the inhibitory effect on A549 lung cancer cells was the strongest. PC-SLNs improved the area under the curve (CU: 1.40-fold; PTX: 2.88-fold), prolonged the residence time (CU: 6.94-fold; PTX: 2.51-fold), and increased the half-life (CU: 5.62-fold; PTX: 6.46-fold), achieving long circulation. PC-SLNs were used to treat lung cancer in a nude mouse xenograft tumor model and the tumor suppression rate reached 78.42%, while those of PTX and (CU + PTX) were 40.53% and 51.56%, respectively. As PC-SLNs can prevent P-glycoprotein efflux, reverse MDR and downregulate the NF-κB pathway. PC-SLNs are a potential antineoplastic agent that is more effective and less toxic in treating lung cancer.

Topics: Animals; Cell Line, Tumor; Curcumin; Humans; Liposomes; Lung Neoplasms; Mice; Nanoparticles; Paclitaxel

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Lung Neoplasms; Molecular Docking Simulation; Tumor Suppressor Protein p53

This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine (VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen species (ROS) was detected by fluorescence activated cell sorting (FACS) analysis. Apoptosis was analyzed by Annexin V assay of the flow cytometry. Inhibitors and RNA interference were used to examine the signaling pathway regulated by the kinases. The obtained data demonstrated that CUR induces chemoresistant cell apoptosis by generating ROS and application of

Topics: Apoptosis; Curcumin; Eukaryotic Initiation Factor-2; Humans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Reactive Oxygen Species

As the main component of turmeric (. LUAD mRNA expression data were obtained from TCGA database and differentially expressed genes (DEGs) were identified using R software. Functional enrichment analysis was conducted to further clarify its biological properties and hub genes were identified by a protein-protein interaction (PPI) network analysis. Survival analysis and molecular docking were used to analyze the effectiveness of the hub genes. By an in vitro study, we evaluated whether curcumin could influence the proliferation, migration, and invasion activities of LUAD cells.. In this study, 1783 DEGs from LUAD tissue samples compared to normal samples were evaluated. Functional enrichment analysis and the PPI network revealed the characteristics of the DEGs. We performed a topological analysis and identified 10 hub genes. Of these, six genes (. The results of this study suggest that the therapeutic effects of curcumin on LUAD may be achieved through the intervention of

Topics: Adenocarcinoma of Lung; Biomarkers, Tumor; Computational Biology; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Molecular Docking Simulation

Curcumin is a natural medicine with a wide range of anti-tumour activities. However, due to β-diketone moiety, curcumin exhibits poor stability and pharmacokinetics which significantly limits its clinical applications. In this article, two types of dicarbonyl curcumin analogues with improved stability were designed through the calculation of molecular stability by density functional theory. Twenty compounds were synthesised, and their anti-tumour activity was screened. A plurality of analogues had significantly stronger activity than curcumin. In particular, compound B2 ((2E,2'E)-3,3'-(1,4-phenylene)bis(1-(2-chlorophenyl)prop-2-en-1-one)) exhibited excellent anti-lung cancer activity

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Diarylheptanoids; Humans; Lung Neoplasms; Pyroptosis; Reactive Oxygen Species

A co-delivery system of SN38 (7-ethyl-10-hydroxyl camptothecin) prodrug and CUR (curcumin) was designed for the treatment of lung cancer by pulmonary delivery. SN38 was linked to cell-penetrating peptide (CPP) TAT via a polyethylene glycol (PEG) linker to form the SN38 prodrug (TAT-PEG-SN38). Liposomes co-loaded with amphiphilic TAT-PEG-SN38 and curcumin (Lip-TAT-PEG-SN38/CUR) were successfully prepared by a microfluidic method for the treatment of lung cancer via pulmonary delivery. Lip-TAT-PEG-SN38/CUR showed nanometer-sized sphericity and a particle size of 171.21 nm. Besides, Lip-TAT-PEG-SN38/CUR exhibited enhanced antiproliferative effect, increased cell apoptosis induction and improved cell cycle arrest compared to the single agents in vitro. The combination induced significant tumor inhibition in a BALB/c mouse lung cancer model. These results indicated that our SN38 prodrug and curcumin co-delivery system was a promising candidate for lung cancer treatment.

Topics: Animals; Camptothecin; Cell Line, Tumor; Cell-Penetrating Peptides; Curcumin; Drug Delivery Systems; Liposomes; Lung Neoplasms; Mice; Nanoparticles; Polyethylene Glycols; Prodrugs

The synthesized 1,5 diarylpenta-1,4-dien-3-one derivatives (compounds 1-6) as synthetic curcumin analogues were tested for their potential anticancer activity against human ovarian and lung adenocarcinoma cells. The absorption, distribution, metabolism, excretion, and toxicity (ADMET/pharmacokinetic) parameters of all the compounds were predicted by admetSAR software. The pharmacokinetics, pharmacodynamics and bioactivity scores properties based on Lipinski rule and Ghose filter, calculated with the help of Molinspiration and ChemDraw. Molecular docking evaluation of all the compounds was also performed by using AutoDock Vina and iGEMDOCK against three most common human anticancer targets; epidermal growth factor receptor (EGFR), heat shock protein (Hsp 90-α), and vascular endothelial growth factor receptor-2 (VEGFR2). The obtained results were compared with the reference compound 7 and drugs 8-10 (7: GO-035; 8: Quinazolin; 9: Naquotinib and 10: Ribofuranuronamide). Finding indicates, all the compounds were potentially interacting with VEGFR2 through the average -9.1 binding energy (BE) with closer contact <5.0 Å deep in the active site of the ligand-receptor complex. All the compounds showed excellent oral bioavailability, bioactivity score, and none of the compounds are virtually found to be toxic. Compounds 1-6 were also successfully characterized by the physical properties as well as spectroscopic techniques (FT-IR and

Topics: Adenocarcinoma of Lung; Alkadienes; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Screening Assays, Antitumor; ErbB Receptors; Female; Heat-Shock Proteins; Humans; Ligands; Lung Neoplasms; Molecular Docking Simulation; Molecular Structure; Ovarian Neoplasms; Reactive Oxygen Species; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

In this study, a turmeric polysaccharide (TP-0) was isolated through hot water extraction and ethanol precipitation to produce a novel active polysaccharide from turmeric other than curcuminoids. TP-0 was found to be primarily composed of eight different monosaccharides, such as galactose (15.9%), galacturonic acid (15.2%), arabinose (11.4%), and rhamnose (9.7%), which are typical rhamnogalacturonan (RG)-I sugars. When stimulated with TP-0, peritoneal macrophages secreted a variety of immunostimulatory cytokines. In addition, intravenous and oral administration of TP-0 significantly enhanced the natural killer (NK) cells and cytotoxic T lymphocyte (CTL)-mediated cytotoxicity against tumor cells. In an assay for lung cancer induced by Colon26-M3.1 carcinoma, prophylactic intravenous and oral administration of TP-0 effectively inhibited lung cancer. These findings reveal that TP-0, a typical RG-I-type polysaccharide that is isolated from turmeric, has potent anti-metastatic activities, and these activities are linked to various immunological factors such as macrophages, NK cells, and CTL. PRACTICAL APPLICATIONS: Many studies related with turmeric have only focused that a curcuminoid of turmeric has beneficial effects on human health system. Nevertheless, in this study, it was confirmed that polysaccharide isolated from turmeric showed potent anti-cancer effects via activities of various immunological factors such as macrophages, NK cells, and CTL. These results suggest the high potential for development value of turmeric as a new candidate for immunostimulating-related health functional food ingredients.

Topics: Arabinose; Curcuma; Cytokines; Diarylheptanoids; Ethanol; Food Ingredients; Galactose; Humans; Immunologic Factors; Lung Neoplasms; Polysaccharides; Rhamnogalacturonans; Rhamnose; Water

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Deoxycytidine; Gemcitabine; Lung Neoplasms; Mice; Mice, Nude

Ferroptosis is a classification of programmed cell death, which activates oxidative cell death in an iron and lipid peroxides-dependent manner. Targeting ferroptosis is a novel therapeutic approach for cancer therapy. Lung cancer is the leading cause of cancer related deaths all over the world. Circular RNAs (circRNAs), as a form of noncoding RNAs with a specific closed circular sequence are emerging as a new field in cancer research. However, the regulatory mechanisms of circRNAs in ferroptosis during lung cancer development are still elusive. In this work, we elucidate the potential prognostic value and the crucial role of circular RNA circFOXP1 in ferroptosis of lung cancer. We found that the expression of circFOXP1 was remarkably up-regulated in clinical lung sample tissues compared with adjacent tissues. The up-regulation of circFOXP1 was closely correlated with the poor overall survival of lung cancer patients. The knockdown of circFOXP1 suppressed the cell viability of lung cancer cells. The colony formation counts of lung cancer cells were repressed by the depletion of circFOXP1 as well. The Edu-positive lung cancer cells were attenuated by the silencing of circFOXP1. The migration and invasion of lung cancer cells were suppressed by circFOXP1 short hairpin RNA (shRNA). The expression of E-cadherin was enhanced, and vimentin expression was reduced by the knockdown of circFOXP1. Moreover, the treatment of ferroptosis activator erastin or RSL3 repressed the cell viability of lung cancer cells and the overexpression of circFOXP1 rescued the phenotype. The levels of malondialdehyde (MDA), iron, and lipid reactive oxygen species (ROS) were enhanced by the silencing of circFOXP1 in both erastin and RSL3-stimulated lung cancer cells. Mechanically, circFOXP1 increased SLC7A11 expression by directly sponging miR-520a-5p in lung cancer cells. The inhibitor of miR-520a-5p or the overexpression of SLC7A11 reversed circFOXP1 shRNA-induced ferroptosis phenotypes in lung cancer cells. Importantly, circFOXP1 contributed to tumor growth of lung cancer cells by enhancing SLC7A11 in vivo. Collectively, we concluded that circular RNA circFOXP1 is a potential diagnostic biomarker and contributes to malignant progression by repressing ferroptosis of lung cancer. Targeting circFOXP1 may be served as a promising therapeutic approach for lung cancer.

Topics: Amino Acid Transport System y+; Antineoplastic Agents; Carcinogenesis; Cellular Senescence; Curcumin; Ferroptosis; Forkhead Transcription Factors; Humans; Lung Neoplasms; MicroRNAs; Mitochondria; Quercetin; Repressor Proteins

Characterized by the abysmal 18% five year survival chances, non-small cell lung cancers (NSCLCs) claim more than half of their sufferers within the first year of being diagnosed. Advances in biomedical engineering and molecular characterization have reduced the NSCLC diagnosis via timid screening of altered gene expressions and impaired cellular responses. While targeted chemotherapy remains a major option for NSCLCs complications, delayed diagnosis, and concurrent multi-drug resistance remain potent hurdles in regaining normalcy, ultimately resulting in relapse. Curcumin administration presents a benign resolve herein, via simultaneous interception of distinctly expressed pathological markers through its pleiotropic attributes and enhanced tumor cell internalization of chemotherapeutic drugs. Studies on NSCLC cell lines and related xenograft models have revealed a consistent decline in tumor progression owing to enhanced chemotherapeutics cellular internalization via co-delivery with curcumin. This presents an optimum readiness for screening the corresponding effectiveness in clinical subjects. Curcumin is delivered to NSCLC cells either (i) alone, (ii) in stoichiometrically optimal combination with chemotherapeutic drugs, (iii) through nanocarriers, and (iv) nanocarrier co-delivered curcumin and chemotherapeutic drugs. Nanocarriers protect the encapsulated drug from accidental and non-specific spillage. A unanimous trait of all nanocarriers is their moderate drug-interactions, whereby native structural expressions are not tampered. With such insights, this article focuses on the implicit NSCLC curative mechanisms viz-a-viz, free curcumin, nanocarrier delivered curcumin, curcumin + chemotherapeutic drug and nanocarrier assisted curcumin + chemotherapeutic drug delivery.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Humans; Lung Neoplasms; Neoplasm Recurrence, Local

Curcumin has been shown to suppress the progression of lung cancer, however, the underlying mechanisms are largely unknown. Here, we aimed to investigate the effects of curcumin on the stemness of non-small cell lung cancer (NSCLC) cells. We found that curcumin reduced the sphere formation ability at the concentrations without affecting the cell viability of NSCLC cells and normal pulmonary epithelial cells, which is evident by the decrease of sphere size and number. In addition, curcumin decreased ALDH activity and the expression of stemness markers (CD133, EpCAM, Oct4). RNA sequencing analysis revealed that the Hippo pathway was mostly enriched in cells with curcumin treatment. Indeed, the expression of cancer stem cell markers was significantly decreased by curcumin treatment by analyzing the RNA sequencing data. Gene set enrichment analysis (GSEA) showed that curcumin negatively regulated the cancer stem cell function and positively modulated cancer stem cell differentiation ability. Furthermore, curcumin enhanced the cisplatin sensitivity of NSCLC cells. Mechanistically, it was found that curcumin promoted the nuclear-cytoplasm translocation of TAZ, but not YAP, the critical effectors of Hippo pathway. In addition, curcumin destabilzed TAZ protein stability and promoted TAZ protein degradation in lung cancer cells, which is dependent on the proteasome degradation system, not by autophagy lysosome degradation system. Overexpression of TAZ rescued the inhibition of curcumin on the stemness of lung cancer cells. Thus, our results suggest that curcumin can attenuate the stemness of lung cancer cells through promoting TAZ protein degradation and thus activating Hippo pathway.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Cytoplasm; Humans; Lung Neoplasms; Transcription Factors

Lung cancer is one of the most aggressive malignancies and the efficacy of chemotherapy or concurrent chemoradiation is limited in clinical application. Curcumin has been reported to block cancer development by modulating multiple signaling pathways. However, whether curcumin can inhibit gemcitabine-resistant non-small cell lung cancer through regulation of lncRNA and the involved molecular mechanisms are rarely reported.. MTT assay, clonogenic assay, apoptosis assay, qRT-PCR, Western blotting, immunohistochemistry, xenograft experiment were carried out in the present study.. The results showed that curcumin suppressed gemcitabine-resistant non-small cell lung cancer cell proliferation and induced apoptosis. Curcumin upregulated the expression of lncRNA-MEG3 and PTEN, and MEG3 overexpression could increase the level of PTEN expression, while MEG3 knockdown decreased the level of PTEN expression in gemcitabine-resistant non-small cell lung cancer cells. Curcumin treatment failed to inhibit the proliferation and induce apoptosis in MEG3 knockdown or PTEN knockdown cells.. These findings show the antitumor activity of curcumin for potential clinical application in gemcitabine-resistant non-small cell lung cancer treatment.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Curcumin; Deoxycytidine; Drug Resistance, Neoplasm; Gemcitabine; Humans; Lung Neoplasms; PTEN Phosphohydrolase; RNA, Long Noncoding; Signal Transduction; Tumor Cells, Cultured

Emerging studies showed curcumin can inhibit glioblastoma and breast cancer cells via regulating ferroptosis. However, the role of ferroptosis in the inhibitory effect of curcumin on non-small-cell lung cancer (NSCLC) remains unclear.. Cell counting kit-8 (CCK-8) assay was used to measure the viability of A549 and H1299 cells under different conditions. Cell proliferation was examined by Ki67 immunofluorescence. The morphological changes of cells and tumor tissues were observed by optical microscope and hematoxylin and eosin (H&E) staining. Intracellular reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and iron contents were determined by corresponding assay kit. The related protein expression levels were detected by western blot and immunohistochemistry. Transmission electron microscope was used to observe ultrastructure changes of A549 and H1299 cells.. Curcumin inhibited tumor growth and cell proliferation, but promoted cell death. Characteristic changes of ferroptosis were observed in curcumin group, including iron overload, GSH depletion and lipid peroxidation. Meanwhile, the protein level of ACSL4 was higher and the levels of SLC7A11 and GPX4 were lower in curcumin group than that in control group. Incubation of ferroptosis inhibitors ferrostatin-1 (Fer-1) or knockdown of iron-responsive element-binding protein 2 (IREB2) notably weakened curcumin-induced anti-tumor effect and ferroptosis in A549 and H1299 cells. Further investigation suggested that curcumin induced mitochondrial membrane rupture and mitochondrial cristae decrease, increased autolysosome, increased the level of Beclin1 and LC3, and decreased the level of P62. Curcumin-induced autophagy and subsequent ferroptosis were both alleviated with autophagy inhibitor chloroquine (CQ) or siBeclin1.. Curcumin induced ferroptosis via activating autophagy in NSCLC, which enhanced the therapeutic effect of NSCLC.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Curcumin; Disease Models, Animal; Ferroptosis; Humans; Lung Neoplasms; Mice; Transfection

Cancer stem cells (CSCs) represent a small subpopulation within a tumour. These cells possess stem cell-like properties but also initiate resistance to cytotoxic agents, which contributes to cancer relapse. Natural compounds such as curcumin that contain high amounts of polyphenols can have a chemosensitivity effect that sensitises CSCs to cytotoxic agents such as cisplatin. This study was designed to investigate the efficacy of curcumin as a chemo-sensitiser in CSCs subpopulation of non-small cell lung cancer (NSCLC) using the lung cancer adenocarcinoma human alveolar basal epithelial cells A549 and H2170. The ability of curcumin to sensitise lung CSCs to cisplatin was determined by evaluating stemness characteristics, including proliferation activity, colony formation, and spheroid formation of cells treated with curcumin alone, cisplatin alone, or the combination of both at 24, 48, and 72 h. The mRNA level of genes involved in stemness was analysed using quantitative real-time polymerase chain reaction. Liquid chromatography-mass spectrometry was used to evaluate the effect of curcumin on the CSC niche. A combined treatment of A549 subpopulations with curcumin reduced cellular proliferation activity at all time points. Curcumin significantly (

Topics: Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Self Renewal; Cisplatin; Curcumin; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Kruppel-Like Factor 4; Lung Neoplasms; Neoplastic Stem Cells; RNA, Messenger; Spheroids, Cellular

Curcumin exerts a suppressive effect in tumor growth by acting as a modulator of multiple molecular targets. Circular RNA hsa_circ_0007580 (circ-PRKCA) accelerates the tumorigenesis of non-small cell lung cancer (NSCLC). However, whether curcumin can regulate circ-PRKCA to inhibit NSCLC progression is unclear.. Cell viability, colony formation, apoptosis, migration, and invasion were analyzed using Cell Counting Kit-8 (CCK-8), plate clone, flow cytometry, or transwell assay. Expression of circ-PRKCA, microRNA (miR)-384, and ITGB1 mRNA (integrin subunit beta 1) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Curcumin repressed NSCLC growth through regulating circ-PRKCA expression was validated by xenograft assay. The targeting relationship between circ-PRKCA or ITGB1 and miR-384 was verified by dual-luciferase reporter assay. The level of ITGB1 protein was measured by western blotting.. Circ-PRKCA and ITGB1 expression were elevated in NSCLC tissues and cells, but miR-384 had an opposing tendency. After curcumin treatment, the expression tendency of circ-PRKCA, miR-384, and ITGB1 in NSCLC cells was overturned. Furthermore, curcumin impeded viability, colony formation, migration, invasion, and accelerated apoptosis of NSCLC cells, but these impacts were partially reversed by circ-PRKCA elevation, miR-384 downregulation, or ITGB1 overexpression. Also, the inhibitory effect of curcumin on xenograft tumor was further enhanced after circ-PRKCA knockdown. Notably, circ-PRKCA regulated ITGB1 expression through sponging miR-384 in curcumin-treated NSCLC cells.. Curcumin inhibited NSCLC growth through downregulating circ-PRKCA, which regulated ITGB1 expression by adsorbing miR-384. This study provided a new mechanism to understand how curcumin inhibited the progression of NSCLC.

Topics: A549 Cells; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Curcumin; Humans; Integrin beta1; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Protein Kinase C-alpha; RNA, Circular; Signal Transduction; Xenograft Model Antitumor Assays

The application of traditional chemotherapy drugs for lung cancer has obvious limitations, such as toxic side effects, uncontrolled drug-release, poor bioavailability, and drug-resistance. Thus, to address the limitations of free drugs and improve treatment effects, we developed novel T7 peptide-modified nanoparticles (T7-CMCS-BAPE, CBT) based on carboxymethyl chitosan (CMCS), which is capable of targeted binding to the transferrin receptor (TfR) expressed on lung cancer cells and precisely regulating drug-release according to the pH value and reactive oxygen species (ROS) level. The results showed that the drug-loading content of docetaxel (DTX) and curcumin (CUR) was approximately 7.82% and 6.48%, respectively. Good biosafety was obtained even when the concentration was as high as 500 μg/mL. More importantly, the T7-CMCS-BAPE-DTX/CUR (CBT-DC) complexes exhibited better in vitro and in vivo anti-tumor effects than DTX monotherapy and other nanocarriers loaded with DTX and CUR alone. Furthermore, we determined that CBT-DC can ameliorate the immunosuppressive micro-environment to promote the inhibition of tumor growth. Collectively, the current findings help lay the foundation for combinatorial lung cancer treatment.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chitosan; Curcumin; Docetaxel; Drug Carriers; Drug Liberation; Humans; Hydrogen-Ion Concentration; Lung; Lung Neoplasms; Lymphocytes, Tumor-Infiltrating; Macrophages; Mice; Myeloid-Derived Suppressor Cells; Nanoparticles; Reactive Oxygen Species; T-Lymphocytes; Tumor Microenvironment; Xenograft Model Antitumor Assays

Tumor angiogenesis has been proven to potentiate tumor growth and metastasis; therefore, the strategies targeting tumor-related angiogenesis have great potentials in antitumor therapy.. Here, the GA&Gal dual-ligand-modified liposomes co-loaded with curcumin and combretastatin A-4 phosphate (CUCA/GA&Gal-Lip) were prepared and characterized. A novel "BEL-7402+HUVEC" co-cultured cell model was established to mimic tumor microenvironment. The cytotoxicity and migration assays were performed against the novel co-cultured model. Angiogenesis ability was evaluated by tube formation test, and in vivo metastatic ability was evaluated by lung metastasis test.. The result demonstrated that dual-ligand-modified liposomes showed greater inhibition of tumor angiogenesis and metastasis in comparison with other combined groups. Significantly, the mechanism analysis revealed that curcumin and combretastatin A-4 phosphate could inhibit tumor angiogenesis and metastasis via down-regulation of VEGF and VEGFR2 expression, respectively, and that GA&Gal-Lip could improve antitumor effect by GA/Gal-mediated active-targeting delivery.. CUCA/GA&Gal-Lip hold great potentials in hepatoma-targeting delivery of antitumor drugs and can achieve anti-angiogenic and anti-metastatic effects by simultaneously blocking VEGF/VEGFR2 signal pathway, therefore exhibiting superior anti-hepatoma efficacy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Drug Liberation; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Ligands; Liposomes; Liver Neoplasms; Lung Neoplasms; Mice, Inbred BALB C; Neovascularization, Pathologic; Stilbenes; Xenograft Model Antitumor Assays

Diarylpentanoid (DAP), an analog that was structurally modified from a naturally occurring curcumin, has shown to enhance anticancer efficacy compared to its parent compound in various cancers. This study aims to determine the cytotoxicity, antiproliferative, and apoptotic activity of diarylpentanoid MS13 on two subtypes of non-small cell lung cancer (NSCLC) cells: squamous cell carcinoma (NCI-H520) and adenocarcinoma (NCI-H23). Gene expression analysis was performed using Nanostring PanCancer Pathways Panel to determine significant signaling pathways and targeted genes in these treated cells. Cytotoxicity screening revealed that MS13 exhibited greater inhibitory effect in NCI-H520 and NCI-H23 cells compared to curcumin. MS13 induced anti-proliferative activity in both cells in a dose- and time-dependent manner. Morphological analysis revealed that a significant number of MS13-treated cells exhibited apoptosis. A significant increase in caspase-3 activity and decrease in Bcl-2 protein concentration was noted in both MS13-treated cells in a time- and dose-dependent manner. A total of 77 and 47 differential expressed genes (DEGs) were regulated in MS13 treated-NCI-H520 and NCI-H23 cells, respectively. Among the DEGs, 22 were mutually expressed in both NCI-H520 and NCI-H23 cells in response to MS13 treatment. The top DEGs modulated by MS13 in NCI-H520-DUSP4, CDKN1A, GADD45G, NGFR, and EPHA2-and NCI-H23 cells-HGF, MET, COL5A2, MCM7, and GNG4-were highly associated with PI3K, cell cycle-apoptosis, and MAPK signaling pathways. In conclusion, MS13 may induce antiproliferation and apoptosis activity in squamous cell carcinoma and adenocarcinoma of NSCLC cells by modulating DEGs associated with PI3K-AKT, cell cycle-apoptosis, and MAPK pathways. Therefore, our present findings could provide an insight into the anticancer activity of MS13 and merits further investigation as a potential anticancer agent for NSCLC cancer therapy.

Topics: Alkadienes; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Proliferation; Curcumin; Humans; Lung Neoplasms; Signal Transduction; Tumor Cells, Cultured

Systemic chemotherapy is still the primary treatment for advanced-stage nasopharyngeal carcinoma (NPC), but only limited therapeutic success has been achieved in the past decade because of drug resistance and systemic toxicity. Curcumin (Cur) is an effective alternative to chemotherapeutics because it showed remarkable therapeutic potential in the treatment of NPC. However, lack of tissue specificity and poor penetration in solid tumors are the major obstacles to effective therapy. Therefore, in this work, a self-assembled sub-30 nm therapeutic lipid nanoparticle loaded with Cur, named as Cur@α-NTP-LN, was constructed, specifically targeting scavenger receptor class B member 1 (SR-B1) and enhancing its therapeutic effects on NPC in vivo. Our results showed that Cur@α-NTP-LNs were effective and superior to free Cur on NPC cell-specific targeting, suppressing cell proliferation and inducing cell apoptosis. In vivo and ex vivo optical imaging revealed that Cur@α-NTP-LNs exerted high targeting efficiency, specifically accumulating in NPC xenograft tumors and delivering Cur into the tumor center after systemic administration. Furthermore, Cur@α-NTP-LNs exhibited a remarkable inhibitory effect on the growth of NPC subcutaneous tumors, with over 71 and 47% inhibition compared to Cur- and α-NTP-LNs-treated groups, respectively. In addition, Cur@α-NTP-LNs almost blocked NPC metastasis in a lung metastasis model of NPC and significantly improved the survival rate. Thus, the sub-30 nm Cur@α-NTP-LNs enhanced the solubility of Cur and demonstrated the ability of targeted Cur delivery into the center of the solid NPC tumor, performing synergistic inhibitory effects on the growth of NPC tumor and its metastasis with high efficiency.

Topics: Administration, Cutaneous; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Liposomes; Lung Neoplasms; Mice; Nanoparticles; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Particle Size; Peptides; Solubility

In recent years, nanotechnology with modern advances in the macromolecular design of nano-carriers has proved to be helpful in the development of drugs delivery systems. This research represents a novel co-administration of nano-vehicles, known as liposomes. Liposomes efficiently encapsulate curcumin and bromocriptine (BR) in a polymer structure, which results in enhanced aqueous solubility of the mentioned hydrophobic agents and higher bioavailability of the drugs.. Preparation of curcumin and BR liposomes were carried out by the thin film method, and the amounts of purified drug and its release were analyzed. After dose determination, the human lung cancer cells (QU-DB) were exposed to BR and curcumin liposomes for 12, 24, and 48 h. Then the viability and apoptosis assays were carried out by using tetrazolium dye and flow cytometry technique, respectively.. In this research, in vitro anti-cancer effects of former nano-formulations on lung cancer cells was confirmed, and no cytotoxicity effects of these nano-preparations were observed in the normal cells (HFLF-PI5).. Our findings suggest the nano-liposomal drugs as effective anti-cancer agents; however, additional clinical examinations are required.

Topics: Apoptosis; Bromocriptine; Cell Line, Tumor; Cell Survival; Curcumin; Drug Delivery Systems; Drug Liberation; Humans; Liposomes; Lung Neoplasms; Nanoparticles; Particle Size

Natural phenolic drugs have good safety and various biological activities. However, poor bioavailability and inadequate bioactivity severely limit their application. A novel composite alkali polysaccharide nanovesicle was formed with supramolecule- and nano- technologies to efficiently deliver natural phenolic antitumor drugs. Alkali polysaccharide nanovesicles (ASDLM) containing supramolecular diferuloylmethane (DLM) had the additional effects of alkali polysaccharide nanovesicles and supramolecules of drug and high-molecular-weight polymers. DLM was isolated from the external environment when double loaded by cyclodextrin and nanovesicles; The nanosize, negative/positive charges and supramolecular structure were beneficial attributes that helped to increase the bioavailability and antitumor activity; supramolecular DLM-loaded nanovesicles made of natural biodegradable excipients showed good safety. Compared to free DLM, ASDLM exhibited superior physicochemical characteristics, favorable changes in the in vitro/in vivo kinetic performance, a possible in vitro-in vivo correlation, enhanced in situ gastrointestinal absorption, increased bioavailability, and an elevated anti-lung cancer efficiency. Composite alkali polysaccharide nanovesicles conjugated with supramolecular-/nano- technology may provide a valuable platform for the oral delivery of botanical drugs to meet clinical requirements.

Topics: A549 Cells; Administration, Oral; Animals; Antineoplastic Agents; Apoptosis; Biological Availability; Curcumin; Drug Carriers; Drug Compounding; Excipients; Humans; Intestinal Absorption; Intestinal Mucosa; Lung Neoplasms; Male; Mice; Nanoparticles; Polysaccharides; Rats; Xenograft Model Antitumor Assays

Curcumin has been proved to inhibit cell proliferation and induce cell apoptosis in non-small cell lung cancer (NSCLC). However, little is known about antimetastatic effects and molecular mechanisms of curcumin in NSCLC. In this study, we investigated the involvement of miR-206 in curcumin's anti-invasion and anti-migration in NSCLC. Cell proliferation was determined by MTT assay. Cell migration and invasion were analyzed by wound healing assay and transwell assay. MiRNA-206 expression was detected by real-time PCR. Western blot was used to detect the protein expression of PI3K/AKT/mTOR signaling pathway. Curcumin significantly inhibited migration and invasion in A549 cells, accompanied by significantly elevated miR-206 expression. Overexpression of miR-206 could inhibit migration and invasion of A549 cells, but it could also significantly decrease the phosphorylation levels of mTOR and AKT. The inhibition of miR-206 promoted cell migration, invasion and increased the phosphorylation level of mTOR and AKT. Furthermore, miR-206 mimics improved the inhibitory effects of curcumin on cell migration, invasion and the phosphorylation level of mTOR and AKT in A549 cells. On the contrary, MiR-206 inhibitors reversed the inhibitory effects of curcumin on cell migration, invasion and the phosphorylation level of mTOR and AKT. In conclusion, curcumin inhibited cell invasion and migration in NSCLC by elevating the expression of miR-206 which further suppressed the activation of the PI3K/AKT/mTOR pathway.

Topics: A549 Cells; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Proliferation; Curcumin; Humans; Lung Neoplasms; MicroRNAs; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Up-Regulation

Lung cancer remains the leading cancer-associated deaths worldwide. Cisplatin (CDDP) was used in combination with curcumin (CUR) for the treatment of non-small cell lung cancer. The aim of this study was to prepare and characterize CDDP prodrug and CUR co-encapsulated layer-by-layer nanoparticles (CDDP-PLGA/CUR LBL NPs) to induce cooperative response, maximize the therapeutic effect, overcome drug resistance, and reduce adverse side effects.. CDDP prodrug (CDDP-PLGA) was synthesized. CDDP-PLGA/CUR LBL NPs were constructed and their physicochemical properties were investigated by particle-size analysis, zeta potential measurement, drug loading, drug entrapment efficiency, and in vitro drug release behavior. In vitro cytotoxicity against human lung adenocarcinoma cell line (A549 cells) was investigated, and in vivo anti-tumor efficiency of CDDP-PLGA/CUR LBL NPs was evaluated on mice bearing A549 cell xenografts.. CDDP-PLGA/CUR LBL NPs have a size of 179.6 ± 6.7 nm, a zeta potential value of -29.9 ± 3.2 mV, high drug entrapment efficiency of 85.6 ± 3.9% (CDDP) and 82.1 ± 2.8% (CUR). The drug release of LBL NPs exhibited a sustained behavior, which made it an ideal vehicle for drug delivery. Furthermore, CDDP-PLGA/CUR LBL NPs could significantly enhance in vitro cytotoxicity and in vivo antitumor effect against A549 cells and lung cancer animal model compared to the single drug-loaded LBL NPs and free drug groups.. CDDP-PLGA/CUR LBL NPs were reported for the first time in the combination therapy of lung cancer. The results demonstrated that the CDDP-PLGA/CUR LBL NPs might be a novel promising system for the synergetic treatment of lung carcinoma.

Topics: A549 Cells; Antineoplastic Agents; Capsules; Cisplatin; Combined Modality Therapy; Curcumin; Drug Liberation; Humans; Lung Neoplasms; Molecular Structure; Nanomedicine; Particle Size; Prodrugs; Surface Properties

Curcumin is a naturally active phenolic compound extracted from the rhizome of the plant Curcuma longa, which has been demonstrated to serve as an anticancer drug in different types of cancer, including non‑small‑cell lung cancer (NSCLC). Accumulating evidence has suggested that curcumin may exert epigenetic regulatory effects on microRNAs (miRs). Therefore, the present study aimed to investigate the role of miR‑192‑5p, and the effects of curcumin, in NSCLC, alongside the underlying mechanisms. Human NSCLC cells, A427 and A549, were treated with curcumin, and the expression levels of miR‑192‑5p and c‑Myc were detected using reverse transcription‑quantitative PCR and western blotting. Cellular proliferation was analyzed using Cell Counting Kit‑8 assays and cell viability was determined using a MTT assay. Additionally, the migratory and invasive abilities of cells were analyzed using Transwell and Matrigel assays, respectively. The binding sites between miR‑192‑5p and c‑Myc were predicted using TargetScanHuman software, and confirmed using a dual‑luciferase reporter assay and RNA immunoprecipitation. Finally, the Wnt pathway regulator, β‑catenin, and cyclin D1 expression levels were determined using western blotting. Curcumin treatment inhibited NSCLC cell proliferation, migration, invasion and viability in a dose‑dependent manner, in addition to promoting a dose‑dependent increase in the expression levels of miR‑192‑5p and a reduction in c‑Myc expression levels. Notably, the genetic knockdown of miR‑192‑5p blocked the inhibitory effects of curcumin on NSCLC progression and instead promoted NSCLC progression, which was observed to be partially reversed by c‑Myc silencing; thus, c‑Myc was suggested to be a direct target gene of miR‑192‑5p as demonstrated by the TargetScanHuman database, dual‑lucierase and RIP assay results. In addition, the curcumin‑induced decreased expression levels of β‑catenin, cyclin D1 and c‑Myc were rescued following the genetic knockdown of miR‑192‑5p. In conclusion, these findings suggested that the upregulation of miR‑192‑5p may underlie the inhibitory effects of curcumin on NSCLC cells through targeting c‑Myc and inactivating the Wnt/β‑catenin signaling pathway.

Topics: A549 Cells; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Proliferation; Curcumin; Genes, myc; HEK293 Cells; Humans; Lung Neoplasms; MicroRNAs; Wnt Signaling Pathway

Curcumin is a natural phytochemical polyphenol with significant anti-cancer effects and negligible side effects. In this study, the therapeutic capacity of nanomicellar-curcumin for treating lung metastasis was evaluated in an immunocompetent mouse model of metastatic melanoma.. Two doses of nanomicellar-curcumin (i.e. 10 and 20 μM) were used to induce cytotoxicity in 3 melanoma cell lines. A total of 60 mice were allocated to 20 mice in each of three groups (10 for survival and 10 for assays). Groups were no treatment control, PBS control, nanomicellar-curcumin 20 mg/kg IP 4 times a week, for three weeks). Immunohistochemistry, TUNEL assay, and Western blots were used on lung samples.. Nanomicellar-curcumin inhibited the in vitro growth of B16 F10 melanoma cells at 20 μM over 72 h. In vivo, 20 mg/kg nanomicellar-curcumin injected IP, delayed tumor cell growth and significantly extended mouse survival rate. Tumor infiltration of regulatory T cells and angiogenesis were reduced, while IFN-γ and CXCL10 were increased.. Nanomicellar-curcumin can inhibit lung metastasis and growing melanoma via activation of apoptosis, activated T cells and inhibition of angiogenesis, tumor growth and regulatory T cells.

Topics: Animals; Apoptosis; Cell Proliferation; Cell Survival; Curcumin; Disease Models, Animal; Humans; Lung Neoplasms; Melanoma, Experimental; Neoplasm Metastasis; Neovascularization, Pathologic; T-Lymphocytes, Regulatory

The anticancer effects of curcumin are based on the induction of apoptosis, but the specific mechanisms have not yet been fully elucidated. To address this issue, we investigated the effects of curcumin on the intrinsic apoptosis pathway using mitochondria from A549 cells. Curcumin decreased the levels of 14-3-3 proteins, key molecules that inhibit the activation of proapoptotic factors known as BH3-only proteins (e.g. Bad). Curcumin-induced suppression of 14-3-3 protein levels was associated with reduced cytosolic Bad and elevation of mitochondrial Bad, leading to a drop in the mitochondrial membrane potential. 14-3-3 proteins generally interact with Bad phosphorylated by AKT, thus preventing its translocation to the mitochondria where it can promote cell death. Curcumin not only decreased the expression of 14-3-3 proteins but also promoted Bad dephosphorylation in an AKT-dependent fashion. Our results provide novel evidence for the induction of apoptosis by curcumin at multiple stages of the mitochondrial cascade.

Topics: 14-3-3 Proteins; A549 Cells; Antineoplastic Agents; Apoptosis; bcl-Associated Death Protein; Curcumin; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial

To develop docetaxel (DT) and curcumin (CUR) co-loaded nanostructured lipid carriers (DTCR-NLCs) for ratiometric co-targeting to non-small cell lung carcinoma (NSCLC) cells.. The DTCR-NLCs were developed by employing a high-pressure homogenisation technique and optimised by employing a rotatable central composite design response surface methodology (RCCD-RSM) via the design of experiments (DoE) approach.. The optimised DTCR-NLCs had a particle size (D90) of 150.2 ± 5.2 nm, Pdi of 0.263 ± 0.15, zeta potential of +26.3 ± 5.2 mv. The % drug loading (% DL) of DT and CUR was observed to be 1.38 ± 0.98 and 2.99 ± 1.24, respectively. Dissolution studies depicted a pH-independent drug release (≈98% drug release at 144 h). The DTCR-NLCs were stable and haemocompatible. MTT cell viability assay of DTCR-NLCs demonstrated considerably increased cytotoxicity towards NCI-H460 cells.. The developed DTCR-NLCs heralds the future of an efficacious and safer Taxane therapy for NSCLC.

Topics: Antineoplastic Agents; Calorimetry, Differential Scanning; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Cobalt; Curcumin; Docetaxel; Drug Delivery Systems; Drug Screening Assays, Antitumor; Hemolysis; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Lipids; Lung Neoplasms; Microspheres; Nanostructures; Particle Size; Temperature; Tetrazolium Salts; Thiazoles; X-Ray Diffraction

Despite the increasing number of available therapeutic methods, the prognosis of non‑small cell lung cancer (NSCLC) remains poor. Furthermore, side effects are an important limiting factor in the treatment of NSCLC. Therefore, developing an efficacious, safe, affordable and easily accessible chemotherapeutic agent is necessary for NSCLC treatment. As a natural chemical produced by Zingiberaceae plants, curcumin exerts distinct antitumor effects on several tumor types. In the present study, curcumin was observed to inhibit not only cell proliferation and cell cycle transition, but also cell migration in NSCLC, as determined by a series of experiments (such as MTS assay, colony formation assay, flow cytometric analysis, Transwell migration assay and western blotting). Mechanistically, curcumin induced G2/M phase arrest by controlling cell cycle‑ and epithelial‑mesenchymal transition (EMT)‑related checkpoints. Furthermore, curcumin significantly inhibited the expression of Toll‑like receptor 4 (TLR4)/MyD88 and EGFR in a dose‑ and time‑dependent manner. Conversely, EGF reversed the inhibitory action of curcumin on TLR4/MyD88. In clinical specimens, TLR4 and MyD88 were highly expressed in NSCLC tissues, and a significant positive association was observed between TLR4 and MyD88 expression. These data suggested that curcumin may control the EGFR and TLR4/MyD88 pathways to synergistically downregulate downstream cell cycle‑ and EMT‑related regulators, in order to block cell proliferation and metastasis in NSCLC. These findings provide evidence for the clinical application of curcumin.

Topics: Adult; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Myeloid Differentiation Factor 88; Signal Transduction; Toll-Like Receptor 4

This study was designed to explore the effects of curcumin on proliferation, migration and invasion of human lung adenocarcinoma LTEP-A2 cells and determine its mechanism. Human lung adenocarcinoma LTEP-A2 cell was cultured in vitro. After incubation with different concentrations of curcumin (5, 10, 15 μmol/L), the effects of curcumin on proliferation, migration and invasion of human lung adenocarcinoma LTEP-A2 cells were observed by MTT assay, wound healing and transwell assay. The expression levels of COX-2 and MMP-9 were detected by western blot. Compared with the blank control group, curcumin decreased the survival rate of LTEP-A2 cells, shorten the cell migration distance and decrease the number of LTEP-A2 cells penetrating membrane. The expression levels of COX-2 and MMP-9 were both down-regulated by curcumin. Curcumin can inhibit the proliferation, migration and invasion of human lung adenocarcinoma LTEP-A2 cells. The mechanism may be related to the down-regulation of COX-2 and MMP-9 expression.

Topics: Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Cyclooxygenase 2; Humans; Lung Neoplasms; Matrix Metalloproteinase 9

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Crizotinib; Curcumin; Drug Resistance, Neoplasm; Drug Synergism; Humans; Lung Neoplasms; Protein Kinase Inhibitors

Galbanic acid (GBA), which is known as a sesquiterpene coumarin, has been reported to have various anti-tumor activities in different cells. Our study intended to investigate whether curcumin potentiates GBA-induced anti-tumor effect in non-small cell lung cancer cells.. The combined effect of GBA and curcumin on cell viability was examined by MTT analysis. Cellular apoptosis was evaluated by flow cytometry analysis. Autophagy was defined by autophagosome observed by confocal microscopy after infected with GFP-LC3 adenovirus. In addition, the expression of marker proteins involved in cell apoptosis, autophagy, and Akt/mTOR signaling pathway were estimated by qRT-PCR and Western Blotting assay.. 15 μM curcumin combined with 40 μM GBA could obtain better synergistic repressive efficacy on cell viability and notably induced cell apoptosis in A549 cells. Besides, curcumin in alliance with GBA could significantly inhibit cell migration and invasion. GFP-LC3 infection experiments elaborated that curcumin could potentiate GBA induced cell autophagy and restrain the phosphorylation of Akt/mTOR/P70s6k signaling pathway. What's more, the reaction of migration, apoptosis, and autophagy induced by curcumin and GBA treatment could be reversed by mTOR inhibitor rapamycin and AKT activator insulin.

Topics: A549 Cells; Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Coumarins; Curcumin; Humans; Lung Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

In this study, the novel carrier materials were screened to structure targeting nano-micelles (named 'nano-dandelion') for synchronous delivery of curcumin (Cur) and baicalin (Bai), which could effectively overcome the tumor resistance. Mannose (Man) was found to bind better to CD206 receptors on the surface of tumor-associated macrophages (TAMs), thereby increasing the number of nano-dandelion engulfed by TAMs. Furthermore, oligomeric hyaluronic acid (oHA) was able to target CD44 receptors, resulting in recruitment of a higher number of nano-dandelion to locate and engulf tumor cells. The disulfide bond (S-S) in 3,3'-dithiodipropionic acid (DA) could be broken by the high concentration of glutathione (GSH) in the tumor microenvironment (TME). Based on this, we selected DA to connect hydrophobic fragments (quercetin, Que) and oHA. A reduction-sensitive amphiphilic carrier material, quercetin-dithiodipropionic acid-oligomeric hyaluronic acid-mannose-ferulic acid (Que-S-S-oHA-Man-FA; QHMF) was fabricated and synthesized by

Topics: A549 Cells; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Curcumin; Drug Carriers; Drug Combinations; Flavonoids; Humans; Hyaluronic Acid; Lung Neoplasms; Macrophages; Mice, Nude; Nanoparticles; Polymers

1,7-Bis(4-hydroxyphenyl)-1,4-heptadien-3-one (EB30) is a diarylheptanoid-like compound isolated from Viscum coloratum. This curcumin analog exhibits significant cytotoxic activity against HeLa, SGC-7901, and MCF-7 cells. However, little is known about the anticancer effects and mechanisms of EB30 in human lung cancer. The current study reports that EB30 significantly reduced the cell viability of A549 and NCI-H292 human lung cancer cells. Further examination revealed that EB30 not only induced cell cycle arrest and promoted the generation of reactive oxygen species (ROS) but also induced cell apoptosis through the intrinsic and extrinsic signaling pathways. Furthermore, EB30 upregulated the expression levels of p-ERK1/2 and p-P90RSK, whereas downregulating the phosphorylation of Akt and P70RSK. Cell viability was further inhibited by the combination of EB30 with LY294002 (a specific PI3K inhibitor) or U0126 (a MEK inhibitor). The current study indicates that EB30 is a potential anticancer agent that induces cell apoptosis via suppression of the PI3K/Akt pathway and activation of the ERK1/2 pathway.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; Plant Extracts; Proto-Oncogene Proteins c-akt; Signal Transduction; Viscum

The present study explored chemopreventive aspects of curcumin and resveratrol in the experimental model of lung carcinogenesis in rats. The main aim was to establish efficacy of combined phytochemicals treatment over individual treatments in rat cancer model. The study was performed in terms of both biophysical and biochemical parameters. The rats were segregated into five groups, which included normal control, benzo[a]pyrene (BP) treated, BP + curcumin treated, BP + resveratrol treated, and BP + curcumin + resveratrol treated groups. The results confirmed significant changes in the biochemical indices of the BP treated rats. Further, radiorespirometric studies showed significant rise in the

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Benzo(a)pyrene; Carcinogenesis; Curcumin; Cytochrome P-450 Enzyme System; Drug Synergism; Lung; Lung Neoplasms; Male; Rats, Wistar; Resveratrol

To date, there are some chemically synthesized curcumin derivatives which were produced and identified to evade the disadvantages of physiochemical stability and solubility of curcumin. Here, one novel curcumin derivative, (2-(3-{(1E)-{(E)-3-(4-hydroxy-3-methoxybenzylidene)-2-oxocyclohexylidene)methyl)-1H-indol-1-yl)acetic acid}, (abbreviated as MOMI-1) was first used to detect the antiproliferation activity with MTT assays in different cancer cells including A549 lung cancer cells, MCF-7, and HEPG2 cell lines, and exhibited its wide inhibition spectrum. Next, we found that MOMI-1 could induce autophagic genesis of A549 cells by acridine orange or monodansylcadaverine (MDC) staining and green fluorescent protein-light chain 3 (GFP-LC3) recombinant plasmid transfection analysis, respectively. Western blot analysis confirmed the LC3-I/II conversion, beclin-1 increase and p62 reduction of A549 cells after exposure of MOMI-1, which suggested the typical autophagy induction. The following cell cycle test showed that MOMI-1 could block A549 cells in G0/G1 phase. Furthermore, wounding healing experiment and transwell assays demonstrated that MOMI-1 also possessed the antimigration ability of A549 cells. Our current results confirmed that MOMI-1 could inhibit the proliferation and induce autophagy of A549 cells, which provide a new potential chemical candidate of antigrowth of A549 lung cancer cells. Future work needs to focus on the mechanism of autophagy pathway of A549 cells.

Topics: 3T3 Cells; A549 Cells; Animals; Antineoplastic Agents; Autophagy; Cell Proliferation; Curcumin; G1 Phase; Humans; Lung Neoplasms; Mice; Resting Phase, Cell Cycle; Wound Healing

Excision repair cross-complementary 1 (ERCC1) overexpression in lung cancer cells is strongly correlated with its resistance to platinum-based chemotherapy. Overexpression of thymidine phosphorylase (TP) reverts platinum-induced cancer cell death.. Curcumin has been reported to enhance antitumor properties through the suppression of TP and ERCC1 in non-small cell lung carcinoma cells (NSCLC). Nevertheless, whether two other curcuminoids, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) from Curcuma longa demonstrate antitumor activity like that of curcumin remain unknown.. MTT assay was conducted to determine the cell cytotoxicity. Western blotting was used to determine the protein expressions. Docking is the virtual screening of a database of compounds and predicting the strongest binders based on various scoring functions. BIOVIA Discovery Studio 4.5 (D.S. 4.5) were used for docking.. Firstly, when compared with curcumin and BDMC, DMC exhibited the most potent cytotoxic effect on NSCLC, most importantly, MRC-5, a lung fetal fibroblast, was insensitive to DMC (under 30 µM). Secondly, DMC alone significantly inhibited on-target cisplatin (CDDP) resistance protein, ERCC1, via PI3K-Akt-snail pathways, and TP protein expression in A549 cells. Thirdly, DMC treatment markedly increased post-target CDDP resistance pathway including Bax and cytochrome c. DMC significantly decreased Bcl-2 protein expressions. Finally, MTT assay indicated that DMC significantly increased CDDP-induced cytotoxicity and was confirmed with an increased Bax/Bcl-2 ratio, indicating upregulation of caspase-3.. We concluded that enhancement of the cytotoxicity to CDDP by coadminstration with DMC was mediated by down-regulation of the expression of TP and ERCC1, regulated by PI3K-Akt-Snail pathway inactivation.

Topics: A549 Cells; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cisplatin; Curcuma; Curcumin; Diarylheptanoids; DNA-Binding Proteins; Down-Regulation; Endonucleases; Humans; Lung Neoplasms; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Thymidine Phosphorylase

The rate of lung cancer incidence is alarmingly mounting, despite the decline of smoking and tobacco consumption. Recent reports indicate a very high correlation between the growing fast food culture and lung cancer incidence. Benzo[a]pyrene (B[a]P) is a potent carcinogen abundantly present in grilled and deep-fried food and in tobacco smoke. Our previous studies have proved the efficacy of curcumin in curbing B[a]P-induced lung carcinogenesis. However, the poor pharmacokinetic profile of the compound considerably hampers its potential as an effective chemopreventive. This study was intended to evaluate whether encapsulation of curcumin in chitosan nanoparticles can improve the cellular uptake and prolong the tissue retention of curcumin yielding better chemoprevention. The curcumin-loaded chitosan nanoparticles (chitosan nanocurcumin) exhibited a size of 170-200 nm in transmission electron microscopy.

Topics: Animals; Antineoplastic Agents; Benzo(a)pyrene; Biological Availability; Chitosan; Curcumin; Lung Neoplasms; Male; Mice; Nanoparticles

Lung cancer is the leading cause of cancer death worldwide. To overcome the toxic side effects and multidrug resistance (MDR) during doxorubicin (DOX) chemotherapy, a urokinase plasminogen activator receptor (uPAR) targeting U11 peptide decorated, pH-sensitive, dual drugs co-encapsulated nanoparticles (NPs) system is employed in this study. A U11 peptide conjugated, pH-sensitive DOX prodrug (U11-DOX) was synthesized and used as materials to produce NPs. A curcumin (CUR) and U11-DOX co-encapsulated NPs system (U11-DOX/CUR NPs) was constructed to treat lung cancer. After the characterization of biophysical properties of this NPs system, synergistic chemotherapeutic efficacy was evaluated in both cultured cancer cells and tumor-bearing animal model. U11-DOX/CUR NPs had a uniformly spherical shape with a core-shell structure. The mean particle size and zeta potential of the U11-DOX/CUR NPs was 121.3 nm and -33.5 mV, with a DOX and CUR EE of 81.7 and 90.5%, respectively. The DOX release from U11-DOX/CUR NPs was 83.5, 55.2, and 32.8% correspondence to the pH of 5.0, 6.0 and 7.4. Cellular uptake efficiency of U11-DOX/CUR NPs was significantly higher than non U11 peptide decorated DOX/CUR NPs. U11-DOX/CUR NPs displayed a pronounced synergy effects in vitro and an obvious tumor tissue accumulation efficiency in vivo. In vivo antitumor experiment showed that U11-DOX/CUR NPs could inhibit the tumor growth to a level of 85%.In vitro and in vivo studies demonstrated that U11-DOX/CUR NPs is a sustained released, pH responsive, synergistic antitumor system. This study suggests that the U11-DOX/CUR NPs have promising potential for combination treatment of lung cancer.

Topics: A549 Cells; Animals; Antineoplastic Combined Chemotherapy Protocols; Curcumin; Doxorubicin; Drug Carriers; Drug Delivery Systems; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen-Ion Concentration; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Nanomedicine; Nanoparticles; Prodrugs; Xenograft Model Antitumor Assays

Curcumin induces cytotoxic cell death in several human cancer cells. Here, we have investigated the effects of curcumin on non-small-cell lung cancer (NSCLC) with an aim to identify underlying mechanisms of its cytotoxic effect.. The effects of various concentrations of curcumin on the NSCLC cell lines A549 and SPC-A1 were evaluated by MTT assay, colony-forming assay and flow cytometry. Additionally, protein expression associated with different signaling pathways was assessed using western blotting.. Curcumin exhibited cytotoxicity against NSCLC, evident from the inhibition of cell proliferation, G2/M arrest, DNA damage, endoplasmic reticulum stress and mitochondrial apoptosis. The anticancer effect was related to reactive oxygen species (ROS) accumulation and could be reversed by ROS scavengers, catalase and N-acetyl-l-cysteine. Curcumin decreased mitochondrial transmembrane potential and induced ROS production, thereby activating the DNA damage/repair pathway and mitochondrial apoptosis.. These results indicate that curcumin could be an effective therapeutic candidate for NSCLC.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; DNA Damage; Endoplasmic Reticulum Stress; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species; Signal Transduction

Presently, curcumin derivatives had been paid more attention in view of their high bioavailability or water solubility, which herein possibly replaced the curcumin for their functional applications in future. Here, one novel chemically synthesized curcumin derivative, ZYX01, was used to identify anti-proliferation activity of human non-small lung cancer cells A549 and its anti-proliferative mechanism. Our study showed that ZYX01 could induce autophagic death of A549 cells by morphological observation, MTT assay, acridine orange staining and MDC assay, which possess a dose-and time-dependent manner. ZYX01-treated A549 cells possessed an increase in LC3-II/LC3-I ratio, upregulation of beclin-1 and downregulation of p62 expression. We further confirmed the cellular AMPK/ULK1/Beclin-1 signaling pathway in A549 cells after ZYX01 treatment. The anti-migration effect of ZYX01 in A549 cells was also explored by wound healing assay and transwell experiment. Current results had confirmed that ZYX01 induced A549 cells autophagy through AMPK/ULK1/Beclin-1 pathway and shed light on the future study on the anti-cancer molecular mechanism.

Topics: A549 Cells; Adenylate Kinase; Autophagy; Autophagy-Related Protein-1 Homolog; Beclin-1; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Proliferation; Curcumin; Cytoplasmic Vesicles; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Microtubule-Associated Proteins; Signal Transduction

Curcumin attracted attention due to its promising anti-cancer properties and safety performance. However, its poor aqueous solubility and low bioavailability have to be overcome before it goes into clinic use. Here, porous composite particles are prepared by loading curcumin into mesoporous material SBA-15, and its therapeutic effect on lung cancer via inhalation administration have also been evaluated. The inclusion of curcumin in host material SBA-15 was confirmed by the reduced surface area and pore diameter of the composite material, and the aerodynamic performance of the composite material was investigated by FT-4 and NGI. Phagocytosis experiments on RAW264.7, the toxicity of material extracts on BEAS-2B cells, and the haemolysis experiments showed that the mesoporous materials had good biocompatibility at 10-400 μg/mL. The B16F10 melanoma metastatic lung mouse model was used to investigate the therapeutic effect of lung cancer after inhalable administration. It was found that the body weight of the curcumin composite particle-administered group decreased more slowly and the lung disease developed slower than the curcumin crude drug group, indicating that the composite particles has a certain inhibitory effect on tumours.

Topics: Administration, Inhalation; Animals; Biological Availability; Cell Culture Techniques; Curcumin; Drug Carriers; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Models, Animal; Neoplasm Metastasis; Particle Size; Phagocytosis; RAW 264.7 Cells; Silicon Dioxide; Solubility

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are being wildly used as target therapy in non-small-cell lung cancer (NSCLC). However, NSCLC patients with wild-type EGFR and KRAS mutation are primary resistant to EGFR-TKIs such as gefitinib. Curcumin has been known as a potential therapeutic agent for several major human cancers. In this study, we investigated the effect of curcumin on the reversal of gefitinib resistance in NSCLC cells as well as their molecular bases.. H157 (wild-type EGFR and KARS mutation) and H1299 (wild-type EGFR and HRAS mutation) cells were treated with gefitinib or curcumin alone, or the two combination, and then cell viability, EGFR activity, expressions of Sp1 and Sp1-dependent proteins and receptor tyrosine kinases, markers of autophagy and apoptosis were examined by using CCK-8, colony formation, immunoblot, quantitative PCR, immunofluoscence, and flow cytometry assays. Also xenograft experiments were conduced to test the synergism of curcumin to gefitinib.. Our results showed that curcumin significantly enhanced inhibitory effect of gefitinib on primary gefitinib-resistant NSCLC cell lines H157 and H1299. Combination treatment with curcumin and gefitinib markedly downregulated EGFR activity through suppressing Sp1 and blocking interaction of Sp1 and HADC1, and markedly suppressed receptor tyrosine kinases as well as ERK/MEK and AKT/S6K pathways in the resistant NSCLC cells. Meanwhile, combination treatment of curcumin and gefitinib caused dramatic autophagy induction, autophagic cell death and autophagy-mediated apoptosis, compared to curcumin or gefitinib treatment alone, as evidenced by the findings that curcumin and gefitinib combination treatment-produced synergistic growth inhibition and apoptosis activation can be reversed by pharmacological autophagy inhibitors (Baf A1 or 3-MA) or knockdown of Beclin-1 or ATG7, also can be partially returned by pan-caspase inhibitor (Z-VAD-FMK) in H157 and H1299 cells. Xenograft experiments in vivo yielded similar results.. These data indicate that the synergism of curcumin on gefitinib was autophagy dependent. Curcumin can be used as a sensitizer to enhance the efficacy of EGFR-TKIs and overcome the EGFR-TKI resistance in NSCLC patients with wild-type EGFR and/or KRAS mutation.

Topics: Animals; Antineoplastic Agents; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Curcumin; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Mutation; Protein Binding; Proto-Oncogene Proteins p21(ras); Signal Transduction

Background: Metastasis is a major cause of death from cancer in triple-negative breast cancer (TNBC). Apoptosis\ evasion is a critical feature of metastatic tumor cells. Chemopreventive and apoptotic potential of curcumin has been\ shown in breast cancer. However, the precise mechanism of these effects against metastatic tumor cells has not been\ clearly addressed yet. Methods: 4T1 cell line was used for induction of metastatic animal model of breast cancer.\ Primary and metastatic tumor cells were extracted from subcutaneous tumor and lung of cancerous mice, respectively.\ MTT assay was used to determine the effect of curcumin on viability of tumor cells. Quantitative real-time polymerase\ chain reaction was performed to analyze the effect of curcumin on death receptor-5 (DR-5) gene expression. Results:\ Our data revealed that, compared with primary tumor cells, metastatic tumor cells were more resistance to apoptosis\ effects of curcumin. The DR-5 gene expression was up-regulated in both primary and metastatic tumor cells after\ curcumin treatment, but this up-regulation was significantly higher in primary tumor cells compared with metastatic cells.\ Conclusion: These findings provided important insights regarding the molecular mechanism of apoptosis resistance of\ metastatic tumor cells and can be used for designing a targeted therapeutic strategies in combat with metastatic TNBC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Receptors, TNF-Related Apoptosis-Inducing Ligand; Triple Negative Breast Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

We prepared octreotide (OCT)-modified curcumin plus docetaxel micelles to enhance active targeting and inhibit tumor metastasis by destroying vasculogenic mimicry (VM) channels. Soluplus was applied as an amphiphilic material to form micelles via film dispersion. The cytotoxic effects, active cellular targeting, and inhibitory effects on metastasis were systematically evaluated

Topics: A549 Cells; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Curcumin; Docetaxel; Drug Carriers; Drug Delivery Systems; Humans; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Micelles; Octreotide; Polyethylene Glycols; Polyvinyls

Turmeric (Curcuma longa L, Zingiberaceae) rhizomes exhibit versatile biological activities including the significant anti-cancer property. As an herbal medicine, the therapeutic effects of turmeric may be expressed by multi-components which have complicated integration effects on multi-targets. Therefore, having previously found three A549 cell-binding curcuminoids (curcumin, Cur; demethoxycurcumin, DMcur; bisdemethoxycurcumin, BMcur) from turmeric, studies were undertaken in this paper to determine the anti-cancer mechanism and integration effects of these curcuminoids by using chemical markers' knockout and UHPLC-LTQ Orbitrap MS-based metabolomics. Four curcuminoid-containing fractions including a mixture of 3 cell-binding curcuminoids (CE), and three individual curcuminoids with natural proportion in turmeric were prepared by chemical markers' knockout method. CE, Cur, DMcur and BMcur fractions showed significant anti-cancer activity on A549 cells. The activities of CE, Cur and BMcur fractions were comparative with the turmeric crude extract (TcE). In the metabolomics study, CE and three individual curcuminoid fractions changed the expression of 25 metabolites in A549 cells, which were involved in glycerophospholipid catabolism, sphingolipid metabolism and fatty acid metabolism, etc. Among them, glycerophospholipid catabolism was disordered greatly in CE group, while sphingolipid metabolism was suggested to be closely related to DMcur and BMcur activity. Furthermore, the metabolomics data showed that three curcuminoids existed synergistic and antagonistic actions and the use of multi-curcuminoids is more powerful than use of single curcuminoid on the metabolic alterations of A549 cells.

Topics: A549 Cells; Antineoplastic Agents; Cell Line, Tumor; Chromatography, High Pressure Liquid; Curcuma; Curcumin; Diarylheptanoids; Humans; Lung Neoplasms; Metabolomics; Phytotherapy; Plant Extracts; Rhizome

Topics: Animals; Antineoplastic Agents; Curcuma; Female; Genes, fos; Genes, jun; Lung Neoplasms; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Neoplasm Metastasis; Plant Extracts; Plant Roots; Receptors, CCR7

EF24 and F35 both were effective monocarbonyl curcumin analogues (MCACs) with excellent anti-tumor activity, however, drug defect such as toxicity may limit their further development. To get anti-lung cancer drugs with high efficiency, low toxicity and chemosensitization, a series of analogues based on EF24 and F35 were designed and synthesized. A number of compounds were found to exhibit cytotoxic activities selectively towards lung cancer cells compared to normal cells. Among these compounds, 5B was considered as an optimal anti-tumor agent for lung cancer cells with IC

Topics: A549 Cells; Antineoplastic Agents; Curcumin; Drug Design; Humans; Lung Neoplasms; MAP Kinase Signaling System; NF-kappa B; Reactive Oxygen Species

Lung cancer is responsible for increase in mortality due to cancer-related deaths, and new approaches are being explored for the betterment of the situation. In the present study, chemopreventive efficacy of curcumin and quercetin was investigated against benzo(a)pyrene (BP)-induced lung carcinogenesis. The mice were segregated into five groups, which included normal control, BP-treated, BP + curcumin-treated, BP + quercetin-treated, and BP + curcumin + quercetin-treated groups. The morphological and histological analyses of tumor nodules confirmed lung carcinogenesis22 weeks after weeks single intraperitoneal injection of BP at a dose of 100 mg/kg body weight to mice. Curcumin and quercetin when administered individually as well as in combination significantly elevated the expression of acetylated-p53, which was otherwise depressed due to BP treatment. Also, both the phytochemicals significantly reduced the BP-inflicted increased levels of phosphorylated-p53. Furthermore, observed increase in the number of apoptotic cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), assay and increased activities of caspase 3 and 9 confirmed the induction of apoptosis by curcumin and quercetin. Moreover, the histological slides also showed noticeable improvement in the histoarchitecture of lungs by phytochemicals. The present study concludes that prophylactic treatment with curcumin and quercetin induces apoptosis in the lungs by modulation of p53 posttranslational modifications.

Topics: Animals; Benzo(a)pyrene; Carcinogens; Curcumin; Lung; Lung Neoplasms; Male; Mice; Protein Processing, Post-Translational; Quercetin; Tumor Suppressor Protein p53

The regulatory T cells (Treg) play an important role in the tumor tolerance. The methods to regulate the Treg population in cancer-bearing hosts are limited currently. The effect of curcumin on inhibiting cancer has been recognized, but the mechanism remains elusive. This study tests a hypothesis that administration of curcumin down regulates Tregs in lung cancer (LC) patients. In this study, a group of LC patients was treated with curcumin. The peripheral Tregs and T helper (Th) 1 cells were analyzed by flow cytometry. The mechanism by which curcumin regulated the Tregs was observed by cell culture approaches. The results showed that the frequency of peripheral Treg was markedly higher in LC patients than that in healthy subjects, which was suppressed after treating with curcumin for 2 weeks. The peripheral Th1 cells were increased in LC patients after the curcumin therapy. The data of the in vitro experiments showed that curcumin converted the LC patient-isolated Tregs to Th1 cells via repressing the gene transcription of forkhead protein-3 and increasing the expression of interferon-γ. In conclusion, curcumin can convert LC patient-isolated Tregs to Th1 cells. The results suggest that curcumin may improve the antitumor immunity by regulating the tumor specific immune tolerance.

Topics: Adult; Aged; Curcumin; Female; Forkhead Transcription Factors; Humans; Interferon-gamma; Lung Neoplasms; Male; Middle Aged; T-Lymphocytes, Regulatory; Th1 Cells; Tumor Cells, Cultured

The anti-cancer potential of curcumin, a natural NFκβ inhibitor, has been reported extensively in breast, lung and other cancers. In vitro and in vivo studies indicate that the therapeutic efficacy of curcumin is enhanced when formulated in a nanoparticulate carrier. However, the mechanism of action of curcumin at the molecular level in the hypoxic tumour micro-environment is not fully understood. Hence, the aim of our study was to investigate the mechanism of action of curcumin formulated as nanoparticles in in vitro models of breast and lung cancer under an hypoxic microenvironment.. Biodegradable poly(lactic-co-glycolic acid) PLGA nanoparticles (NP), loaded with curcumin (cur-PLGA-NP), were fabricated using a solvent evaporation technique to overcome solubility issues and to facilitate intracellular curcumin delivery. Cytotoxicity of free curcumin and cur-PLGA-NP was evaluated in MDA-MB-231 and A549 cell lines using migration, invasion and colony formation assays. All treatments were performed under an hypoxic micro-environment and whole cell lysates from controls and test groups were used to determine the expression of HIF-1α and p65 levels using ELISA assays.. A ten-fold increase in solubility, three-fold increase in anti-cancer activity and a significant reduction in the levels of cellular HIF-1α and nuclear p65 (Rel A) were observed for cur-PLGA-NP, when compared to free curcumin.. Our findings indicate that curcumin can effectively lower the elevated levels of HIF-1α and nuclear p65 (Rel A) in breast and lung cancer cells under an hypoxic tumour micro-environment when delivered in nanoparticulate form. This applied means of colloidal delivery could explain the improved anti-cancer efficacy of curcumin and has further potential applications in enhancing the activity of anti-cancer agents of low solubility.

Topics: A549 Cells; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lactic Acid; Lung Neoplasms; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Solubility; Transcription Factor RelA

Tobacco smoke is a major risk factor for lung cancer. Epithelial‑mesenchymal transition (EMT) is decisive in cancer invasion and metastasis, and therefore promotes cancer progression. Mitogen‑activated protein kinase (MAPK) pathways are implicated in various aspects of cancer development and progression, including the EMT process. The chemopreventive effect of curcumin on carcinogenesis has been reported in vivo and in vitro. The present study investigated tobacco smoke‑induced alterations in the MAPK/activator protein‑1 (AP‑1) pathways, and pulmonary EMT changes in the lungs of mice, and further observed the chemopreventive effect of curcumin. The protein expression levels analyzed by western blot analysis demonstrated that 12 weeks of tobacco smoke exposure activated extracellular‑signal‑regulated kinase (ERK) 1/2, c‑Jun N‑terminal kinase (JNK) and p38 MAPK pathways, in addition to AP‑1, in the lungs of mice, while reducing the activation of ERK5/MAPK pathways. The results also indicated that the mRNA and protein levels of the epithelial markers E‑cadherin and zona occludens‑1 were reduced following tobacco smoke exposure. Conversely, the expression levels of mRNA and protein for the mesenchymal markers vimentin and N‑cadherin were increased. Curcumin treatment inhibited tobacco smoke‑induced MAPK/AP‑1 activation, including ERK1/2, JNK and p38 MAPK pathways, and AP‑1 proteins, and reversed EMT alterations in lung tissue. The results of the present study provide new insights into the molecular mechanisms of tobacco smoke‑associated lung cancer and may open up new avenues in the search for potential therapeutic targets in lung tumorigenesis.

Topics: Animals; Anticarcinogenic Agents; Curcumin; Drug Evaluation, Preclinical; Epithelial-Mesenchymal Transition; Lung; Lung Neoplasms; Male; MAP Kinase Signaling System; Mice, Inbred BALB C; Nicotiana; Smoke; Smoking

Curcumin is known to exhibit anticancer effects on various cancers with selective cytotoxicity in tumor cells. In the present study, the effects of curcumin‑induced multiple PCDs on human non‑small cell lung cancer (NSCLC) cells and the potential molecular mechanisms of apoptosis and autophagy triggered by curcumin via the PI3K/Akt/mTOR signaling pathway were explored, further confirmed by co‑culture of curcumin with mTOR blocker rapamycin and PI3K/Akt inhibitor LY294002. The anti‑proliferation effect of different stimulus was measured by MTT assay. Apoptosis was detected by flow cytometry. Autophagy induction was detected by MDC labeling and western blotting of Beclin1, LC3, and p62 expression. The mRNA and protein expression levels of Akt and mTOR were assayed by real‑time fluorescence quantitative (qRT‑PCR) technique and western blotting. Our results showed that curcumin inhibited the viability of A549 cells time‑ and dose‑dependently. In addition, a dosage-dependent A549 cell apoptosis‑induction phenomena was observed by the curcumin intervention. Moreover, obvious autophagy was induced after curcumin‑treatment, characterized by the formation of fluorescent particles [autophagic vesicles (AVs)] and significant increase in ratio of LC3‑Ⅱ/LC3‑Ⅰ and Beclin1 as well as decreased p62 expression. Furthermore, the effect of curcumin on a substantial downregulation of phosphatidylinositol 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was observed. It is worth noting that the inhibition of mTOR by rapamycin or of PI3K/Akt by LY294002 augmented curcumin‑induced apoptosis and autophagy, leading to significant inhibition of cell proliferation. From these findings, it can be speculated that curcumin potently inhibit the cell growth of NSCLC A549 cells through inducing both apoptosis and autophagy by inhibition of the PI3K/Akt/mTOR pathway. These results support the potential use of curcumin as a novel candidate in treatment of human lung cancer.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Biomarkers, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Lung carcinoma is the leading cause of mortality due to cancer worldwide. Autophagy has a significant role in the development and progression of non‑small cell lung carcinoma (NSCLC). A previous study has revealed that tetrahydrocurcumin (THC), a traditional Chinese medicine isolated from Curcuma wenyujin (Chen & Ling, 1981), induces autophagy in human A549 NSCLC cells. The present study evaluated THC‑induced autophagy in A549 cells using various assays, including the Cell Counting Kit‑8, acridine orange staining, flow cytometry, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR), and western blot analysis of the markers of autophagy. THC inhibited the growth and proliferation of A549 cells (P<0.05). Acridine orange staining and flow cytometry revealed that THC treatment significantly enhanced autophagic cell proliferation inhibition (P<0.05). The RT‑qPCR analysis revealed that THC treatment increased Beclin‑1 expression level and compared with the control group (P<0.05). The light chain 3 (LC3)‑II/LC3‑I ratio was reduced in THC‑treated cells when compared with the control group (P<0.05). Protein expression of various markers of autophagy, including p62, phosphorylated (p)‑mechanistic target of rapamycin (mTOR), phosphoinositide 3‑kinase (PI3K), p‑PI3K, protein kinase B (Akt), and p‑Akt was significantly reduced in THC‑treated cells (P<0.05). In conclusion, the present study revealed the underlying mechanisms associated with THC‑induced autophagy. A promising method of enhancing the therapeutic efficacy of THC against NSCLC cells may include inducing autophagy via inhibition of the PI3K/Akt/mTOR signaling pathway.

Topics: Autophagy; Beclin-1; Biomarkers; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Humans; Lung Neoplasms; Models, Biological; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Nanoscale drug delivery systems have emerged as promising alternatives to overcome the problems associated with by conventional chemotherapy for cancer treatment such as poor drug stability and bio-distribution. Herein, we report a single walled carbon nanotubes (SWCNTs) based drug delivery system functionalized with polysaccharides such as alginate (ALG) and chitosan (CHI), which can be loaded with an anticancer drug curcumin (CUR). Modification of SWCNTs renders high drug loading efficiency and sustained drug release, imperative for drug activity. These were characterized through various tools viz, microscopic (transmission electron microscopy, scanning electron microscopy and atomic force microscopy) and zeta potential analysis. Incorporation of CUR inside the modified SWCNTs was studied through Fourier transform infrared spectroscopy, fluorescence and UV-visible spectroscopy. In vitro release studies were conducted to gain an insight into the pH-dependent release behavior of the entrapped CUR from modified SWCNTs. The anti-cancer potential was further demonstrated using human lung adenocarcinoma (A549) cells as a model system. Various cell culture based assays were performed to study the ability of released CUR from modified SWCNTs for inhibiting the cancer cell proliferation by inducing apoptosis.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Lung Neoplasms; Nanotubes, Carbon; Tumor Cells, Cultured

Our earlier studies reported a unique potentiated combination (TriCurin) of curcumin (C) with two other polyphenols. The TriCurin-associated C displays an IC50 in the low micromolar range for cultured HPV+ TC-1 cells. In contrast, because of rapid degradation in vivo, the TriCurin-associated C reaches only low nano-molar concentrations in the plasma, which are sub-lethal to tumor cells. Yet, injected TriCurin causes a dramatic suppression of tumors in TC-1 cell-implanted mice (TC-1 mice) and xenografts of Head and Neck Squamous Cell Carcinoma (HNSCC) cells in nude/nude mice. Here, we use the TC-1 mice to test our hypothesis that a major part of the anti-tumor activity of TriCurin is evoked by innate and adaptive immune responses. TriCurin injection repolarized arginase1

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Catechin; Curcumin; Female; Head and Neck Neoplasms; Humans; Killer Cells, Natural; Lung Neoplasms; Macrophages; Mice; Mice, Inbred C57BL; Mice, Nude; Papillomaviridae; Papillomavirus Infections; Resveratrol; T-Lymphocytes, Cytotoxic; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

To investigate the synergistic mechanisms of Paris Saponin II (PSII) and Curcumin (CUR) in lung cancer.. The combination changed the cellular uptake of CUR and PSII, apoptosis, cell cycle arrest and cytokine levels were analysed on different lung cancer cells.. The combination displayed a synergistic anti-cancer effect through promoting the cellular uptake of CUR on different lung cancer cells. Hoechst H33258 staining and FACS assay indicated that the combination of PSII and CUR induced cell cycle arrest and apoptosis. Western blot and cytokine antibody microarray suggested that the combination activated death receptors such as DR6, CD40/CD40L, FasL and TNF-α to induce cancer cells apoptosis, and up-regulated IGFBP-1 leading to inhibition of PI3K/Akt pathway and increase of p21 and p27, which therefore induced a G2 phase arrest in NCI-H446 cells. Meanwhile, the combination suppressed PCNA and NF-κB pathway in 4 kinds of lung cancer cells. They activated the phosphorylation of p38 and JNK, and inhibited PI3K in NCI-H460 and NCI-H446 cells, enhanced the phosphorylation of JNK in NCI-H1299 cells, and increased the phosphorylation of p38 and ERK, and suppressed PI3K in NCI-H520 cells.. PSII combined with CUR had a synergistic anti-cancer effect on lung cancer cells. These findings provided a rationale for using the combination of curcumin and PSII in the treatment of lung cancer in future.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Diosgenin; Drug Synergism; Fas Ligand Protein; G2 Phase Cell Cycle Checkpoints; Humans; Insulin-Like Growth Factor Binding Protein 1; Lung Neoplasms; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Tumor Necrosis Factor; Saponins; Signal Transduction

Many curcumin derivatives were produced and characterized to improve the physiochemical instability and low solubility of curcumin. Here, MHMM-41 (a novel curcumin derivative) was used to treat non-small lung cancer cells of human (known as A549) and to identify its anti-proliferative activities. Our results suggested that MHMM-41 display no significant cytotoxicity toward normal human lung fibroblast 2BS cells and mouse embryonal fibroblast 3T3 cells. It also had better anti-proliferative activity than curcumin in A549 cells. Further study showed a significant increase of apoptotic A549 cells in time and dose dependent manners. The activation of caspase-3, 8, 9, 12, Bax and PARP proteins were detected. Consequently, MHMM-41 treatment led to the reduction of mitochondrial membrane potential by JC-1 staining and characteristic nuclei fragmentation by Hoechst 33,342 staining, respectively, which showed that A549 apoptosis could be triggered by the extrinsic and intrinsic mitochondrial pathways. The release of ROS was also measured by flow cytometry. Further, wound healing assay and transwell experiments confirmed the anti-migration ability of MHMM-41 in A549 cells. Our current study suggested the potentials of MHMM-41 to inhibit the A549 cell proliferation. However, the intensive mechanical research on the anti-proliferation of A549 cells needs to be performed in the future.

Topics: 3T3 Cells; A549 Cells; Animals; Apoptosis; Cell Movement; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Humans; Lung Neoplasms; Mice; Reactive Oxygen Species

In this study, a novel arginine, glycine, aspartic acid peptide (RGD)-modified paclitaxel and curcumin co-loaded liposomes were developed to evaluate their antitumor activity in vitro and in vivo.. Co-loaded liposomes were prepared using the solvent evaporation method. The particles had spherical shapes under electron microscopy with sizes <130 nm.. By comparison with the free drug, RGD-modified paclitaxel and curcumin co-loaded liposomes and paclitaxel and curcumin co-loaded liposomes have sustained-release properties in vitro. In vivo, there was no significant difference in pharmacokinetic parameters between the RGD-modified paclitaxel and curcumin co-loaded liposomes and paclitaxel and curcumin co-loaded liposomes. A strong green fluorescence was observed in the cytoplasmic region after incubation of RGD-modified paclitaxel and curcumin co-loaded liposomes for 2 h. RGD-modified paclitaxel and curcumin co-loaded liposomes showed a superior antiproliferative effect on A549 cells with a possible mechanism that suppressed the multidrug resistance phenomenon and exhibited a clear synergistic effect.. The results indicate that RGD-modified paclitaxel and curcumin co-loaded liposomes had a better antitumor effect in vivo than the non-modified LPs. These results indicate that RGD-modified co-loaded liposomes are a promising candidate for antitumor drug delivery.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Curcumin; Drug Delivery Systems; Drug Liberation; Female; Humans; Liposomes; Lung Neoplasms; Male; Mice, Inbred BALB C; Oligopeptides; Paclitaxel; Rats, Sprague-Dawley; Xenograft Model Antitumor Assays

Curcumin is expected to have beneficial effects including an anti-cancer effect. However, its lower bioavailability is a critical concern and limits the utility of curcumin in clinical practice. In this study, we investigated whether transpulmonary delivery of curcumin is pharmacologically effective along with improving its bioavailability in mice with lung metastasis.. C57BL/6J mice were injected with B16F10 melanoma cells via their tail vein and given curcumin by pulmonary administration every other day. The lung tissue of the vehicle-treated mice on day 17 was covered by nodules of metastatic melanoma.. Pulmonary curcumin administration significantly and dose-dependently protected the lung metastasis of melanoma. The phosphorylation of JNK (c-Jun NH2 terminal kinase) and HLJ1 expression levels in the lung metastatic nodules of the melanoma were significantly increased by pulmonary curcumin administration. The anti-metastatic effect of curcumin was blunted in mice injected with HLJ1 knocked-down B16F10 melanoma. Systemic bioavailability after pulmonary administration was 61-times higher than after oral administration. Additionally, the curcumin concentration in the lung tissue was sustained to a high level until 24 h after pulmonary administration.. This study showed the usefulness of curcumin to suppress lung metastasis of melanoma by pulmonary administration, a method that may overcome the low-bioavailability of curcumin.

Topics: Animals; Antineoplastic Agents; Curcumin; HSP40 Heat-Shock Proteins; Lung Neoplasms; Male; MAP Kinase Kinase 4; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Phosphorylation

Curcumin is acknowledged for its antioxidant, anti-inflammatory, anti-cancer, and wound-healing properties. However, the biological activity and the molecular mechanisms of T59, which is a new derivative of curcumin, are not fully understood. The present study was aimed to determine the cytoxicity role of T59 in human lung cancer and the molecular mechanisms. Cytotoxicity and cell apoptosis effects induced by T59 were determined by MTT, AO staining, Annexin V, and JC-1. Compared with curcumin, T59 exerted more effective cytotoxicity and cell apoptosis effects in A549 and H1975. With the decreasing level of the mitochondrion membrane potential, the generation of reactive oxygen species (ROS) was increased and induced by T59. Furthermore, the expressions of cleaved-caspase-3 and Bax were increased, which were reversed by NAC mainly through the PI3K/AKT signaling pathway. Our results suggested that T59 has the potential for further investigation and study to act as an anti-cancer therapeutic against human lung cancer.

Topics: Acetylcysteine; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Membrane Potentials; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; TOR Serine-Threonine Kinases

Combined delivery of a therapeutic small interfering RNA (siRNA) and a chemotherapeutic agent to cancer cells is promising as anticancer therapy, which could offer enhanced cell killing potential and low side effect. However, simultaneous delivery to tumor is challenging. In our study, cholesterol-modified low molecular weight chitosan (MW ~ 15 kDa) was employed as a self-assembled delivery system for both siRNA and a hydrophobic chemotherapeutic agent, curcumin to cancer cells. The siRNA/curcumin loaded nanoparticles (C-CCM/siRNA) were physico-chemically characterized for particle size (165 ± 2.6 nm) and zeta potential (+24.8 ± 2.2 mV). The ability of CCM to condense siRNA was determined by ethidium bromide exclusion and gel retardation assay using electrophoresis. The result demonstrated that the condensation of C-CCM with siRNA was optimum at minimum N/P ratio of 40. C-CCM/siRNA was stable at 4 °C for a period of >1 month. C-CCM/siRNA was taken up efficiently by human lung carcinoma cells, A549 in a time-dependent manner. The cellular internalization of C-CCM/siRNA was observed via clathrin-mediated endocytosis as determined by using specific endocytosis inhibitors. The study demonstrated the feasibility of the use of cholesterol conjugated chitosan as a co-delivery system for both siRNA and a hydrophobic drug for combination cancer therapy.

Topics: A549 Cells; Chitosan; Cholesterol; Curcumin; Drug Carriers; Humans; Lung Neoplasms; RNA, Small Interfering

Curcumin has been reported to possess anti-tumor effects on multiple cancers, including lung cancer. However, the mechanisms of its anti-tumor effect on lung cancer have not been fully elucidated. Our study attempted to identify the effect of curcumin on A549 cells and further explore the potential mechanism.. Different concentrations of curcumin were exposed to A549 cells for 24 h and cell viability was measured by CCK-8 assay. The expression of UCA1 was overexpressed in A549 cells by transfection with pEX-UCA1. Cell proliferation was determined by BrdU staining and assessing the expression of CyclinD1 using western blot and RT-PCR assay. Apoptotic cells were measured by flow cytometry assay. Western blot was performed to assess the expression of apoptosis-related, Wnt and mTOR pathways-related factors.. Curcumin incubation dramatically reduced viability of A549 cells in a dosage-dependent manner. Curcumin (0.6 μM) significantly reduced BrdU+-positive cells, declined the expression of CyclinD1, and enhanced cell apoptosis. Interestingly, we found that curcumin inhibited the expression of UCA1 and UCA1 overexpression abolished the effect of curcumin on cell apoptosis. In addition, we also found that curcumin inhibited Wnt and mTOR pathways through down-regulation of UCA1.. We demonstrated that curcumin inhibited the growth of A549 cells through downregulation of UCA1, which might provide new insight for the treatment of lung cancer.

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Down-Regulation; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Long Noncoding; TOR Serine-Threonine Kinases; Wnt Signaling Pathway

Curcumin, a natural polyphenolic compound isolated from the plant

Topics: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung; Autophagy; Curcumin; Enzyme Induction; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplasm Proteins; Sialyltransferases

Matrix-metalloproteinases, which are overexpressed in many types of cancer, can be applied to improve the bioavailability of chemotherapeutic drugs and guide therapeutic targeting. Thus, we aimed to develop enzyme-responsive nanoparticles based on a functionalized copolymer (mPEG-Peptide-PCL), which was sensitive to matrix metalloproteinase, as smart drug vesicles for enhanced biological specificity and reduced side effects.. The rate of in vitro curcumin (Cur) release from Cur-P-NPs was not markedly accelerated in weakly acidic tumor microenvironment, indicating a stable intracellular concentration and a consistent therapeutic effect. Meanwhile, P-NPs and Cur-P-NPs displayed prominent biocompatibility, biostability, and inhibition efficiency in tumor cells. In addition, Cur-P-NPs showed higher fluorescence intensity than Cur-NPs in tumor cells, implying enhanced cell permeability and targeting ability. Moreover, the internalization and intracellular transport of Cur-P-NPs were mainly via macropinocytosis. Studies of pharmacodynamics and cellular uptake in vitro and biodistribution in vivo demonstrated that Cur-P-NPs had stronger target efficiency and therapeutic effect than Cur-DMSO and Cur-NPs in tumor tissue.. Results indicate that Cur-P-NPs can be employed for active targeted drug delivery in cancer treatment and other biomedical applications.

Topics: Animals; Antineoplastic Agents; Biological Availability; Cell Line, Tumor; Cell Survival; Cell-Penetrating Peptides; Curcumin; Drug Carriers; Drug Liberation; Humans; Lung Neoplasms; Matrix Metalloproteinases; Mice, Nude; Molecular Targeted Therapy; Nanoparticles; Particle Size; Polyesters; Polyethylene Glycols

Five-year survival rate at early lung tumour was about 70%; however, its early diagnosis rate was still at a low level, so the enhancement of diagnosis level for early lung tumour is the key factor to increase the survival rate. Diagnosis and therapy of early lung tumour are still challenged.. The magnetic nanochains (NCs) with biocompatibility and transverse relaxivity (r. The results of cell test indicated that CTX-conjugated NCs could obviously target non-small-cell lung cancer cells and limit their growth. The in vivo results of magnetic resonance imaging and fluorescence imaging indicated that the CTX-NCs-Cur significantly targeted the tumour site and enhanced images contrast of the small-size tumour. Moreover, the results of everyday tail-vein injection confirmed that CTX-NCs-Cur could significantly limit the growth of early tumour, due to blocking Cl ion channels from CTX-NCs-Cur-MMP-2 composite and intracellular ROS increase from Cur treatment.. We provided a mechanism about the effect of CTX-NCs-Cur on the targeting and limiting early tumour, and these results indicated the application foreground of CTX-NCs-Cur in tumour diagnosis and therapy.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Humans; Lung Neoplasms; Magnetics; Nanoparticles; Particle Size; Scorpion Venoms

Curcumin is a naturally occurring polyphenol which has been demonstrated to possess diverse biological activities. We previously reported that curcumin is a biologically active copper chelator with antitumor activity. Copper transporter 1 (CTR1) on the plasma membrane of eukaryotic cells mediates both copper as well as anticancer drug cisplatin uptake.. This study aims to investigate whether curcumin enhances cisplatin sensitivity of human non-small cell lung cancer (NSCLC) through influencing Cu-Sp1-CTR1 regulatory loop.. The combination effect of curcumin and cisplatin on cell proliferation and apoptosis was determined in vitro and in vivo. Platinum level in A549 cells and tumor tissue was measured by atomic absorption spectrometry (AAS). The binding ability of specificity protein 1 (Sp1) to CTR1 and Sp1 promoters was detected by ChIP assay and luciferase reporter assay system.. Here we show that combined curcumin and cisplatin treatment markedly inhibited A549 cells proliferation and induced its apoptosis. Using a mouse model of A549 xenograft, we demonstrated that curcumin inhibits copper influx and increases uptake of platinum ion in tumor. Curcumin treatment enhances the binding of Sp1 to CTR1 and Sp1 promoters, thus induces CTR1 expression and chemosensitization to cisplatin treatment. This process is regulated by the Cu-Sp1-CTR1 regulatory loop. Moreover, the enhancement mediated by curcumin on cisplatin therapeutic efficacy in cultured human NSCLC cell lines (A549, H460, H1299) was dependent on CTR1.. Our results demonstrated copper chelator curcumin enhances the benefits of platinum-containing chemotherapeutic agents and CTR1 could be a promising therapeutic target for non-small cell lung cancer treatment.

Topics: A549 Cells; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cation Transport Proteins; Cell Proliferation; Cisplatin; Copper; Copper Transporter 1; Curcumin; Humans; Lung; Lung Neoplasms; Mice; Sp1 Transcription Factor; Xenograft Model Antitumor Assays

Malignant pleural mesothelioma (MPM) is a rare form of cancer that is associated with asbestos exposure. Unfortunately, current therapies have limited efficacy. Previous studies have indicated that curcumin exerts antiproliferative and antitumor effects, and has low toxicity. The present study aimed to evaluate the anticancer effects of curcumin on the RN5 MPM cell line. The inhibitory effects of curcumin on cell viability were determined using the sulforhodamine B assay. In addition, cell cycle progression was analyzed by propidium iodide (PI) staining and flow cytometry, and curcumin‑induced apoptosis was measured by Annexin V/PI double staining. The translocation of apoptosis-inducing factor (AIF) was assessed by western blotting and immunofluorescence, and the expression levels of the phosphoinositide 3-kinase (PI3K)-AKT serine/threonine kinase (Akt)‑mammalian target of rapamycin (mTOR) signaling pathway proteins and mitochondria-associated proteins were evaluated by western blotting. In vivo antitumor effects were evaluated in a subcutaneous murine model. Briefly, tumors were harvested from the mice, and immunohistochemistry was conducted to evaluate cell proliferation, apoptosis and angiogenesis. The results indicated that curcumin inhibited RN5 cell viability and induced apoptotic cell death. In addition the findings suggested that curcumin-induced cell apoptosis occurred via the mitochondrial pathway, and caspase‑independent and AIF-dependent pathways. Further analysis revealed that curcumin may act as a PI3K-Akt-mTOR signaling pathway inhibitor by downregulating PI3K, p-Akt, p-mTOR and p-p70 ribosomal protein S6 kinase. Furthermore, curcumin inhibited tumor angiogenesis in vivo. In conclusion, curcumin may be potent enough to be developed as a novel therapeutic agent for the treatment of MPM.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis Inducing Factor; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Signal Transduction; Xenograft Model Antitumor Assays

The spice-derived phenolic, malabaricone B (mal B) showed selective toxicity to human lung cancer (A549), malignant melanoma (A375) and T cell leukemia (Jurkat) cell lines, without showing toxicity to human normal intestinal (INT407), human kidney (HEK293) and lung fibroblast (WI-38) cells. Among the chosen cancer cell lines, mal B showed maximum cytotoxicity to the A549 cells (IC50 = 8.1 ± 1.0 μM), which was significantly better than that of curcumin (IC50 = 26.7 ± 3.1 μM). Further morphological studies by phase contrast microscopy and a clonogenic assay of the A549 cells revealed that mal B treatment increased the number of shrinking cells and also abolished the clonal proliferation of the cells. Mal B induced apoptotic cell death was confirmed by DNA laddering and quantified by cytoplasmic oligonucleosome formation and annexin V/PI assays. The mal B-induced apoptosis was mediated by an increase in the intracellular reactive oxygen species (ROS), because the cell-permeable antioxidants, N-acetylcysteine (NAC) and PEG-SOD, strongly inhibited its cytotoxicity to the A549 cells. Mal B increased the BAX level while simultaneously decreasing the BCL-2 and BCL-XL levels in the A549 cells, triggering the mitochondrial apoptotic pathway as revealed from the release of cytochrome c, and the activation of caspase-9 and caspase-3. Pre-treatment of cells with caspase-9, caspase-3 and pan-caspase inhibitors made them more resistant to mal B treatment. This effect of mal B was strongly associated with the concomitant decrease in anti-apoptotic (IAP1, IAP2 and survivin), angiogenic (growth factors) and cancer invasiveness (matrix metalloproteinase-9, COX-2) modulating proteins. Mal B induced cytotoxicity was unaffected by the shRNA-mediated depletion of p53 in A549 cells. Most importantly, mal B sensitized a wide range of human carcinoma cells regardless of their p53 status. Finally, mal B (100 mg kg-1) also inhibited lung tumor (xenograft) growth in SCID mice.

Topics: A549 Cells; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspase 9; Cell Line, Tumor; Curcumin; Cytochromes c; DNA Fragmentation; HEK293 Cells; Humans; Inhibitory Concentration 50; Lung Neoplasms; Membrane Potential, Mitochondrial; Mice; Mice, SCID; Mitochondria; Reactive Oxygen Species; Resorcinols; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

In recent decades, the death rate from lung cancer appears to be an increasing yearly trend, particularly for non-small-cell lung cancer (NSCLC). Curcumin is a yellow pigment found in turmeric rhizomes, reported to exhibit various anti-inflammatory, anti-angiogenic, anti-proliferative, and antioxidant properties. Many reports have suggested that curcumin could induce apoptosis in malignant cells, and therefore, has great potential in tumor treatment. However, little is known about the effect of curcumin on NSCLC or its associated mode of action. Therefore, in this study, we explored curcumin's effect on NSCLC and investigated its associated mechanism.. The non-small-cell lung cancer (NSCLC) cell line A549 was cultured and subjected to MTT and clonogenic survival assays to assess cell proliferation. Reactive oxygen species (ROS) levels were measured using a Fluostar Omega Spectrofluorimeter. Superoxide dismutase (SOD) and γ-glutamyl cysteine synthetase (γ-GCS) activity in A549 cells were both determined by a commercial determination kit. Expression levels of p-GSK3β (Ser9), c-Myc, cyclin D1, β-catenin α-tubulin, and proliferating cell nuclear antigen (PCNA) were analyzed by Western blot.. Results of the MTT and clonogenic survival assay indicated that curcumin reduced A549 proliferation. ROS levels and SOD and γ-GCS activities were detected. Curcumin decreased intracellular ROS levels and increased SOD and γ-GCS activity. Meanwhile, the ROS inhibitor N-Acetylcysteine (NAC) reversed the decrease in ROS levels and the increase in SOD and γ-GCS activity. These results indicate that oxidative stress is involved in the curcumin-induced reduction of A549 viability. Curcumin also strongly inhibited β-catenin and p-GSK3β (Ser9) protein expression, as well as the expression of downstream cyclin D1 and c-Myc. Similarly, NAC reversed the inhibition of β-catenin and p-GSK3β (Ser9) protein expression, as well as the expression of downstream cyclin D1 and c-Myc.. We showed that curcumin inhibits NSCLC proliferation via the Wnt/β-catenin pathway.

Topics: A549 Cells; beta Catenin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Curcumin; Glycogen Synthase Kinase 3 beta; Humans; Lung Neoplasms; Oxidative Stress; Superoxide Dismutase; Wnt Signaling Pathway

Curcumin is widely considered beneficial to human health, but insolubility and instability greatly hamper reproducible exploitation of the advantageous traits. Here we report on the development, characterization and evaluation of a curcumin-loaded nanoemulsion (CUR-NEM) that is highly effective in preventing post-surgery tumor reincidence and metastasis. The method of fabrication utilized safe excipients and generated particles of 200 nm (PDI ≤ 0.2) with negative zeta potential (-30 mV) and a high yield of curcumin (95%), which can be converted by lyophilization to a dry powder. In vitro assays showed that CUR-NEM is safe in non-cancerous human cells (HEK-293T) and preferentially cytotoxic in gastric (AGS), colon (HT29-ATCC, HT29-US), breast (MDA-MB-231) and melanoma (B16F10) cells. In addition, in melanoma cells the nanoformulation increases intracellular curcumin accumulation and reactive oxygen species (ROS) formation, while preventing cell-migration and invasion. In vivo studies in C57BL/6 mice demonstrated that a single dose, applied topically to the wounded area after surgical excision of primary tumors formed upon subcutaneous injection of syngeneic B16F10 cells, was sufficient to completely prevent reincident tumor growth and spontaneous lung metastasis, while in untreated animals 70% reincidence and metastasis were observed. In vivo experiments also showed that the fluorescence signal due to curcumin was maintained at least 15 days after topical application of CUR-NEM, while when administered in DMSO the curcumin signal disappeared within 4 days. Importantly, the administration of a dose 22 times larger than that applied topically to animals after tumor surgery did not alter biochemical parameters. Due to the safety and efficacy of the formulation, we envisage it as ideal for topical application in cancer patients following surgery, to prevent tumor reincidence and metastasis. In addition, other routes of administration/protocols could also be proposed to treat/prevent malignant tumors in patients.

Topics: A549 Cells; Adenocarcinoma; Animals; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Drug Carriers; Emulsions; HEK293 Cells; Humans; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nanoparticles; Neoplasm Metastasis; Neoplasms; Reactive Oxygen Species; Solvents

Demethoxycurcumin (DMC), through a self-assembled amphiphilic carbomethyl-hexanoyl chitosan (CHC) nanomatrix has been successfully developed and used as a therapeutic approach to inhibit cisplatin-induced drug resistance by suppressing excision repair cross-complementary 1 (ERCC1) in non-small cell lung carcinoma cells (NSCLC). Previously, DMC significantly inhibited on-target cisplatin resistance protein, ERCC1, via PI3K-Akt-snail pathways in NSCLC. However, low water solubility and bioavailability of DMC causes systemic elimination and prevents its clinical application. To increase its bioavailability and targeting capacity toward cancer cells, a DMC-polyvinylpyrrolidone core phase was prepared, followed by encapsulating in a CHC shell to form a DMC-loaded core-shell hydrogel nanoparticles (DMC-CHC NPs). We aimed to understand whether DMC-CHC NPs efficiently potentiate cisplatin-induced apoptosis through downregulation of ERCC1 in NSCLC. DMC-CHC NPs displayed good cellular uptake efficiency. Dissolved in water, DMC-CHC NPs showed comparable cytotoxic potency with free DMC (dissolved in DMSO). A sulforhodamine B (SRB) assay indicated that DMC-CHC NPs significantly increased cisplatin-induced cytotoxicity by highly efficient intracellular delivery of the encapsulated DMC. A combination of DMC-CHC NPs and cisplatin significantly inhibited on-target cisplatin resistance protein, ERCC1, via the PI3K-Akt pathway. Also, this combination treatment markedly increased the post-target cisplatin resistance pathway including bax, and cytochrome c expressions. Thymidine phosphorylase (TP), a main role of the pyrimidine salvage pathway, was also highly inhibited by the combination treatment. The results suggested that enhancement of the cytotoxicity to cisplatin via administration of DMC-CHC NPs was mediated by down-regulation of the expression of TP, and ERCC1, regulated via the PI3K-Akt pathway.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Chitosan; Cisplatin; Curcumin; Diarylheptanoids; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Microscopy, Confocal; Nanoparticles; Proto-Oncogene Proteins c-akt

The nuclear factor-kappa B (NF-κB) signaling pathway has been targeted for the therapy of various cancers, including lung cancer. EF24 was considered as a potent inhibitor of NF-κB signaling pathway. In this study, a series of asymmetric EF24 analogues were synthesized and evaluated for their anti-cancer activity against three lung cancer cell lines (A549, LLC, H1650). Most of the compounds exhibited good anti-tumor activity. Among them, compound 81 showed greater cytotoxicity than EF24. Compound 81 also possessed a potent anti-migration and anti-proliferative ability against A549 cells in a concentration-dependent manner. Moreover, compound 81 induced lung cancer cells death by inhibiting NF-κB signaling pathway, and activated the JNK-mitochondrial apoptotic pathway by increasing reactive oxygen species (ROS) generation resulting in apoptosis. In summary, compound 81 is a valuable candidate for anti-lung cancer therapy.

Topics: Antineoplastic Agents; Apoptosis; Benzylidene Compounds; Cell Line, Tumor; Drug Design; Humans; Lung; Lung Neoplasms; Mitochondria; NF-kappa B; Piperidones; Reactive Oxygen Species; Signal Transduction

It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future.. In this study, CUR-loaded methoxy polyethylene glycol-polylactide (CUR/mPEG-PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently.. The average size of CUR/mPEG-PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067-0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG-PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG-PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG-PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG-PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax.. The mPEG-PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG-PLA micelles have promising clinical potential in treating NSCLC.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Apoptosis; Biological Availability; Carcinoma, Non-Small-Cell Lung; Curcumin; Drug Carriers; Drug Delivery Systems; Human Umbilical Vein Endothelial Cells; Humans; Lung Neoplasms; Micelles; Polyesters; Polyethylene Glycols

Metastasis is common in lung cancer and is associated with poor clinical outcomes and increased mortality. Curcumin is a natural anti-cancer agent that inhibits the metastasis of various cancers by modulating the expression of micro (mi) RNAs such as miR-98, which acts as a tumor suppressor. This study investigated the effect of curcumin on miR-98 expression and in vitro cell line growth and invasiveness in lung cancer. Curcumin treatment enhanced the expression of miR-98 and reduced that of the miR-98 target gene

Topics: 3' Untranslated Regions; Animals; Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Movement; Curcumin; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; MicroRNAs; RNA Interference; RNA-Binding Proteins; Transcriptional Activation; Xenograft Model Antitumor Assays

The aim of this work was to prepare pectin-poly (vinyl pyrrolidone) [PVP] based curcumin particulates to enhance the anticancer potential of curcumin, solubility and allow its localized controlled release. Pectin-PVP based curcumin particulates (PECTIN-PVP CUR) were prepared by spray drying technique in different ratios and were evaluated for surface morphology, micromeritics, flowability, particle size, drug content, in vitro dissolution, inhalable fraction, anti-angiogenesis/angiolysis and cytotoxicity. Results of micromeritic properties, Carr's index, Hausner's ratio and angle of repose were satisfactory. The batch CP3 was considered as optimum, due to excellent flowability, acceptable aggregation and enhanced solubility. The particle size and size distribution data of selected batch CP3 showed 90% of curcumin particulates having size less than 2.74μm, which may deposit to lungs. Twin Impinger studies showed that 29% of respirable fraction was generated, which could be directly delivered to lungs. The in vitro dissolution data showed many fold increase in dissolution rate. Angiolytic activity and MTT assay of PECTIN-PVP CUR have demonstrated enhancement in the anti-tumor potential, compared to curcumin alone. Altogether, PECTIN-PVP CUR were found suitable for local delivery and enhance its anticancer potential of curcumin.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Humans; Lung Neoplasms; Particle Size; Pectins; Povidone; Solubility

Curcumin (diferuloylmethane) has chemopreventive and therapeutic properties against many types of tumors, both in vitro and in vivo. Previous reports have shown that curcumin exhibits anti-invasive activities, but the mechanisms remain largely unclear.. In this study, both microRNA (miRNA) and messenger RNA (mRNA) expression profiles were used to characterize the anti-metastasis mechanisms of curcumin in human non-small cell lung cancer A549 cell line.. Microarray analysis revealed that 36 miRNAs were differentially expressed between the curcumin-treated and control groups. miR-330-5p exhibited maximum upregulation, while miR-25-5p exhibited maximum downregulation in the curcumin treatment group. mRNA expression profiles and functional analysis indicated that 226 differentially expressed mRNAs belonged to different functional categories. Significant pathway analysis showed that mitogen-activated protein kinase, transforming growth factor-β, and Wnt signaling pathways were significantly downregulated. At the same time, axon guidance, glioma, and ErbB tyrosine kinase receptor signaling pathways were significantly upregulated. We constructed a miRNA gene network that contributed to the curcumin inhibition of metastasis in lung cancer cells. let-7a-3p, miR-1262, miR-499a-5p, miR-1276, miR-331-5p, and miR-330-5p were identified as key microRNA regulators in the network. Finally, using miR-330-5p as an example, we confirmed the role of miR-330-5p in mediating the anti-migration effect of curcumin, suggesting the importance of miRNAs in the regulation of curcumin biological activity.. Our findings provide new insights into the anti-metastasis mechanism of curcumin in lung cancer.

Topics: A549 Cells; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Proliferation; Curcumin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Lung Neoplasms; MicroRNAs; Neoplasm Invasiveness; Signal Transduction

Curcumin, a dietary supplement or herbal medicine from Curcuma longa, has shown antitumor activity in different cancer cell lines and clinical trials. CA916798, a novel protein, is overexpressed in multidrug-resistant tumor cells. This study aimed to assess the effects of curcumin on regulating chemosensitivity in cisplatin-resistant non-small cell lung cancer (NSCLC) cells in vitro and to explore the underlying molecular mechanisms. Human cisplatin-sensitive A549 and cisplatin-resistant A549/CDDP lung adenocarcinoma cells were treated with curcumin to assess cell viability and gene modulations using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. CA916798 shRNA and point mutations were used to assess the CA916798 functions and phosphorylation sites. Bisdemethoxycurcumin sensitized cisplatin-resistant lung cancer cells to various chemotherapeutic agents, including cisplatin. Bisdemethoxycurcumin reduced the levels of CA916798 mRNA and protein in A549 and A549/CDDP cells, while it also suppressed phosphatidylinositol-3-kinase (PI3K)/AKT signaling. CA916798, as a downstream gene, interacted with AKT after bisdemethoxycurcumin treatment in A549 and A549/CDDP cells. Moreover, A549/CDDP cells expressing the point-mutated CA916798-S20D protein were more resistant to cisplatin and bisdemethoxycurcumin, whereas tumor cells expressing CA916798-S20A, CA916798-S31A, CA916798-S60A, CA916798-S93A, or CA916798-T97A (different sites of amino acid phosphorylation) showed similar sensitivity or resistance to cisplatin and bisdemethoxycurcumin, compared with the control cells. Bisdemethoxycurcumin is able to sensitize cisplatin-resistant NSCLC cells to chemotherapeutic agents by inhibition of CA916798 and PI3K/AKT activities. Moreover, phosphorylation of CA916798 at the S20 residue plays a critical role in mediating bisdemethoxycurcumin antitumor activity.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Albumin nanoparticles are well-known as effective drug carriers used to deliver hydrophobic chemotherapeutic agents. Albumin nanoparticles encapsulating curcumin and doxorubicin were fabricated using slightly modified nanoparticle albumin-bound (nab™) technology, and the synergistic effects of these two drugs were examined. Albumin nanoparticles encapsulating curcumin, doxorubicin, and both curcumin and doxorubicin were prepared using a high pressure homogenizer. The sizes of albumin nanoparticles were ∼130nm, which was considered to be suitable for the EPR (enhanced permeability and retention) effect. Albumin nanoparticles gradually released drugs over a period of 24h without burst effect. To confirm the synergistic effect of two drugs, in vitro cytotoxicity assay was performed using B16F10 melanoma cells. The cytotoxic effect on B16F10 melanoma cells was highest when co-treated with both curcumin and doxorubicin compared to single treatment of either curcumin and doxorubicin. The combined index calculated by medium-effect equation was 0.6069, indicating a synergistic effect. Results of confocal laser scanning microscopy and fluorescence-activated cell sorting corresponded to results from an in vitro cytotoxicity assay, indicating synergistic cytotoxicity induced by both drugs. A C57BL/6 mouse model induced by B16F10 lung metastasis was used to study in vivo therapeutic effects. When curcumin and doxorubicin were simultaneously treated, the metastatic melanoma mass in the lungs macroscopically decreased compared to curcumin or doxorubicin alone. Albumin nanoparticles encapsulating two anticancer drugs were shown to have an effective therapeutic result and would be an excellent way to treat resistant lung cancers.

Topics: Albumins; Animals; Antineoplastic Agents; Apoptosis; Curcumin; Doxorubicin; Drug Carriers; Lung Neoplasms; Mice; Mice, Inbred C57BL; Nanoparticles; Particle Size

In our previous studies, we have identified one curcumin analog MHMD could induce apoptosis of lung cancer cells A549 via extrinsic and intrinsic pathways in our previous studies. But the specific regulatory genes and molecular mechanisms remain poorly understood. Here, the transcriptomic profile of A549 cells was detected with RNA-seq technique after MHMD treatment at 48 h. A total of 16584651 clean data from 21831774 sequence reads were obtained and 80.75% of them could be mapped on the human test genome. 18635 unigenes with the mean length of 4027 bp were finally assembled. 850 up-regulated and 855 down-regulated genes were differently expressed in MHMD-incubated A549 cells, which were involved in many cellular pathways of MHMD-treated A549 cells. Furthermore, the major genes involved in the apoptotic and NSCLC pathways were analyzed. mRNAs of four genes (casp7, p53, tgfa, prkar1b) were validated by RT-PCR, which suggested that MHMD indeed activated the apoptotic pathway of A549 cells.

Topics: A549 Cells; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Curcumin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Transcriptome

The ultimate goal of the study was to find a role of curcumin in targeting lung cancer stem cells by reducing their self-renewal efficiency causing DNA damage.. Circulating lung cancer stem cells were isolated by sphere formation assay and further analysed by flow-cytometry and qRT-PCR for the presence of stem cell and stem cell transcription markers. The IC50 values of gemcitabine and curcumin were analysed by MTT assay, while curcumin induced DNA damage was scrutinized by single cell gel electrophoresis assay.. Our results demonstrated that curcumin significantly affect the self-renewal ability of circulating lung cancer stem cells. The no. of spheres formed in the presence of curcumin was shown to be significantly decreased. Additionally, our results depicted that 4.52±0.72 % and 95.47±0.72 % (p < 0.0001) of DNA material was found to be present in head and tail, respectively, suggesting curcumin's functional potential to cause DNA damage. Thus, we can conclude that curcumin can be used to target lung cancer stem cells which is responsible for the disease progression and metastasis by causing DNA damage or inhibiting their DNA repair mechanisms.

Topics: Carcinoma, Non-Small-Cell Lung; Curcumin; DNA Damage; Flow Cytometry; Humans; Lung Neoplasms; Neoplastic Cells, Circulating; Neoplastic Stem Cells

Previously we showed that BDMC, an analogue of curcumin suppresses growth of human breast and laryngeal cancer cell line by causing apoptosis. Here, we demonstrate the enhanced anti-cancer activity of a heterocyclic ring (indole) incorporated curcumin analogue ((1E, 6E)-1, 7-di (1H-indol-3-yl) hepta-1, 6-diene-3, 5-Dione), ICA in short, in comparison to curcumin.. ICA was synthesized by a one pot condensation reaction. Anti-cancer potential of ICA was assessed in three human cancer cell lines of different origin (Lung adenocarcinoma (A549), leukemia (K562) and colon cancer (SW480)) by MTT assay. Mode of cell death was determined by acridine orange-ethidium bromide (Ao-Eb) staining. Putative cellular targets of ICA were investigated by molecular docking studies. Cell cycle analysis following curcumin or ICA treatment in SW480 cell line was carried out by flow cytometry. Expression levels of Cyclin D1 and apoptotic markers, such as Caspase 3, 8 and 9 were studied by western blot analysis in SW480 cell line treated with or without ICA and curcumin.. The yield of ICA synthesis was found to be 69% with a purity of 98%. ICA demonstrated promising anti-cancer activity compared to curcumin alone, as discerned by MTT assay. ICA was non-toxic to the cell line of normal origin. We further observed that ICA is ∼2 fold more potent than curcumin in inhibiting the growth of SW480 cells. Ao-Eb staining revealed that ICA could induce apoptosis in all the cell lines tested. Molecular docking studies suggest that ICA may possibly exhibit its anticancer effect by inhibiting EGFR in A549, Bcr-Abl in K562 and GSK-3β kinase in SW480 cell line. Moreover, ICA showed strong binding avidity for Bcl-2 protein in silico, which could result in induction of apoptosis. Cell cycle analysis revealed that both curcumin and ICA induced concomitant cell cycle arrest at G0/G1 and G2/M phase. Western blot shows that ICA could effectively down regulate the expression of cell cycle protein cyclin D1, while promoting the activation of Caspase 3, 8 and 9 when compared to curcumin in human colon cancer cell line SW480.. The result of this study indicates that ICA could hold promise to be a potential anti-cancer agent. Since ICA has shown encouraging results in terms of its anti-cancer activity compared to curcumin, further research is necessary to fully delineate the underlying molecular mechanism of its anticancer potential.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Binding Sites; Cell Line, Tumor; Colonic Neoplasms; Computer Simulation; Curcumin; Diarylheptanoids; Gene Expression Regulation; Humans; Indoles; Leukemia; Lung Neoplasms; Models, Biological; Models, Molecular; Molecular Structure; Protein Conformation; Structure-Activity Relationship

Topics: A549 Cells; Administration, Inhalation; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Chitosan; Curcumin; Doxorubicin; Drug Carriers; Drug Liberation; Elastin; Humans; Hydrogen-Ion Concentration; Lung Neoplasms; Microspheres; Particle Size; Solubility

Malignant mesothelioma (MM) is a primary tumor arising from the serous membranes. The resistance of MM patients to conventional therapies, and the poor patients' survival, encouraged the identification of molecular targets for MM treatment. Curcumin (CUR) is a "multifunctional drug". We explored the in vitro effects of CUR on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, autophagy of human (MM-B1, H-Meso-1, MM-F1), and mouse (#40a) MM cells. In addition, we evaluated the in vivo anti-tumor activities of CUR in C57BL/6 mice intraperitoneally transplanted with #40a cells forming ascites.CUR in vitro inhibited MM cells survival in a dose- and time-dependent manner and increased reactive oxygen species'intracellular production and induced DNA damage. CUR triggered autophagic flux, but the process was then blocked and was coincident with caspase 8 activation which activates apoptosis. CUR-mediated apoptosis was supported by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of caspase 9, cleavage of PARP-1, increase of the percentage of cells in the sub G1 phase which was reduced (MM-F1 and #40a) or abolished (MM-B1 and H-Meso-1) after MM cells incubation with the apoptosis inhibitor Z-VAD-FMK. CUR treatment stimulated the phosphorylation of ERK1/2 and p38 MAPK, inhibited that of p54 JNK and AKT, increased c-Jun expression and phosphorylation and prevented NF-κB nuclear translocation. Intraperitoneal administration of CUR increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM treatment using CUR.

Topics: Animals; Antinematodal Agents; Autophagy; Caspase 8; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Inbred C57BL; Phosphorylation; Xenograft Model Antitumor Assays

The natural compound curcumin (Cur) can regulate growth inhibition and apoptosis in various cancer cell lines, although its clinical applications are restricted by extreme water insolubility and instability. To overcome these hurdles, we fabricated a Cur-coordinated reactive oxygen species (ROS)-responsive nanoparticle using the interaction between boronic acid and Cur.. We synthesized a highly biocompatible 4-(hydroxymethyl) phenylboronic acid (HPBA)-modified poly(ethylene glycol) (PEG)-grafted poly(acrylic acid) polymer (PPH) and fabricated a Cur-coordinated ROS-responsive nanoparticle (denoted by PPHC) based on the interaction between boronic acid and Cur. The mean diameter of the Cur-coordinated PPHC nanoparticle was 163.8 nm and its zeta potential was -0.31 mV. The Cur-coordinated PPHC nanoparticle improved Cur stability in physiological environment and could timely release Cur in response to hydrogen peroxide (H. The Cur-coordinated nanoparticles developed in this study improved Cur stability, which could further release Cur in a ROS-dependent manner in cancer cells.

Topics: Antineoplastic Agents; Apoptosis; Curcumin; Drug Delivery Systems; Humans; Hydrogen Peroxide; Lung Neoplasms; Nanoparticles; Oxidants; Polymers; Reactive Oxygen Species; Tumor Cells, Cultured

Metal-based chemotherapeutics such as cisplatin are widely used treatment of lung cancer which is the major cause of cancer-related mortality worldwide. Recent studies demonstrated that novel metal-based compounds have strong cytotoxic activity in a similar way as cisplatin. Therefore, metal-based compounds have been synthesized and investigated in order to determine their cytotoxic activities. It has been also reported curcumin, which has been derived from turmeric plant, has powerful cytotoxic effect on various cancer cell lines. In the light of these data, it has been investigated the cytotoxic effects of combination of curcumin (0.78-100μM) and palladium (II) 5,5-diethylbarbiturate complex with bis(2-pyridylmethyl)amine [Pd(II) complex] (0.39-50μM) against non small lung cancer cell lines, A549 and H1299. It has been found that combination of Pd(II) complex and curcumin enhanced the cytotoxic activity and apoptotic cell death at 48h, compared to single use of each agent, only in H1299 cell line (combination index <1). Apoptosis was evident by annexin v staining positivity, increased caspase 3/7 activity and the presence of pyknotic nuclei. Pro-apoptotic genes of TNFRSF10A and HRK were found to be involved in apoptotic cell death. In conclusion, the application of this combination may be regarded as a novel and effective approach for the treatment of lung cancer due to its promising cytotoxic and apoptotic effect.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Humans; Lung Neoplasms; Palladium

Cancer stem cells (CSCs) are highly implicated in the progression of human cancers. Thus, targeting CSCs may be a promising strategy for cancer therapy. Wnt/β-catenin and Sonic Hedgehog pathways play an important regulatory role in maintaining CSC characteristics. Natural compounds, such as curcumin, possess chemopreventive properties. However, the interventional effect of curcumin on lung CSCs has not been clarified. In the present study, tumorsphere formation assay was used to enrich lung CSCs from A549 and H1299 cells. We showed that the levels of lung CSC markers (CD133, CD44, ALDHA1, Nanog and Oct4) and the number of CD133-positive cells were significantly elevated in the sphere-forming cells. We further illustrated that curcumin efficiently abolished lung CSC traits, as evidenced by reduced tumorsphere formation, reduced number of CD133-positive cells, decreased expression levels of lung CSC markers, as well as proliferation inhibition and apoptosis induction. Moreover, we demonstrated that curcumin suppressed the activation of both Wnt/β-catenin and Sonic Hedgehog pathways. Taken together, our data suggested that curcumin exhibited its interventional effect on lung CSCs via inhibition of Wnt/β-catenin and Sonic Hedgehog pathways. These novel findings could provide new insights into the potential therapeutic application of curcumin in lung CSC elimination and cancer intervention. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Apoptosis; Cell Proliferation; Curcumin; Hedgehog Proteins; Humans; Lung Neoplasms; Neoplastic Stem Cells; Signal Transduction; Wnt Signaling Pathway

Lung cancer is the leading cause of cancer-related deaths. Curcumin is a well-known natural product with anticancer ability, however, its poor bioavailability and pharmacokinetic profiles have limited its application in anticancer therapy. Previously, we reported that L48H37, a novel analog of curcumin with higher bioavailability, ameliorated LPS-induced inflammation, but the anticancer effect of L48H37 is still unknown. In the present study, we have investigated the effects of L48H37 in human lung cancer cells. Our results show that L48H37 decreases lung cancer cell growth and colony formation. These alterations were mediated through induction of G2/M cell cycle arrest and apoptosis in lung cancer cells. After L48H37 treatment, ER stress-related proteins were increased, and the expression of p-STAT3 was decreased in a dose-dependent manner. L48H37 also induced the accumulation of ROS in lung cancer cells, and pretreatment with NAC could fully reverse L48H37-induced reactive oxygen species (ROS) increase. Blocking ROS was able to reverse L48H37-induced endoplasmic reticulum (ER) stress, cell cycle arrest, and apoptosis. Finally, we show that L48H37 inhibits the growth of lung cancer xenografts without exhibiting toxicity. Treatment of mice bearing human lung cancer xenografts with L48H37 was also associated with indices of ER stress activation. In summary, our results provide evidence for a novel anti-tumor candidate for the treatment of lung cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Endoplasmic Reticulum Stress; Female; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Reactive Oxygen Species; STAT3 Transcription Factor; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The present study was aimed to unravel the inhibitory mechanisms of curcumin for lung cancer metastasis via constructing a miRNA-transcription factor (TF)-target gene network. Differentially expressed miRNAs between human high-metastatic non-small cell lung cancer 95D cells treated with and without curcumin were identified using a TaqMan human miRNA array followed by real-time PCR, out of which, the top 6 miRNAs (miR-302b-3p, miR-335-5p, miR-338-3p, miR-34c-5p, miR-29c-3p and miR-34a-35p) with more verified target genes and TFs than other miRNAs as confirmed by a literature review were selected for further analysis. The miRecords database was utilized to predict the target genes of these 6 miRNAs, TFs of which were identified based on the TRANSFAC database. The findings of the above procedure were used to construct a miRNA-TF-target gene network, among which miR-34a-5p, miR-34c-5p and miR-302b-3p seemed to regulate CCND1, WNT1 and MYC to be involved in Wnt signaling pathway through the LEF1 transcription factor. Therefore, we suggest miR-34a-5p/miR-34c-5p/miR-302b-3p -LEF1-CCND1/WNT1/MYC axis may be a crucial mechanism in inhibition of lung cancer metastasis by curcumin.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Movement; Curcumin; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Lung; Lung Neoplasms; MicroRNAs; Neoplasm Invasiveness

The aim of the study wasto fabricate curcumin-loaded PLGA-PEG-Fe3O4 nanoparticles and comprise the effects of pure curcumin and curcumin-nanomagnetic encapsulated in PLGA-PEG on cell cytotoxicity and hTERT gene expression in A549 lung cancer cell line.. Lung cancer is the most common cancer in men and one of the four main cancers that occurs in women. Telomerase is active in more than 85% of various cancerous cells such as lung cancer while its activity is very low in normal cells. Strong evidences of antitumor effects of curcumin; such as the activation of apoptosis, inhibition of angiogenesis and prevention of metastasis, have been confirmed. However, extensive clinical application of this relatively efficacious agent in cancer therapy has been limited because of poor aqueous solubility, and consequently, minimal systemic bioavailability. Nanoparticle-based targeted drug delivery approach has the potential for rendering curcumin specifically at the favorite site using an external magnetic field. It can also improve availability and circumvent the pitfalls of poor solubility.. Curcumin and Fe3O4 were encapsulated inside the PLGA-PEG co-polymer. Then, the curcumin loaded PLGA-PEG-Fe3O4 nanoparticles were characterized using SEM, FTIR and VSM. In the next step, the cytotoxic effect of different concentrations (0-120 µM) of free curcumin and equivalent doses of curcumin-loaded PLGA-PEG-Fe3O4 was assessed using MTT assay at 24-72 hours. Also, gene expression levels of hTERT were measured through Realtime PCR.. By encapsulation of curcumin-Fe3O4, cytotoxicity of the drug substantially increased for all concentrations. IC50 of pure curcumin and nano-encapsulated curcumin during 24, 48 and 72 hours was obtained as 50.5, 49.1 and 48.3 µM and 23.7, 13.6 and 7.3 µM, respectively. Moreover, nano-encapsulated curcumin showed time-dependent cytotoxic effect on A549 cell line during 24, 48, 72 hours in comparison to pure curcumin. In addition, the expression level of the hTERT was reduced with increasing concentrations in both pure and nano-encapsulated curcumin. Compared to pure form, nano-encapsulated curcumin caused further decline in the expression levels of the gene.. Curcumin incorporating with Fe3O4 loaded into PLGA-PEG co-polymer, as an effective targeted carrier, can make a promising horizon in targeted lung cancer therapy.

Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Ferrosoferric Oxide; Humans; Lactic Acid; Lung Neoplasms; Molecular Structure; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Stereoisomerism; Structure-Activity Relationship; Telomerase; Tumor Cells, Cultured

Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Movement; Cell Polarity; Curcuma; Epithelial-Mesenchymal Transition; Humans; Lung; Lung Neoplasms; Macrophages; Mice; Neoplasm Invasiveness; RAW 264.7 Cells; Sesquiterpenes

The elevation of oxidative stress preferentially in cancer cells by inhibiting thioredoxin reductase (TrxR) and/or enhancing reactive oxygen species (ROS) production has emerged as an effective strategy for selectively targeting cancer cells. In this study, we designed and synthesized 21 ligustrazine-curcumin hybrids (10a-u). Biological evaluation indicated that the most active compound 10d significantly inhibited the proliferation of drug-sensitive (A549, SPC-A-1, LTEP-G-2) and drug-resistant (A549/DDP) lung cancer cells but had little effect on nontumor lung epithelial-like cells (HBE). Furthermore, 10d suppressed the TrxR/Trx system and promoted intracellular ROS accumulation and cancer cell apoptosis. Additionally, 10d inhibited the NF-κB, AKT, and ERK signaling, P-gp-mediated efflux of rhodamine 123, P-gp ATPase activity, and P-gp expression in A549/DDP cells. Finally, 10d repressed the growth of implanted human drug-resistant lung cancer in mice. Together, 10d acts a novel TrxR inhibitor and may be a promising candidate for intervention of lung cancer.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Lung Neoplasms; Mice; Molecular Structure; Neoplasms, Experimental; Pyrazines; Reactive Oxygen Species; Structure-Activity Relationship; Thioredoxin-Disulfide Reductase

Nonsmall cell lung carcinoma (NSCLC) is a devastating primary lung tumor resistant to conventional therapies. Bisdemethoxycurcumin (BDMC) is one of curcumin derivate from Turmeric and has been shown to induce NSCLC cell death. Although there is one report to show BDMC induced DNA double strand breaks, however, no available information to show BDMC induced DNA damage action with inhibited DNA repair protein in lung cancer cells in detail. In this study, we tested BDMC-induced DNA damage and condensation in NCI-H460 cells by using Comet assay and DAPI staining examinations, respectively and we found BDMC induced DNA damage and condension. Western blotting was used to examine the effects of BDMC on protein expression associated with DNA damage and repair and results indicated that BDMC suppressed the protein levels associated with DNA damage and repair, such as 14-3-3σ (an important checkpoint keeper of DDR), O6-methylguanine-DNA methyltransferase, DNA repair proteins breast cancer 1, early onset, mediator of DNA damage checkpoint 1 but activate phosphorylated p53 and p-H2A.X (phospho Ser140) in NCI-H460 cells. Confocal laser systems microscopy was used for examining the protein translocation and results show that BDMC increased the translocation of p-p53 and p-H2A.X (phospho Ser140) from cytosol to nuclei in NCI-H460 cells. In conclusion, BDMC induced DNA damage and condension and affect DNA repair proteins in NCI-H460 cells in vitro. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1859-1868, 2016.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Curcumin; Diarylheptanoids; DNA Damage; DNA Repair; Histones; Humans; Lung Neoplasms; Phosphorylation; Protein Transport; Tumor Suppressor Protein p53

Curcuminoids are the major natural phenolic compounds found in the rhizome of many Curcuma species. Curcuminoids consist of a mixture of curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Although numerous studies have shown that curcumin induced cell apoptosis in many human cancer cells, however, mechanisms of BDMC-inhibited cell growth and -induced apoptosis in human lung cancer cells still remain unclear. Herein, we investigated the effect of BDMC on the cell death via the cell cycle arrest and induction of apoptosis in NCI H460 human lung cancer cells. Flow cytometry assay was used to measure viable cells, cell cycle distribution, the productions of reactive oxygen species (ROS) and Ca

Topics: Antineoplastic Agents; Apoptosis; Caspases; cdc25 Phosphatases; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Curcumin; Cyclin A; Cyclin E; Diarylheptanoids; DNA Damage; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species; S Phase; Signal Transduction

Natural compounds such as curcumin have the ability to enhance the therapeutic effectiveness of common chemotherapy agents through cancer stem-like cell (CSC) sensitisation. In the present study, we showed that curcumin enhanced the sensitivity of the double-positive (CD166+/EpCAM+) CSC subpopulation in non-small cell lung cancer (NSCLC) cell lines (A549 and H2170) to cisplatin-induced apoptosis and inhibition of metastasis. Our results revealed that initial exposure of NSCLC cell lines to curcumin (10-40 µM) markedly reduced the percentage of viability to an average of ~51 and ~54% compared to treatment with low dose cisplatin (3 µM) with only 94 and 86% in both the A549 and H2170 cells. Moreover, sensitisation of NSCLC cell lines to curcumin through combined treatment enhanced the single effect induced by low dose cisplatin on the apoptosis of the double-positive CSC subpopulation by 18 and 20% in the A549 and H2170 cells, respectively. Furthermore, we found that curcumin enhanced the inhibitory effects of cisplatin on the highly migratory CD166+/EpCAM+ subpopulation, marked by a reduction in cell migration to 9 and 21% in the A549 and H2170 cells, respectively, indicating that curcumin may increase the sensitivity of CSCs to cisplatin-induced migratory inhibition. We also observed that the mRNA expression of cyclin D1 was downregulated, while a substantial increased in p21 expression was noted, followed by Apaf1 and caspase-9 activation in the double-positive (CD166+/EpCAM+) CSC subpopulation of A549 cells, suggested that the combined treatments induced cell cycle arrest, therefore triggering CSC growth inhibition via the intrinsic apoptotic pathway. In conclusion, we provided novel evidence of the previously unknown therapeutic effects of curcumin, either alone or in combination with cisplatin on the inhibition of the CD166+/EpCAM+ subpopulation of NSCLC cell lines. This finding demonstrated the potential therapeutic approach of using curcumin that may enhance the effects of cisplatin by targeting the CSC subpopulation in NSCLC.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cisplatin; Curcumin; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplastic Stem Cells; Signal Transduction

Lung cancer is an invasive and progressive, fatal disease with few treatment choices and poor overall survival rates in nonsurgical stages. Leptin (LEP), an adipocyte derivative cytokine, participates in carcinogenesis. Increased amounts of systemic and pulmonary LEP indicate lung cancer. Curcumin (CUR) and silibinin (SIL) are herbal compounds which have many anticancer properties, but they have hydrophobic structures and low solubility in water. In this study, evaluated CUR-SIL dual drug-loaded poly (ɛ-caprolactone) [PCL]-co-poly ethylene glycol (PEG) magnetic nanoparticles (MNPs) were used to determine the inhibitory effect on LEP gene expression. The physicochemical properties of free and CUR-SIL-loaded PCL-PEG were fully characterized. The cytotoxic effect of CUR-SIL-loaded PCL-PEG magnetic nanoparticles was determined by MTT assay. Afterward, the inhibition of LEP gene expression was specified through real-time PCR. Results indicated that CUR-SIL cytotoxicity is time- and dose-dependent. CUR-SIL loaded MNPs showed the IC50 limit in lower concentrations in comparison to net CUR-SIL. CUR-SIL loaded MNPs reduced LEP expression more than net CUR-SIL. These results revealed the possibilities of CUR-SIL-loaded MNPs as a natural and effective antitumor drug delivery system to fight lung tumors.

Topics: Cell Line, Tumor; Coated Materials, Biocompatible; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Leptin; Lung Neoplasms; Magnetite Nanoparticles; Neoplasm Proteins; Polyesters; Polyethylene Glycols; Silybin; Silymarin

Novel catanionic lipid nanosystems (CLNs) incorporating curcumin (CCM) were developed, and improvements in pharmacokinetics and enhanced anti-lung cancer activity were observed. CCM was present in a lipid matrix surrounded by cationic, anionic and zwitterionic surfactants, forming the core-shell nanosystems. Compared with free CCM, the CCM-CLNs had much higher oral and intravenous bioavailabilities due to enhanced absorption and reduced clearance. The CCM-CLNs exhibited greater cytotoxicity in Lewis lung cancer (LLC) cells, which might have been due to increased antiproliferative, proapoptotic and anti-invasive activities and induction of cell cycle arrest. The CCM-CLNs increased the antitumor efficacy of CCM and decreased the tumor growth rate in tumor-bearing mice. This is the first report of induction of apoptosis in LLC cells by CCM through the PI3K/Akt/FoxO1/Bim signaling pathway. Catanionic lipid nanocarriers show promise for the therapeutic delivery of insoluble anti-tumor drugs.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Humans; Lipids; Lung Neoplasms; Mice; Nanoparticles; Phosphatidylinositol 3-Kinases; Signal Transduction

Cisplatin is a well-studied and widely used chemotherapeutic agent and is effective in the treatment of the advanced human non-small cell lung cancer (NSCLC). Curcumin is a yellow pigment derived from the rhizome of Curcuma longa and has been proved to have antioxidant and antitumor properties. XRCC1 is an important scaffold protein involved in base excision repair and plays an important role in the development of lung cancer. In this study, we characterize the role of curcumin in the cytotoxicity, p38 MAPK activation, and XRCC1 expression affected by cisplatin in NSCLC cells. We show that curcumin enhanced the cytotoxicity induced by cisplatin in two NSCLC cells, A549 and H1703. Treatment with cisplatin alone increased XRCC1 mRNA and protein expression through p38 MAPK activation. Moreover, SB2023580 (p38 inhibitor) decreased the XRCC1 mRNA and protein stability upon cisplatin treatment. Knockdown of XRCC1 in NSCLC cells by transfection of XRCC1 siRNA or inactivation of p38 MAPK resulted in enhancing the cytotoxicity and cell growth inhibition induced by cisplatin. Curcumin inhibited the expression of XRCC1 in cisplatin-exposed NSCLC cells. Furthermore, transfection with constitutive active MKK6 or HA-p38 MAPK vectors rescued the XRCC1 protein level and also the cell survival suppressed by cisplatin and curcumin combination in A549 and H1703 cells. These findings suggested that the downregulation of XRCC1 expression by curcumin can enhance the chemosensitivity of cisplatin in NSCLC cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Curcumin; DNA-Binding Proteins; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Activation; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MAP Kinase Kinase 6; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; RNA Interference; RNA, Messenger; Time Factors; Transfection; X-ray Repair Cross Complementing Protein 1

Curcumin is potentially therapeutic for malignant diseases. The mechanisms of this effect might involve a combination of antioxidant, immunomodulatory, proapoptotic, and antiangiogenic activities. However, the exact mechanisms are not fully understood. In the present study, we provided evidences that curcumin suppressed the expression of enhancer of zeste homolog 2 (EZH2) in lung cancer cells both transcriptionally and post-transcriptionally. Curcumin inhibited the expression of EZH2 through microRNA (miR)-let 7c and miR-101. Curcumin decreased the expression of NOTCH1 through the inhibition of EZH2. There was a reciprocal regulation between EZH2 and NOTCH1 in lung cancer cells. These observations suggest that curcumin inhibits lung cancer growth and metastasis at least partly through the inhibition of EZH2 and NOTCH1.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Receptor, Notch1

In this paper, we synthesized three fluorine-substituted mono-carbonyl curcumin analogs and evaluated their cytotoxicity against several cancer cells by the MTT assay. The results exhibited that all the three compounds were more active than the leading curcumin. Especially, 2,2'-F mono-carbonyl curcumin, 1a, surfaced as an important lead compound displaying almost 4-fold cytotoxicity relative to curcumin. More importantly, 1a was more stable in (RPMI)-1640 medium and more massive uptake than curcumin, which may be relationship to their cytotoxicity, apoptotic acitivity and reactive oxygen species generation. And then, the generation of reactive oxygen species can disrupt the intracellular redox balance, induce lipid peroxidation, cause the collapse of the mitochondrial membrane potential and ultimately lead to apoptosis. The results not only suggest that 2,2'-F mono-carbonyl curcumin (1a) may cause cancer cells apoptosis through reactive oxygen species-Mediated pathway, but also gives us an important information for design of mono-carbonyl curcumin analog.

Topics: Antineoplastic Agents; Apoptosis; Biological Transport; Cell Line, Tumor; Curcumin; Diarylheptanoids; Humans; Intracellular Space; Lipid Peroxidation; Lung Neoplasms; Membrane Potential, Mitochondrial; Oxidation-Reduction; Reactive Oxygen Species; Structure-Activity Relationship

Current cancer treatments are not adequate to cure cancer disease, as most chemotherapeutic drugs do not differentiate between cancerous and non-cancerous cells; which lead to systemic toxicity and adverse effects. We have developed a promising approach to deliver a potential anti-cancer compound (curcumin) for lung cancer treatment through pulmonary delivery. Three different sizes of curcumin micellar nanoparticles (Cur-NPs) were fabricated and their cytotoxicity effects (proliferation, apoptosis, cell cycle progression) were evaluated against non-small-cell lung cancer, human lung carcinoma (A549) and human lung adenocarcinoma (Calu-3). The in vitro cytotoxicity assay showed that Cur-NPs were more effective to kill lung cancer cells compared to DMSO-solubilised raw curcumin. The potency of the anti-cancer killing activities was size-dependent. Both raw curcumin and Cur-NPs were not toxic to healthy lung cells (BEAS-2B). Smaller Cur-NPs accumulated within nucleus, membrane and cytoplasm. Cur-NPs also induced apoptosis and caused G2/M arrest in both A549 and Calu-3 cell lines. Compared to raw curcumin, Cur-NPs were more effective in suppressing the expression of the inflammatory marker, Interleukin-8 (IL8). The aerosol performance of Cur-NPs was characterized using the next generation impactor (NGI). All Cur-NPs showed promising aerosolization property with mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) ranging between 4.8-5.2 and 2.0-2.1, respectively. This study suggests that inhaled curcumin nanoparticles could potentially be used for lung cancer treatment with minimal side effects.

Topics: Administration, Inhalation; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Endocytosis; Flavonoids; Humans; Interleukin-8; Lung Neoplasms; Nanoparticles; Nebulizers and Vaporizers; Particle Size; Povidone

Curcumin can inhibit the growth of a variety of cancer cells; however, its poor bioavailability and pharmacokinetic profiles, which are attributed to its instability under physiological conditions, have limited its application in anticancer therapy. In the present study, we screened a double carbonyl analog of curcumin (A17) and analyzed its effects and mechanism of inducing apoptosis in human lung cancer H460 cells. The results showed that A17 not only induced CHOP expression in human lung cancer H460 cells, but also induced the apoptosis of H460 cells in a dose-responsive manner, and this effect was related to corresponding activation of some important components in the endoplasmic reticulum (ER) stress-mediated apoptosis pathway. When CHOP was knocked down by specific siRNA, A17-induced cell apoptosis was attenuated, thereby further demonstrating that the apoptotic pathway is ER stress‑dependent. Our studies demonstrated that A17 has better stability and antitumor activity than curcumin in H460 cells via an ER stress-mediated mechanism. These results imply that A17 could be further explored as a potential anticancer agent for the treatment of human non-small cell lung cancer (NSCLC).

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Curcumin; Endoplasmic Reticulum Stress; Flow Cytometry; Humans; Lung Neoplasms; Signal Transduction

Lung cancer remains the leading cause of cancer mortality. Myeloid-derived suppressor cells (MDSCs) are potent immune-suppressive cells and present in most cancer patients. Recently, several studies have shown that curcumin inhibits the expansion of MDSCs in some cancers. However, it is not clear how curcumin modulates the suppressive function of MDSCs, and whether curcumin achieves anti-tumor effects via regulating the expansion of MDSCs in lung cancer. Here, our results showed that curcumin significantly inhibited tumor growth in a Lewis lung carcinoma (LLC) isogenic tumor model. Curcumin reduced the accumulation of MDSCs in spleen and tumor tissue in LLC isogenic model. And curcumin promoted the maturation and differentiation of MDSCs in tumor tissue. Notably, curcumin inhibited the expression level of immune suppressive factors of MDSCs, arginase-1 (Arg-1) and ROS, in purified MDSCs from tumor tissue in vivo. Expectedly, curcumin also inhibited the immunosuppressive function of isolated MDSCs from tumor tissue and spleen of tumor bearing mice in vitro. Moreover, curcumin decreased the level of IL-6 in the tumor tissue and serum from LLC-bearing mice. Taken together, curcumin indeed possesses anti-cancer effect and inhibits the accumulation and function of MDSCs. And curcumin reduces the level of IL-6 in tumor-bearing mice to impair the expansion and function of MDSCs. These results suggest that inhibition of MDSCs in tumor is requisite for controlling lung cancer.

Topics: Animals; Antineoplastic Agents; Arginase; Carcinoma, Lewis Lung; Cell Differentiation; Curcumin; Female; Humans; Interleukin-6; Lung Neoplasms; Mice; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Neoplasm Transplantation; Reactive Oxygen Species; Tumor Burden

Lung cancer is the most common cancer among men. Since the main reason of cancer cells immortality is telomerase activity, targeting of such enzyme can be a promising approach in cancer therapy. Curcumin is a safe and efficient anticancer agent in this context, but its applications in cancer therapy are limited because of its hydrophobic structure and low solubility in water. Today, using nanocarriers for delivery of such anticancer agents is a well performed method. Here, we developed and compared the efficiency of two nanocarriers (PLGA-PEG and NIPAAm-MAA) in delivery of curcumin and also in levels of hTERT silencing in lung cancer cell line (calu-6). Scanning electron microscopy, MTT assays and real-time PCR were used for imaging, cytotoxicity testing and measuring the expression levels of hTERT after treatment of cells with different concentrations of free curcumin and curcumin loaded nanocarriers. The MTT results demonstrated that the IC50 values of curcumin loaded nanocarriers were in lower concentrations than free curcumin. The hTERT expression levels were decreased by curcumin loaded PLGA-PEG more than curcumin loaded NIPAAm-MAA and free curcumin. Our results showed that the curcumin loaded PLGA-PEG can be a useful nano based carrier for delivery of anti-cancer agents such as curcumin to fight lung cancer.

Topics: Acrylamides; Cell Line, Tumor; Curcumin; Drug Carriers; Gene Expression; Humans; Lactic Acid; Lung Neoplasms; Microscopy, Electron, Scanning; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymethacrylic Acids; Real-Time Polymerase Chain Reaction; Telomerase

Metastasis of lung carcinoma to breast and vice versa accounts for one of the vast majority of cancer deaths. Synergistic treatments are proven to be the effective method to inhibit malignant cell proliferation. It is highly advantageous to use the minimum amount of a potent toxic drug, such as paclitaxel (Ptx) in ng/ml together with a natural and safe anticancer drug, curcumin (Cur) to reduce the systemic toxicity. However, both Cur and Ptx suffer from poor bioavailability. Herein, a drug delivery cargo was engineered by functionalizing reduced graphene oxide (G) with an amphiphilic polymer, PF-127 (P) by hydrophobic assembly. The drugs were loaded via pi-pi interactions, resulting in a nano-sized GP-Cur-Ptx of 140 nm. A remarkably high Cur loading of 678 wt.% was achieved, the highest thus far compared to any other Cur nanoformulations. Based on cell proliferation assay, GP-Cur-Ptx is a synergistic treatment (CI < 1) and is highly potent towards lung, A549 (IC50 = 13.24 μg/ml) and breast, MDA-MB-231 (IC50 = 1.450 μg/ml) cancer cells. These positive findings are further confirmed by increased reactive oxygen species, mitochondrial membrane potential depletion and cell apoptosis. The same dose treated on normal MRC-5 cells shows that the system is biocompatible and cancerous cell-specific.

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Synergism; Female; Graphite; Humans; Hydrophobic and Hydrophilic Interactions; Lung Neoplasms; Membrane Potential, Mitochondrial; Nanoparticles; Oxides; Paclitaxel; Polymers; Reactive Oxygen Species

Lung cancer kills more humans than any other cancer and multidrug resistance (MDR) in cancer stem-like cells (CSC) is emerging as a reason for failed treatments. One concept that addresses this root cause of treatment failure is the utilization of nanoparticles to simultaneously deliver dual drugs to cancer cells with synergistic performance, easy to envision - hard to achieve. (1) It is challenging to simultaneously load drugs of highly different physicochemical properties into one nanoparticle, (2) release kinetics may differ between drugs and (3) general requirements for biomedical nanoparticles apply. Here self-assembled nanoparticles of amphiphilic carboxymethyl-hexanoyl chitosan (CHC) were shown to present nano-microenvironments enabling simultaneous loading of hydrophilic and hydrophobic drugs. This was expanded into a dual-drug nano-delivery system to treat lung CSC. CHC nanoparticles were loaded/chemically modified with the anticancer drug cisplatin and the MDR-suppressing Chinese herbal extract demethoxycurcumin, followed by biofunctionalization with CD133 antibody for enhanced uptake by lung CSC, all in a feasible one-pot preparation. The nanoparticles were characterized with regard to chemistry, size, zeta potential and drug loading/release. Biofunctionalized and non-functionalized nanoparticles were investigated for uptake by lung CSC. Subsequently the cytotoxicity of single and dual drugs, free in solution or in nanoparticles, was evaluated against lung CSC at different doses. From the dose response at different concentrations the degree of synergy was determined through Chou-Talalay's Plot. The biofunctionalized nanoparticles promoted synergistic effects between the drugs and were highly effective against MDR lung CSC. The efficacy and feasible one-pot preparation suggests preclinical studies using relevant disease models to be justified.

Topics: A549 Cells; AC133 Antigen; Antineoplastic Agents; Biomarkers; Chitosan; Cisplatin; Colloids; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs, Chinese Herbal; Humans; Kinetics; Lung Neoplasms; Nanoparticles; Neoplastic Stem Cells; Photoelectron Spectroscopy; Spectroscopy, Fourier Transform Infrared

Curcumin is a novel drug for lung cancer treatment. However, the mechanism underlying the anti-tumor effect of curcumin remains elusive. Previous evidences indicated that, the methylating transferase DNMT1 is downregulated by curcumin, and the transcription factor 21 (TCF21) is suppressed by DNMT1. We hereby attempt to elucidate the correlation between curcumin treatment and TCF21 expression. Exosomes derived from curcumin-pretreated H1299 cells were used to treat BEAS-2B cells, which induced proliferation, colony formation and migration of BEAS-2B cells. An increase in TCF21 expression in response to curcumin was also seen, as revealed by real-time PCR (RT-PCR) and western blot. Analysis using the GEO database (access #GSE21210) indicated that a positive correlation existed between TCF21 levels and lung cancer patient survival. TCF21 overexpression and knockdown was introduced to H1299 cells through lentiviral system, which led to suppression and promotion of tumor growth, respectively. We also demonstrated that DNMT1 expression was downregulated by curcumin. Therefore, curcumin exerts its anti-cancer function by downregulating DNMT1, thereby upregulating TCF21.

Topics: Animals; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Curcumin; DNA (Cytosine-5-)-Methyltransferase 1; Exosomes; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C

The aim of the present study was to assess the cumulative effects of curcumin and quercetin in inducing apoptosis during benzo(a)pyrene (BP) (100 mg/Kg body weight)-induced lung carcinogenesis in mice. BP treatment resulted in a significant increase in the protein expression of Bcl-2 whereas expression of Bax was significantly decreased. Further, BP treatment brought about a significant decrease in the activities of caspase 3, caspase 9 as well as the number of apoptotic cells. Interestingly, separate as well as combined supplementation of curcumin (60 mg/kg body weight) and quercetin (40 mg/kg body weight) to BP-treated animals resulted in a significant decrease in the protein expression of Bcl-2 but caused a significant increase in the protein expression of Bax along with a noticeable improvement in the number of apoptotic cells. Also, supplementation with curcumin and quercetin separately to BP-treated mice brought a significant improvement in the enzyme activities of caspase 9 as well as caspase 3 but the improvement was more pronounced following combined treatment. Therefore, curcumin and quercetin, if given in combination shall exhibit enhanced chemopreventive potential against development of lung carcinogenesis by stimulating the apoptotic machinery.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Benzo(a)pyrene; Carcinogenesis; Caspase 3; Caspase 9; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcr; Quercetin

Curcumin has attracted increasing interest as an anti-cancer drug for decades. The mechanisms of action involve multiple cancer-related signaling pathways. Recent studies highlighted curcumin has epigenetic regulatory effects on miRNA in cancers. In the present study, we demonstrated the proapoptotic effects of curcumin in vitro and in vivo. miRNA microarray and qPCR indicated that miR-192-5p and miR-215 were the most responsive miRNAs upon curcumin treatment in H460 and A427 cells. Functional studies showed miR-192-5p/215 were putative tumor suppressors in non-small cell lung cancer. Curcumin also promoted miR-192-5p/215 expressions in A549 cells (p53 wild type) but not in H1299 cells (p53-null). Conditional knockdown of p53 by tetracycline inducible expression system significantly abrogated curcumin-induced miR-192-5p/215 upregulation in the p53 wild-type H460, A427 and A549 cells. Conversely, ectopic expression of exogenous wild-type but not R273H mutant p53 in the p53-null H1299 cells enabled miR-192-5p/215 response to curcumin treatment. The proapoptotic effects of curcumin also depended on miR-192-5p/215 induction, and antagonizing miR-192-5p/215 expression attenuated curcumin-induced apoptosis in H460, A427 and A549 cells, but not in H1299 cells. Finally, X-linked inhibitor of apoptosis (XIAP) is proved to be a novel transcriptional target of miR-192-5p/215. Taken together, this study highlights that the proapoptotic effects of curcumin depend on miR-192-5p/215 induction and the p53-miR-192-5p/215-XIAP pathway is an important therapeutic target for non-small cell lung cancer.

Topics: Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Curcumin; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Signal Transduction; Tumor Suppressor Protein p53; X-Linked Inhibitor of Apoptosis Protein

Cisplatin (DDP) is the most widely used chemotherapy agent for treatment of malignancies including lung cancer. However, the effectiveness of DDP is often weakened by acquired resistance of tumor cells. DDP kills cancer cells primarily by creating intrastrand and interstrand DNA cross-links, which block DNA replication. The Fanconi anemia (FA)/BRCA pathway is a DNA cross-link damage repair pathway, which regulates cellular resistance to DNA cross-link agents, such as DDP. Some study has shown that natural compound curcumin sensitize human ovarian and breast cancer cells to DDP. However, whether curcumin may reverse resistance to DDP in DDP-resistant lung cancer cells has not been understood. In this study, we showed that curcumin enhanced the proliferation inhibitory effect of DDP and promote DDP-induced apoptosis in A549/DDP cells (DDP-resistant lung adenocarcinoma cells). Moreover, we observed that FA/BRCA pathway DNA damage repair processes, such as DDP-induced FANCD2 monoubiquitination and nuclear foci formation were downregulated in the presence of curcumin, suggesting that curcumin enhanced sensitivity to DDP in A549/DDP cells through the inhibition of FA/BRCA pathway. Furthermore, the calculation of q value and apoptosis analyses revealed that curcumin in combination with DDP could exert a synergistic cytotoxic effect in A549/DDP cells, further demonstrating that curcumin can reverse cisplatin resistance of A549/DDP cells. In conclusion, by suppressing the FA/BRCA pathway DNA repair, curcumin potentiates DDP-induced proliferation inhibitory effect and apoptosis in A549/DDP cell, indicating that curcumin may serve as a chemosensitizer to cross-link-inducing anticancer drugs DDP.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; DNA Repair; Drug Resistance, Neoplasm; Fanconi Anemia Complementation Group D2 Protein; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Signal Transduction; Ubiquitination

Unlike lung adenocarcinoma, little progress has been made in the treatment of squamous cell lung carcinoma (SCC). The Cancer Genome Atlas (TCGA) has recently reported that receptor tyrosine kinase signaling pathways are altered in 26% of SCC tumors, validating the importance of downstream Signal Transducers and Activators of Transcription 3 (STAT3) activity as a prime therapeutic target in this cancer. In the present report we examine the status of an endogenous inhibitor of STAT3, called Protein Inhibitor of Activated STAT3 (PIAS3), in SCC and its potential role in this disease. We examine PIAS3 expression in SCC tumors and cell lines by immunohistochemistry of a tissue microarray and western blotting. PIAS3 mRNA expression and survival data are analyzed in the TCGA data set. SCC cell lines are treated with curcumin to regulate PIAS3 expression and cell growth. PIAS3 protein expression is decreased in a majority of lung SCC tumors and cell lines. Analysis of PIAS3 mRNA transcript levels demonstrated that low PIAS3 levels predicted poor survival; Cox regression analysis revealed a hazard ratio of 0.57 (95% CI: 0.37-0.87), indicating a decrease in the risk of death by 43% for every unit elevation in PIAS3 gene expression. Curcumin treatment increased endogenous PIAS3 expression and decreased cell growth and viability in Calu-1 cells, a model of SCC. Our results implicate PIAS3 loss in the pathology of lung SCC and raise the therapeutic possibility of upregulating PIAS3 expression as a single target that can suppress signaling from the multiple receptor tyrosine kinase receptors found to be amplified in SCC.

Topics: Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Curcumin; Humans; Lung Neoplasms; Molecular Chaperones; Prognosis; Protein Inhibitors of Activated STAT; RNA, Messenger

A microarray analysis of differential genes by curcumin treatment was performed and the crucial pathways associated with non-small cell lung cancer (NSCLC) were investigated. Total RNAs from 0, 10 or 20 μM curcumin treated NSCLC 95D cells were used to prepare microarray chips. The differentially expressed genes (DEGs) were identified using the RankProducts package and their function was predicted by DAVID and gene set enrichment analysis. The pathway crosstalk was analyzed by mapping the gene expression profiles into protein-protein interaction databases. Validation of the microarray results was performed by cell viability, cell migration and western blot analyses. A total of 486 (10 μM) and 264 (20 μM) DEGs were screened between the 95D cells in the presence and absence of curcumin. Function enrichment analysis indicated the DEGs were mainly involved in the steroid biosynthetic process and regulation of autophagy. Pathway crosstalk analysis suggested there was a significant interaction between NSCLC and adherens junctions (or Wnt signaling pathways, which are important for cancer cell proliferation and invasion) in both 10 μM and 20 μM curcumin treated 95D cells. Furthermore, early growth response (EGR-1) was demonstrated to regulate the crosstalk between adherens junctions and Wnt signaling pathways, indicating that EGR-1 may also regulate cell proliferation and migration. This hypothesis was validated by in vitro experiments: EGR-1 was decreased after curcumin treatment. Curcumin exhibited a significant anti-proliferation and anti-migration activity in NSCLC 95D cells, possibly by steering the crosstalk between the Wnt signaling pathway and adherens junction via EGR-1.

Topics: Adherens Junctions; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Computational Biology; Curcumin; Early Growth Response Protein 1; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Lung Neoplasms; Wnt Signaling Pathway

This study investigated combined chemopreventive potential of curcumin and resveratrol during benzo(a)pyrene (BP)-induced lung carcinogenesis in mice. The mice were segregated into five groups that included normal control, BP-treated, BP + curcumin-treated, BP + resveratrol-treated, and BP + curcumin + resveratrol-treated groups. A statistically significant increase in the levels of lipid peroxidation (LPO) was observed in the lungs of mice after 22 weeks of single dose of benzo(a)pyrene. Further, BP treatment also resulted in a significant increase in the enzyme activities of aryl hydrocarbon hydroxylase as well as drug-metabolizing enzymes, namely cytocrome P450 and cytochrome b5. On the other hand, reduced glutathione (GSH) levels, the activities of superoxide dismutase (SOD), glutathione reductase (GR), and glutathione-S-transferase (GST) were found to be significantly decreased following BP treatment. Supplementation with curcumin and resveratrol to BP-treated mice significantly decreased the LPO levels, GSH levels, and enzyme activities of drug-metabolizing enzymes. Further, treatment of curcumin and resveratrol to BP-treated mice significantly elevated the activities of SOD, GR, and GST. Histoarchitectural studies showed well-differentiated signs of lung carcinogenesis following BP administration to mice. However, combined treatment with curcumin and resveratrol resulted in a noticeable improvement in the lung histoarchitecture. This study, therefore, concludes that curcumin and resveratrol when supplemented in combination regulate drug-metabolizing enzymes as well as antioxidant enzymes during lung carcinogenesis in mice.

Topics: Animals; Antioxidants; Aryl Hydrocarbon Hydroxylases; Benzo(a)pyrene; Carcinogens; Catalase; Curcumin; Cytochrome P-450 Enzyme System; Cytochromes b5; Glutathione; Glutathione Reductase; Glutathione Transferase; Lipid Peroxidation; Lung; Lung Neoplasms; Male; Mice; Resveratrol; Stilbenes; Superoxide Dismutase

Although carboplatin is one of the standard chemotherapeutic agents for non-small cell lung cancer (NSCLC), it has limited therapeutic efficacy due to activation of a survival signaling pathway and the induction of multidrug resistance. Curcumin, a natural compound isolated from the plant Curcuma longa, is known to sensitize tumors to different chemotherapeutic agents. The aim of this study is to evaluate whether curcumin can chemosensitize lung cancer cells to carboplatin and to analyze the signaling pathway underlying this synergism. We investigated the synergistic effect of both agents on cell proliferation, apoptosis, invasion, migration, and expression of related signaling proteins using the human NSCLC cell line, A549. A549 cell was treated with different concentrations of curcumin and carboplatin alone and in combination. Combined treatment with curcumin and carboplatin inhibited tumor cell growth, migration, and invasion compared with either drug alone. Matrix metalloproteinase (MMP)-2 and MMP-9 were more efficiently downregulated by co-treatment than by each treatment alone. mRNA and protein expression of caspase-3 and caspase-9 and proapoptotic genes was increased in cells treated with a combination of curcumin and carboplatin, whereas expression of the antiapoptotic Bcl-2 gene was suppressed. Co-treatment of both agents substantially suppressed NF-κB activation and increased expression of p53. Phosphorylation of Akt, a protein upstream of NF-κB, was reduced, resulting in inhibition of the degradation of inhibitor of κB(IκBα), whereas the activity of extracellular signal-regulated kinase (ERK1/2) was enhanced. Our study demonstrated that the synergistic antitumor activity of curcumin combined with carboplatin is mediated by multiple mechanisms involving suppression of NF-κB via inhibition of the Akt/IKKα pathway and enhanced ERK1/2 activity. Based on this mechanism, curcumin has potential as a chemosensitizer for carboplatin in the treatment of patients with NSCLC.

Topics: Antineoplastic Agents; Apoptosis; Carboplatin; Carcinoma, Non-Small-Cell Lung; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Drug Screening Assays, Antitumor; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Humans; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Wound Healing

Curcumin (1) down-regulates the expression as well as phosphorylation of epidermal growth factor receptor (EGFR) in lung adenocarcinoma cells expressing gefitinib-resistant EGFR. Thirty-seven newly synthesized curcumin analogues including dimethoxycurcumin (2, DMC) were evaluated for their effects on EGFR expression as well as phosphorylation in two gefitinib-resistant lung adenocarcinoma cell lines, CL1-5 (EGFR(wt)) and H1975 (EGFR(L858R+T790M)). Based on the identified structure-activity relationships, methoxy substitution at C-3', C-4', or both positions favored inhibitory activity (compounds 1, 2, 5, 8-15, 17, 36), while compounds with more polar substituents were generally less active in both cell lines. Compound 36 with a fluorine substituent at C-6' and its protonated counterpart 2 did not lose activity, suggesting halogen tolerance. In addition, a conjugated linker was essential for activity. Among all evaluated curcumin derivatives, compound 2 showed the best inhibitory effects on both wild-type and mutant EGFR by efficiently inducing gefitinib-insensitive EGFR degradation. Compound 23 also reduced gefitinib-induced gastrointestinal damage in the non-transformed intestinal epithelial cell line IEC-18.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Cell Line, Tumor; Curcumin; Drug Resistance, Neoplasm; ErbB Receptors; Gastrointestinal Diseases; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays

Targeting controlled release core-shell nanocarriers with the potential to overcome multidrug resistant (MDR) lung cancer were prepared based on demethoxycurcumin (DMC) loaded amphiphilic chitosan nanoparticles coated with an anti-EGFR antibody layer. The nanocarriers were characterized with regard to size with dynamic light scattering, SEM, and TEM. The characterization confirmed the nanocarriers to have a surface coating of the anti-EGFR antibody and a final size excellently suited for circulating targeting nanocarriers, i.e., <200 nm in diameter. In vitro drug release revealed extended quasi-Fickian release from the nanocarriers, with the anti-EGFR layer further reducing the release rate. Cell culture experiments using normoxic and MDR hypoxic cells overexpressing EGFR confirmed improved DMC delivery for anti-EGFR coated particles and revealed that the DMC was delivered to the cytoplasmic region of the cells, forming nanoprecipitates in lysosomes and endosomes. The effective endocytosis and targeting of the core-shell nanoparticles resulted in the nanocarriers achieving high cytotoxicity also against MDR cells. The therapeutic potential was further confirmed in an A549 xenograft lung tumor mouse model, where DMC loaded core-shell nanocarriers achieved about 8-fold reduction in tumor volume compared with control group over the 8 weeks of the investigation. Both in vitro and in vivo data suggest the anti-EGFR coated core-shell nanocarriers as highly promising for treatment of hypoxic MDR cancers, especially for non-small cell lung cancer.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chitosan; Curcumin; Cytoplasm; Diarylheptanoids; Drug Carriers; Drug Delivery Systems; ErbB Receptors; Humans; Inhibitory Concentration 50; Light; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Nanomedicine; Nanoparticles; Neoplasm Transplantation; Scattering, Radiation

Lung cancer is the most common cause of cancer-related mortality in the US as well as other regions of the world. Curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are the major components of Curcuma longa L. It has been reported that curcumin inhibits the growth of various types of cancer cells in vitro and in vivo. However, the mechanisms involved in the inhibition of cell growth and induced apoptosis by DMC in human lung cancer cells remain unclear. In the present study, we investigated the effect of DMC on cell death via the induction of apoptosis in NCI-H460 human lung cancer cells. Flow cytometric assay was used to examine the total percentage of viable cells, the population of cells in the sub-G1 phase of the cell cycle, the level of reactive oxygen species (ROS), Ca²⁺ production, mitochondrial membrane potential (ΔΨm) and caspase activity. Western blotting was used to examine the changes in the expression of cell cycle- and apoptosis-associated proteins. Confocal microscopy was used to examine the translocation of apoptosis-associated proteins. The results indicated that DMC significantly induced cell morphological changes and decreased the percentage of viable NCI-H460 cells and DMC induced apoptosis based on the cell distribution in the sub-G1 phase. Moreover, DMC promoted ROS and Ca²⁺ production and decreased the level of ΔΨm and promoted the activities of caspase-3, -8 and -9. The Western blotting results showed that DMC promoted the expression of AIF, Endo G and PARP. The levels of Fas ligand (Fas L) and Fas were also upregulated. Furthermore, DMC promoted expression of ER stress-associated proteins such as GRP78, GADD153, IRE1β, ATF-6α, ATF-6β and caspase-4. Based on the findings, we suggest that DMC may be used as a novel anticancer agent for the treatment of lung cancer in the future.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Calcium; Caspases; Cell Cycle Proteins; Cell Line, Tumor; Curcumin; Diarylheptanoids; Endoplasmic Reticulum Chaperone BiP; G1 Phase; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species; Signal Transduction

Curcumin is known for its anti-proliferative effects in lung cancer cells. Studies have demonstrated that an increase in the levels of intracellular free calcium ([Ca2+]i) is involved in curcumin-induced apoptosis. In this study, we aimed to investigate the involvement of calcium overload in the anti-proliferative effects of curcumin on lung cancer cells and the possible mechanisms involved. A549 and H1299 lung cancer cells were incubated with serial diluted curcumin. MTT assay was used to assess the cytotoxic effects of curcumin on the lung cancer cells; the inositol 1,4,5-trisphosphate receptor (IP3R, a key regulator of [Ca2+]i signaling) was blocked by its specific inhibitor, xestospongin C (XSC). Hoechst 33342, Fura-2/AM and rhodamine 123 fluorescence staining was employed to detect the apoptosis, the [Ca2+]i level and mitochondrial potential in the lung cancer cells. The expression levels of B-cell lymphoma-2 (Bcl-2), cleaved caspase-3 and cleaved caspase-9, and the phosphorylation level of IP3R were evaluated by western blot analysis. Our results revealed that curcumin inhibited cell growth, increased the [Ca2+]i level and increased the apoptosis of the lung cancer cells in a concentration-dependent manner. However, XSC attenuated the increase in the [Ca2+]i level and apoptosis, and also reversed the curcumin-induced loss of mitochondrial potential potential. Treatment with curcumin downregulated the expression of Bcl-2, and elevated the phosphorylation level of IP3R in a concentration-dependent manner. However, this effect was not reversed by treatment with XSC. In conclusion, the cytotoxic effects of curcumin on lung cancer cells were induced by calcium overload, which involves Bcl-2 mediated IP3R phosphorylation.

Topics: Apoptosis; Calcium Signaling; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Humans; Lung Neoplasms

Lung cancer has a high worldwide morbidity and mortality. The employment of chemopreventive agents is effective to reduce lung cancer. Nuclear factor erythroid 2-related factor 2 (Nrf2) mitigates insults from both exogenous and endogenous sources and thus has been verified as a target for chemoprevention. Curcumin has long been recognized as a chemopreventive agent, but poor bioavailability and weak Nrf2 induction have prohibited clinical application. Thus, we have developed new curcumin derivatives and tested their Nrf2 induction.. Based on curcumin, we synthesized curcumin analogs with five carbon linkages and established a structure-activity relationship for Nrf2 induction. Among these derivatives, bis[2-hydroxybenzylidene]acetone (BHBA) was one of the most potent Nrf2 inducers with minimal toxicity and improved pharmacological properties and was thus selected for further investigation. BHBA activated the Nrf2 pathway in the canonical Keap1-Cys151-dependent manner. Furthermore, BHBA was able to protect human lung epithelial cells against sodium arsenite [As(III)]-induced cytotoxicity. More importantly, in an in vivo vinyl carbamate-induced lung cancer model in A/J mice, preadministration of BHBA significantly reduced lung adenocarcinoma, while curcumin failed to show any effects even at high doses.. The curcumin derivative, BHBA, is a potent inducer of Nrf2. It was demonstrated to protect against As(III) toxicity in lung epithelial cells in an Nrf2-dependent manner. Furthermore, compared with curcumin, BHBA displayed improved chemopreventive activities in a carcinogen-induced lung cancer model.. Taken together, our results demonstrate that BHBA, a curcumin analog with improved Nrf2-activating and chemopreventive activities both in vitro and in vivo, could be developed into a chemoprotective pharmacological agent.

Topics: Acetone; Animals; Anticarcinogenic Agents; Arsenites; Benzyl Compounds; Carcinogenesis; Cell Line, Tumor; Curcumin; Epithelial Cells; Female; Humans; Lung Neoplasms; Mice; NF-E2-Related Factor 2; Sodium Compounds; Urethane

Unlike chemotherapy drugs, the safety of natural compounds such as curcumin has been well established. However, the potential use of curcumin in cancer has been compromised by its low bioavailability, limited tissue distribution and rapid biotransformation leading to low in vivo efficacy. To circumvent these problems, more potent and bioavailable analogs have been synthesized. In the current study, we investigated the mechanism of anti-tumor effect of one such analog, FLLL12, in lung cancers. IC50 values measured by sulforhodamine B (SRB) assay at 72 h and apoptosis assays (annexin V staining, cleavage of PARP and caspase-3) suggest that FLLL12 is 5-10-fold more potent than curcumin against a panel of premalignant and malignant lung cancer cell lines, depending on the cell line. Moreover, FLLL12 induced the expression of death receptor-5 (DR5). Ablation of the expression of the components of the extrinsic apoptotic pathway (DR5, caspase-8 and Bid) by siRNA significantly protected cells from FLLL12-induced apoptosis (p < 0.05). Analysis of mRNA expression revealed that FLLL-12 had no significant effect on the expression of DR5 mRNA expression. Interestingly, inhibition of global phosphatase activity as well as protein tyrosine phosphatases (PTPs), but not of alkaline phosphatases, strongly inhibited DR5 expression and significantly inhibited apoptosis (p < 0.05), suggesting the involvement of PTPs in the regulation of DR5 expression and apoptosis. We further showed that the apoptosis is independent of p53 and p73. Taken together, our results strongly suggest that FLLL12 induces apoptosis of lung cancer cell lines by posttranscriptional regulation of DR5 through activation of protein tyrosine phosphatase(s).

Topics: Apoptosis; Cell Line, Tumor; Curcumin; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Nuclear Proteins; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; Tumor Protein p73; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

As a mode of cell death, apoptosis could be triggered by the extrinsic, intrinsic mitochondrial and intrinsic endoplasmic reticulum pathways and actin rearrangement is needed during apoptosis. We previously found that one curcumin analog MHMD could induce A549 lung cancer cells apoptosis. But the apoptotic pathways and the actin dynamics during apoptosis are not known. Here, we detected the activation of caspase-3, -8, -9, -12, PARP and the increase ratio of Bax/Bcl-2 by western blotting in MHMD-exposed A549 cells. Alternatively, caspases inhibitors could lead to the disappearance of MHMD-eliciting nuclei fragmentation by Hoechst 33342 staining. Besides, JC-1 and DCFH-DA staining showed the fall of mitochondrial membrane potential and the release of ROS. Moreover, wound healing assay confirmed the MHMD anti-migration ability, which was much more effective than curcumin. Importantly, unlike other anticarcinogenic drugs, MHMD might induce the actin polymerization but not depolymerization in the process of A549 cell apoptosis by phalloidin-FITC staining, which is essential to MHMD-induced extrinsic, intrinsic mitochondrial and intrinsic ER pathways of cell apoptosis.

Topics: Actins; Apoptosis; Caspases; Cell Line, Tumor; Cell Movement; Curcumin; Humans; Lung Neoplasms; Mitochondria; Polymerization

Bisdemethoxycurcumin (BDMC) is an active component of curcumin and a chemotherapeutic agent, which has been suggested to inhibit tumor growth, invasion and metastasis in multiple cancers. But its contribution and mechanism of action in invasion and metastasis of non-small cell lung cancer (NSCLC) are not very clear. Therefore, we tried to study the effects of BDMC on regulation of epithelial-to-mesenchymal transition (EMT), which is closely linked to tumor cell invasion and metastasis.. In this study, we first induced transforming growth factor-β1 (TGF-β1) mediated EMT in highly metastatic lung cancer 95D cells. Thereafter, we studied the effects of BDMC on invasion and migration of 95D cells. In addition, EMT markers expressions were also analyzed by western blot and immunofluorescence assays. The contribution of Wnt inhibitory factor-1 (WIF-1) in regulating BDMC effects on TGF-β1 induced EMT were further analyzed by its overexpression and small interfering RNA knockdown studies.. It was observed that BDMC inhibited the TGF-β1 induced EMT in 95D cells. Furthermore, it also inhibited the Wnt signaling pathway by upregulating WIF-1 protein expression. In addition, WIF-1 manipulation studies further revealed that WIF-1 is a central molecule mediating BDMC response towards TGF-β1 induced EMT by regulating cell invasion and migration.. Our study concluded that BDMC effects on TGF-β1 induced EMT in NSCLC are mediated through WIF-1 and elucidated a novel mechanism of EMT regulation by BDMC.

Topics: Adaptor Proteins, Signal Transducing; Blotting, Western; Cell Line, Tumor; Cell Movement; Curcumin; Diarylheptanoids; Epithelial-Mesenchymal Transition; Humans; Lung Neoplasms; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction

Demethoxycurcumin (DMC) is a key component of Chinese medicine (Turmeric) and has been proven effective in killing various cancer cells. Its role in inducing cytotoxic effects in many cancer cells has been reported, but its role regarding DNA damage on lung cancer cells has not been studied in detail. In the present study, we demonstrated DMC-induced DNA damage and condensation in NCI-H460 cells by using the Comet assay and DAPI staining examinations, respectively. Western blotting indicated that DMC suppressed the protein levels associated with DNA damage and repair, such as 14-3-3σ (an important checkpoint keeper of DNA damage response), DNA repair proteins breast cancer 1, early onset (BRCA1), O6-methylguanine-DNA methyltransferase (MGMT), mediator of DNA damage checkpoint 1 (MDC1), and p53 (tumor suppressor protein). DMC activated phosphorylated p53 and p-H2A.X (phospho Ser140) in NCI-H460 cells. Furthermore, we used confocal laser systems microscopy to examine the protein translocation. The results showed that DMC promotes the translocation of p-p53 and p-H2A.X from the cytosol to the nuclei in NCI-H460 cells. Taken together, DMC induced DNA damage and affected DNA repair proteins in NCI-H460 cells in vitro.

Topics: Apoptosis; Cell Line, Tumor; Curcumin; Diarylheptanoids; DNA Damage; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplasm Proteins

This study investigated the anticancer effect of the curcumin analog JZ534 on lung cancer cell lines H460, A549, H1975, and HCC827. The antiproliferation effect of JZ534 was measured through the methylthiazoletetrazolium assay, and cell colony formation was observed. Cell cycle and apoptosis were determined by flow cytometry, and the preliminary mechanism was studied by Western blot. Results showed that JZ534 significantly inhibited the vitality and colony formation of lung cancer cells. JZ534 induced the G2/M cell cycle arrest of the cancer cells and suppressed the expression of cycle-related proteins, including cyclin B1 and Cdc2. Meanwhile, JZ534 induced cell apoptosis and upregulated the expression of apoptosis-related proteins, including cleaved caspase-3, Bax, and p53. At the same dose, JZ534 showed better antitumor activity than curcumin. These results suggest that JZ534 exhibits excellent anti-lung cancer activity by inhibiting the growth and inducing the apoptosis of lung cancer cells. Therefore, JZ534 is a promising lead compound for cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Curcumin; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; Piperidones

Phytochemicals is one such family of chemopreventive agents that is being researched extensively the world over for its efficacies against several cancer pathways. Curcumin and quercetin belong to the family of phytochemicals and have anti-oxidative and anti-carcinogenic properties. In the present study, chemopreventive efficacy of curcumin and quercetin was investigated against benzo(a)pyrene (BP) induced lung carcinogenesis.. The mice were segregated into five groups which included normal control, BP treated, BP+curcumin treated, BP+quercetin treated and BP+curcumin+quercetin treated groups. Lung carcinogenesis was induced by a single intra-peritoneal (IP) injection of BP (100 mg/kg body weight). Curcumin was supplemented to mice at a dose level of 60 mg/kg body weight in drinking water and quercetin was given at a dose level of 40 mg/kg body wt in drinking water.. The BP treatment resulted in a significant increase in LPO and ROS levels. GSH levels and the activities of SOD, GST as well as GR were found to be significantly decreased following BP treatment. Further, BP treatment brought about a significant increase in the activities of drug metabolizing enzymes (cytochrome P450 and b5). Curcumin and quercetin treatments to mice were able to decrease significantly the levels of LPO, ROS, as well as activities of SOD, GST. Also, the activities of drug metabolizing were markedly decreased by the administration of phytochemicals.. The results of this study suggest that combined treatment with curcumin and quercetin proved beneficial on antioxidant status and drug metabolizing enzymes during experimentally induced lung carcinogenesis in mice.

Topics: Animals; Antioxidants; Benzo(a)pyrene; Curcumin; Disease Models, Animal; Lung; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Quercetin

Invasion and metastasis are the major causes of tumor-related mortality in lung cancer. It is believed that curcumin is an effective drug possessing anti-invasive and anti-metastatic activities in the treatment of cancer. However, the specific mechanisms remain unclear. In the present study, we investigated whether the PKCα/Nox-2/ATF-2/MMP-9 signaling pathway is involved in the invasive behavior of lung cancer and whether curcumin could inhibit invasion by modulating this pathway. The cytotoxic effect of curcumin was evaluated by MTT assay and the capacity of invasion was assessed by Transwell assay. siRNA and plasmid transfection techniques were used to study the function of targeted genes. Real-time PCR and western blot analysis were used to evaluate the expression levels of PKCα, Nox-2, MMP-9 and the phosphorylation of ATF-2. The results showed that curcumin inhibited the proliferation and invasion of A549 cells in a dose-dependent manner. Overexpression of MMP-9 enhanced the invasion of A549 cells. However, inhibition of MMP-9 by siRNA or curcumin suppressed cell invasion. Moreover, we also demonstrated the catalytic role of PKCα in expression of MMP-9 and cellular invasion in A549 cells, which was dependent on the expression of Nox-2 and phosphorylation of ATF-2. Finally, we also showed that curcumin dose-dependently reduced the expression of PKCα, P47phox, Nox-2 and phosphorylated ATF-2, as well as intracellular ROS generation, suggesting the inhibitory effect of curcumin on the activation of the PKCα/Nox-2/ROS/ATF-2 pathway. In conclusion, the PKCα/Nox-2/ROS/ATF-2/MMP-9 signaling pathway is activated in lung cancer A549 cells, which could be modulated by curcumin to inhibit cell invasiveness.

Topics: Activating Transcription Factor 2; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Matrix Metalloproteinase 9; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Protein Kinase C-alpha; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Signal Transduction

The study goal was to evaluate the effects of curcumin on DNA damage and expression of DNA-repair proteins in human lung cancer. Thus, NCI-H460 cells were used to study the effects of curcumin on DNA damage and repair in vitro. We investigated curcumin induces DNA damage by comet the assay and 4',6-diamidino-2-phenylindole (DAPI) staining. The DNA damage/repair-related protein levels were examined and monitored by western blotting and confocal microscopy. Curcumin significantly increased the length of comet tails and DNA condensation in NCI-H460 cells. Curcumin reduced expression of DNA-repair proteins such as 14-3-3 protein sigma (14-3-3σ), O6-methylguanine-DNA methyltransferase (MGMT), breast cancer susceptibility gene 1 (BRCA1), and mediator of DNA damage checkpoint 1 (MDC1). Curcumin also increased phosphorylation of p53 and Histone H2A.X (S140) in the nuclei of NCI-H460 cells. Taken together, our findings indicated that curcumin triggered DNA damage and inhibited expression of DNA-repair-associated proteins in NCI-H460 cells.

Topics: Cell Line, Tumor; Curcumin; DNA Damage; DNA Repair; DNA-Binding Proteins; Humans; Lung Neoplasms; Phosphorylation; Tumor Suppressor Protein p53

Lung cancer is the most common cause of cancer mortality and new cases are on the increase worldwide. However, the treatment of lung cancer remains unsatisfactory. Curcumin has been shown to induce cell death in many human cancer cells, including human lung cancer cells. However, the effects of curcumin on genetic mechanisms associated with these actions remain unclear. Curcumin (2 µM) was added to NCI-H460 human lung cancer cells and the cells were incubated for 24 h. Total RNA was extracted from isolated cells for cDNA synthesis, labeling, microarray hybridization and flour‑labeled cDNA hybridized on chip. Localized concentrations of fluorescent molecules were detected and quantified using Expression Console software (Affymetrix) with default RMA parameters. GeneGo software was used for the key genes involved and their possible interaction pathways. The results showed that ~170 genes were significantly upregulated and 577 genes were significantly downregulated in curcumin‑treated cells. Specifically, the up‑ and downregulated genes included CCNE2, associated with DNA damage; ID3, associated with cell survival and 146 genes with a >2- to 3-fold change including the TP53INP1 gene, associated with DNA damage; CDC6, CDCA5, TAKMIP2, CDK14, CDK5, CDCA76, CDC25A, CDC5L and SKP2, associated with cell cycle; the CARD6, ID1 and ID2 genes, associated with cell survival and the BRMS1L, associated with cell migration and invasion. Additionally, 59 downregulated genes exhibited a >4-fold change, including the DDIT3 gene, associated with DNA damage; while 97 genes had a >3- to 4-fold change including the DDIT4 gene, associated with DNA damage; the CCPG1 gene, associated with cell cycle and 321 genes with a >2- to 3-fold including the GADD45A and CGREF1 genes, associated with DNA damage; the CCPG1 gene, associated with cell cycle, the TNFRSF10B, GAS5, TSSC1 and TNFRSF11B gene, associated with cell survival and the ARHAP29 and CADM2 genes, associated with cell migration and invasion. In conclusion, gene alterations provide information regarding the cytotoxic mechanism of curcumin at the genetic level and provide additional biomarkers or targets for the treatment of human lung cancer.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; DNA Damage; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Proteins

Curcumin, derived from the dietary spice turmeric, holds promise for cancer prevention. This prompts much interest in investigating the action mechanisms of curcumin and its analogues. Two symmetrical hexamethoxy-diarylpentadienones (1 and 2) as cucumin analogues were reported to possess significantly enhanced cytotoxicity compared with the parent molecule. However, the detailed mechanisms remain unclear. In this study, compounds 1 and 2 were identified as the G2/M cell cycle arrest agents to mediate the cytotoxicity toward NCI-H460 cells via Michael acceptor-dependent redox intervention. Compared with curcumin, they could more easily induce a burst of reactive oxygen species (ROS) and collapse of the redox buffering system. One possible reason is that they could more effectively target intracellular TrxR to convert this antioxidant enzyme into a ROS promoter. Additionally, they caused up-regulation of p53 and p21 and down-regulation of redox-sensitive Cdc25C along with cyclin B1/Cdk1 in a Michael acceptor- and ROS-dependent fashion. Interestingly, in comparison with compound 2, compound 1 displayed a relatively weak ability to generate ROS but increased cell cycle arrest activity and cytotoxicity probably due to its Michael acceptor-dependent microtubule-destabilizing effect and greater GST-inhibitory activity, as well as its enhanced cellular uptake. This work provides useful information for understanding Michael acceptor-dependent and redox-mediated cytotoxic mechanisms of curcumin and its active analogues.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Molecular Structure; Oxidation-Reduction; Reactive Oxygen Species; Tumor Suppressor Protein p53

Curcumin has been found to exhibit anticancer activity and certain studies have shown that curcumin triggers the apoptosis of human A549 lung adenocarcinoma cells. However, the mechanism underlying curcumin‑mediated apoptosis is not completely understood. The present study was designed to investigate the effect of curcumin on the induction of apoptosis and apoptosis‑related factors in human A549 lung adenocarcinoma cells. Treatment of A549 cells with curcumin caused a concentration‑dependent inhibition of cell growth and an increase in apoptosis, as confirmed by THE MTT assay, flow cytometry and morphology analysis. Curcumin‑treatment of A549 cells induced a loss of the mitochondrial membrane potential and increased cytosolic cytochrome c. Furthermore, curcumin‑induced apoptosis was accompanied by changes in intracellular oxidative stress‑related enzymes, including decreased intracellular reactive oxygen species levels, increased superoxide dismutase and decreased malondialdehyde and 4‑hydroxynonenal. In addition, induction of apoptosis was also accompanied by phosphorylation and activation of mitogen‑activated protein kinase signaling pathway factors c‑Jun N‑terminal kinase, p38 and extracellular signal-regulated kinase.

Topics: Adenocarcinoma; Apoptosis; Cell Line, Tumor; Curcumin; Humans; Lung Neoplasms; MAP Kinase Signaling System; Oxidative Stress

The objectives of this study were to explore the inhibition mechanism of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus. In addition, human bronchus epithelial cell line BEAS-2B (normal cell) was selected for comparison. A high-performance liquid chromatography (HPLC) method was developed to separate and quantify the various curcuminoids in C. longa extract, including curcumin (1,714.5 μg/mL), demethoxycurcumin (1,147.4 μg/mL), and bisdemethoxycurcumin (190.2 μg/mL). A high-stability nanoemulsion composed of Tween 80, water, and curcuminoid extract was prepared, with mean particle size being 12.6 nm. The cell cycle was retarded at G2/M for both the curcuminoid extract and nanoemulsion treatments; however, the inhibition pathway may be different. H460 cells were more susceptible to apoptosis than A549 cells for both curcuminoid extract and nanoemulsion treatments. Growth of BEAS-2B remained unaffected for both the curcuminoid extract and nanoemulsion treatments, with a concentration range from 1 to 4 μg/mL. Also, the activities of caspase-3, caspase-8, and caspase-9 followed a dose-dependent increase for both A549 and H460 cells for both the treatments, accompanied by a dose-dependent increase in cytochrome C expression and a dose-dependent decrease in CDK1 expression. Interestingly, a dose-dependent increase in cyclin B expression was shown for A549 cells for both the treatments, while a reversed trend was found for H460 cells. Both mitochondria and death receptor pathways may be responsible for apoptosis of both A549 and H460 cells.

Topics: Apoptosis; Caspase 3; Caspase 8; Caspase 9; CDC2 Protein Kinase; Cell Cycle; Cell Line, Tumor; Chromatography, High Pressure Liquid; Curcuma; Curcumin; Cyclin B1; Cyclin-Dependent Kinases; Diarylheptanoids; Dose-Response Relationship, Drug; Emulsions; Humans; Lung Neoplasms; Mitochondria; Nanostructures; Plant Extracts

Curcumin is the main active ingredient extracted from the traditional Chinese medicine, turmeric, which acts against non-small cell lung cancer cell (NSCLC), lowers blood pressure, is anti-inflammatory, choleretic, and exerts anti‑oxidant effects, without any obvious toxicity in the long term. The aim of the present study was to investigate whether the anticancer effect of curcumin inhibited cell proliferation and induced apoptosis of human NSCLC through the upregulation of microRNA‑192-5p (miR-192-5p) and suppression of the PI3K/Akt signaling pathway. In the present study, treatment with curcumin inhibited cell proliferation, induced cell apoptosis and increased the caspase-3 activity of A549 cells. The results also showed that, miR-192-5p relative expression of NCL-H460 cells was relatively lower than that of A549 cells, which was higher, with that of BEAS-2E cells being the highest. miR-192-5p mimics suppressed cell proliferation and increased cell apoptosis of A549 cells. However, anti-miR-192-5p mimics increased cell proliferation and inhibited cell apoptosis of A549 cells. Curcumin treatment effectively increased the relative miR‑192-5p expression and suppressed the PI3K/Akt signaling pathway. miR-192-5p mimics enhanced the effect of curcumin on cell viability and apoptosis and suppressed the PI3K/Akt signaling pathway in A549 cells. Anti-miR-192-5p mimics reversed the effect of curcumin on A549 cells and PI3K/Akt expression. Collectively, our findings suggested that curcumin inhibited cell proliferation and induced apoptosis of human non-small cell lung cancer cells through the upregulation of miR-192-5p and suppression of the PI3K/Akt signaling pathway.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MicroRNAs; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Up-Regulation

Tumor recurrence and drug resistance are the main obstacles blocking effective treatment of cancer patients. Cancer stem cells (CSCs) have been demonstrated to be highly related to tumor recurrence and drug resistance. Thus, eliminating CSCs may be an alternative for cancer therapy. Tumor sphere formation is a functional assay to enrich the CSC-like cells. In the present study, we tested the effects of curcumin on lung cancer stem-like cells and report that in addition to inhibition on the proliferation and colony formation of lung cancer cells, curcumin reduces tumor spheres of H460 cells. Moreover, by molecular docking analysis and tumor sphere assay we discover that curcumin was able to inhibit JAK2 activity and reduce tumor spheres via inhibiting the JAK2/STAT3 signaling pathway. In a lung cancer xenograft nude mouse model, curcumin strongly repressed tumor growth. These results imply curcumin may be a potential drug in lung CSC elimination and cancer therapy.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Resistance, Neoplasm; Humans; Janus Kinase 2; Lung Neoplasms; Mice; Molecular Docking Simulation; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Curcumin is an active component of the medicinal plant turmeric, which has been reported to have anti‑metastatic activities and induce autophagy in numerous cancer types. Bisdemethoxycurcumin (BDMC), one of the major active curcumin derivatives present in turmeric, was previously shown to trigger autophagy in highly metastatic large‑cell lung cancer 95D cells. However, the effects of the induction of autophagy by BDMC on the invasion and migration of 95D cells has remained elusive. Therefore, the present study investigated the effects of BDMC on the invasion and migration of highly metastatic large‑cell lung cancer 95D cells. Meanwhile we observed the effect of autophagy induced by BDMC on the migration and invasion in 95D cells. Transwell assays showed that BDMC exerted an inhibitory effect on the migration and invasion of 95D cells. Furthermore, the expression of vimentin was downregulated, while E‑cadherin expression was upregulated in 95D cells treated with BDMC. In addition, blockage of autophagy through Beclin1‑targeted small interfering RNA attenuated the inhibition of BDMC on 95D-cell migration and invasion. These findings provided direct evidence that BDMC inhibits 95D-cell migration and invasion. Furthermore, the inhibition of 95D-cell migration and invasion was associated with the downregulation of vimentin expression and the upregulation of E‑cadherin expression. Autophagy was involved in the anti‑cancer effects of BDMC on 95D cells. The present study provided novel insight into the underlying mechanisms of the anti-cancer effect of BDMC.

Topics: Antineoplastic Agents; Autophagy; Cadherins; Carcinoma, Large Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Diarylheptanoids; Humans; Lung; Lung Neoplasms; Neoplasm Invasiveness; Vimentin

Curcumin has been shown to have various therapeutic and/or adjuvant therapeutic effects on human cancers, as it inhibits cancer cell proliferation and induces apoptosis through p53-dependent molecular pathways. However, numerous cancer cell types bear a mutant p53 gene, and whether curcumin has any therapeutic effects on p53-deficient/mutant cancer cells has remained elusive. The present study sought to determine whether curcumin exerts any anti-proliferative and cytotoxic effects on the p53-deficient H1299 human lung cancer cell line via a p53-independent mechanism. An MTT assay and flow cytometric analysis indicated that curcumin significantly decreased cell proliferation and induced necrotic cell death. Western blot analysis of the cytosolic and mitochondrial fractions of H1299 cells as well as a fluorometric caspase assay indicated that curcumin-induced necrosis was mitochondria- and caspase-dependent, and resulted in cytochrome c release. Of note, this necrotic cell death was reduced following inhibition of B-cell lymphoma‑2 (Bcl-2)‑associated X protein (Bax) or Bcl‑2 homologous antagonist killer (Bak) as well as overexpression of Bcl-2. In conclusion, the present study suggested that curcumin-induced necrotic cell death was mediated via a p53-independent molecular pathway, which was associated with Bax and Bak translocation, caspase activation and cytochrome c release.

Topics: Antineoplastic Agents; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Caspases; Cell Death; Cell Proliferation; Curcumin; Cytochromes c; Humans; Lung; Lung Neoplasms; Mitochondria; Signal Transduction; Tumor Suppressor Protein p53

The current study aimed to investigate whether the novel folate (FT) modified nanoparticles (NPs) co-loaded with docetaxel (DT) and curcumin (CU) (named as FT-NPs) could enhance the delivery efficiency to tumor compared with the NPs without FT (non-targeted NPs).. FT-NPs were successfully formulated in this article. In vitro cytotoxic activity against A549 cells and in vivo antitumor activity of FT-NPs in S180 cell bearing mice were conducted. Cellular uptake test was used to evaluate uptake efficiency of FT-NPs. Histological observation was used to determine the lung security. Besides, the physical chemical properties such as stability, particle size, zeta potential, drug encapsulation efficiency, transmission electron microscopy (TEM) were also conducted.. FT-NPs exhibited stronger growth inhibition effects on A549 cells compared with non-targeted NPs, moreover, the novel FT-NPs indicated more effective antitumor efficacy in inhibiting tumor growth. Confocal laser scanning microscopy indicated that the uptake of FT-NPs was facilitated and effective. Histological observation meant that FT-NPs were biocompatible and appropriate for pulmonary administration.. These results confirmed that FT-NPs with relatively high drug loading capacity could effectively inhibit tumor growth and reduce toxicity. The novel FT-NPs could produce as an outstanding nanocarrier for the targeted treatment of cancers.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Cell Survival; Chemistry, Pharmaceutical; Curcumin; Docetaxel; Drug Carriers; Folic Acid; HeLa Cells; Humans; Lung Neoplasms; Mice, Inbred C57BL; Nanomedicine; Nanoparticles; Polyesters; Polyethylene Glycols; Sarcoma 180; Solubility; Taxoids; Time Factors; Tumor Burden

Lung cancer is still in the first place in terms of both incidence and mortality. In the present study, we demonstrated the effect of curcumin, a phytochemical of the plant Curcuma longa, on expression and activation of Axl receptor tyrosine kinase (RTK) which plays an important role in cell survival, proliferation and anti-apoptosis. Curcumin treatment of non-small cell lung cancer (NSCLC) A549 and H460 cells, was found to decrease Axl protein as well as mRNA levels in a dose- and time-dependent manner. Axl promoter activity was also reduced by curcumin, indicating that curcumin downregulates Axl expression at the transcriptional level. Moreover, Axl phosphorylation in response to binding of its ligand, Gas6, was abrogated by curcumin, suggesting the inhibitory effect of curcumin on Gas6-induced Axl activation. We next found cytotoxic effect of cucumin on both the parental A549 and H460 cells, and their variants which are resistant to cisplatin (A549/CisR and H460/CisR) and paclitaxel (A549/TR and H460/TR). Exposure of these cells to curcumin resulted in dose-dependent decline of cell viability and clonogenic ability. It is further observed that the anti-proliferative effect of curcumin on A549 cells overexpressing Axl protein was reduced, while that on H460 cells transfected Axl specific siRNA was augmented, confirming that curcumin inhibits cell proliferation via downregulation of Axl expression. In addition, curcumin was found to cause the induction of p21, a cyclin-dependent kinase inhibitor, and reduction of X-linked inhibitor of apoptosis protein (XIAP), an anti-apoptotic molecule, in parental H460 cells as well as chemoresistant cells, H460/CisR and H460/TR. Taken together, our data imply that Axl RTK is a novel target of curcumin through which it exerts anti-proliferative effect in both parental and chemoresistant NSCLC cells.

Topics: Antineoplastic Agents, Phytogenic; Axl Receptor Tyrosine Kinase; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Curcumin; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Transfection

Curcumin has a wide range of pharmacological activities including antioxidant, anti-inflammatory, antidiabetic, antibacterial, wound healing, antiatherosclerotic, hepatoprotective and anti-carcinogenic. However, its clinical applications are limited owing to its poor aqueous solubility, multidrug pump P-gp efflux, extensive in vivo metabolism and rapid elimination due to glucuronidation/sulfation.. The objective of the current work was to prepare novel curcumin loaded mixed micelles (CUR-MM) of Pluronic F-127 (PF127) and Gelucire® 44/14 (GL44) in order to enhance its oral bioavailability and cytotoxicity in human lung cancer cell line A549.. 3(2) Factorial design was used to assess the effect of formulation variables for optimization of mixed micelle batch.. CUR-MM was prepared by a solvent evaporation method. The optimized CUR-MM was evaluated for size, entrapment efficiency (EE), in vitro curcumin release, cytotoxicity and oral bioavailability in rats.. The average size of CUR-MM was found to be around 188 ± 3 nm with an EE of about 76.45 ± 1.18% w/w. In vitro dissolution profile of CUR-MM revealed controlled release of curcumin. Additionally, CUR-MM showed significant improvement in cytotoxic activity (3-folds) and oral bioavailability (around 55-folds) of curcumin as compared to curcumin alone. Such significant improvement in cytotoxic activity and oral bioavailability of curcumin when formulated into mixed micelles could be attributed to solubilization of hydrophobic curcumin into micelle core along with P-gp inhibition effect of both, PF127 and GL44.. Thus the present work propose the formulation of mixed micelles of PF127 and GL44 which can act as promising carrier systems for hydrophobic drugs such as curcumin with significant improvement in their oral bioavailability.

Topics: Administration, Oral; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cell Line, Tumor; Curcumin; Delayed-Action Preparations; Drug Carriers; Humans; Hydrophobic and Hydrophilic Interactions; Lung Neoplasms; Male; Micelles; Particle Size; Poloxamer; Polyethylene Glycols; Rats; Rats, Wistar; Solubility

Exposure to arsenic is one of the major causes of lung cancer due to production of Reactive Oxygen Species (ROS). Herbal medicine is a new approach used for prevention or treatment of cancers. Among various herbal compounds, a lot of attention has been paid to curcumin, as antioxidant, anti-proliferative, anti-carcinogenic and anti-tumor and pro-apoptotic properties of curcumin have been well studied. In the present study, we investigated the effects of curcumin on lung cancer cell lines and arsenic-treated lung cancer cell lines, originated from different stages of lung cancer development. Here, we measured ROS generation and caspase 3/7 activity for both curcumin-treated cell lines and those co-treated with arsenic and curcumin. Then, we studied lipid peroxidation, intracellular ATP content, and cytochrome c release to further investigate how ROS generation and curcumin exert synergistic effects and direct cells toward apoptosis. According to our data, curcumin has a dual effect on ROS generation which is dependent on specific concentration as a threshold and seems to induce apoptosis by two different mechanisms. Moreover, for the first time we report that curcumin delays the drop in ATP levels in these cell lines and hence provides required energy for apoptosis process. Furthermore, western blot analysis reveals that release of cytochrome c is highest when ATP begins to drop in the presence of curcumin. To sum it up, it seems that curcumin is strong candidate for prevention or treatment of lung cancer, especially at stage 2.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Apoptosis; Arsenic; Caspase 3; Caspase 7; Cell Survival; Curcumin; Cytochromes c; Dose-Response Relationship, Drug; Drug Interactions; Humans; Lipid Peroxidation; Lung Neoplasms; Mitochondria; Reactive Oxygen Species; Time Factors

Adipose tissue is now considered as an endocrine organ involved in metabolic and inflammatory reactions. Adiponectin, a 244-amino acid peptide hormone, is associated with insulin resistance and carcinogenesis. Curcumin (diferuloylmethane) is the principal curcuminoid of the popular Indian spice, turmeric. Curcumin possesses antitumor effects, including the inhibition of neovascularization and regulation of cell cycle and apoptosis. However, the effects of adiponectin and curcumin on non-small cell lung cancer (NSCLC) remain unclear. In this study, we evaluated the expression of adiponectin in paired tumors and normal lung tissues from 77 patients with NSCLC using real-time polymerase chain reaction, western blotting, and immunohistochemistry. Kaplan-Meier survival analysis showed that patients with low adiponectin expression ratio (<1) had significantly longer survival time than those with high expression ratio (>1) (p = 0.015). Curcumin inhibited the migratory and invasive ability of A549 cells via the inhibition of adiponectin expression by blocking the adiponectin receptor 1. Curcumin treatment also inhibited the in vivo tumor growth of A549 cells and adiponectin expression. These results suggest that adiponectin can be a prognostic indicator of NSCLC. The effect of curcumin in decreasing the migratory and invasive ability of A549 cells by inhibiting adiponectin expression is probably mediated through NF-κB/MMP pathways. Curcumin could be an important potential adjuvant therapeutic agent for lung cancer in the future.

Topics: Adiponectin; Adult; Aged; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Curcumin; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lung Neoplasms; Male; Matrix Metalloproteinases; Mice, SCID; Middle Aged; Neoplasm Metastasis; NF-kappa B; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Xenograft Model Antitumor Assays

β-elemene, the active component of elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane), is a naturally occurring compound isolated from the traditional Chinese medicinal herb Curcuma wenyujin. Studies have confirmed that β-elemene enhances the radiosensitivity of lung cancer cell lines such as A549, by multiple pathways; however, their underlying mechanisms and pathways are yet to be elucidated. In the present study, two-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry were used to profile the different proteins in A549 cell xenograft models of both treatment groups. The protein/mRNA expression was assessed by reverse transcription-polymerase chain reaction and western blotting techniques in tumor samples from all treatment groups. As a critical player in redox regulation of cancer cells, inhibition of peroxiredoxin-1 (Prx-1) may be an effective option for enhancing the tumor response to radiation. We further verified Prx-1 expression at the transcription and translation levels. β-elemene at a dose of 45 mg/kg had little effect on the Prx-1 protein expression, which was correlated with a moderate antitumor effect. However, a 45 mg/kg dose of β-elemene significantly inhibited the Prx-1 mRNA expression, thereby suggesting a possible influence on the transcriptional process, and radiation significantly increased the Prx-1 mRNA/protein expression compared to the control group (p<0.01). Notably, Prx-1 mRNA/protein expression was significantly lower in the β-elemene/radiation co-treatment group compared to the baseline levels in the control group (p<0.01). These results suggest that radiation-induced Prx-1 expression is directly or indirectly suppressed by β-elemene, thus suggesting a new pathway by which to reverse radioresistance.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Cell Line, Tumor; Curcuma; Down-Regulation; Female; Humans; Lung Neoplasms; Medicine, Chinese Traditional; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Peroxiredoxins; Plant Extracts; Radiation Tolerance; Radiation-Sensitizing Agents; Radiography; RNA, Messenger; Sesquiterpenes; Tandem Mass Spectrometry; Transcription, Genetic; Transplantation, Heterologous

Recent population studies provide clues that the use of curcumin may be associated with reduced incidence and improved prognosis of certain cancers. In the present study, we demonstrated that curcumin acted as a growth inhibitor for lung cancer cells. Our results found that curcumin inhibited cell proliferation, which was associated with upregulation of the cyclin-dependent kinase inhibitors, p27 and p21, and downregulation of cyclin D1. In addition, we showed that curcumin induced the expression of forkhead box protein O1 (FOXO1) through activation of extracellular signal-regulated kinase 1/2 signaling. These findings provide evidence for a mechanism that may contribute to the antineoplastic effects of curcumin and justify further work to explore potential roles for activators of FOXO1 in the prevention and treatment of lung cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Disease Progression; Dose-Response Relationship, Drug; Forkhead Box Protein O1; Forkhead Transcription Factors; Humans; Lung Neoplasms; MAP Kinase Signaling System; Neoplasm Metastasis

Resistance to erlotinib in lung cancer cases includes T790M mutant epidermal growth factor receptor and c-Met gene amplification, but other unknown mechanisms account for about 30% of the resistance. Activation of the nuclear factor kappa B (NFkappaB)-related pathways in association with the reduction in ikappaB level may be one of such potential mechanisms. It is known that curcumin inhibits the inducible activation of NFkappaB at least in part by sustaining ikappaB expression level. Therefore, we evaluated the effects of coadministration of erlotinib and curcumin on lung cancer cells. We found that erlotinib and curcumin augmentatively reduced cell viability. Studies in PC9 cells showed that induction of apoptosis was involved. Expression of ikappaB was elevated in PC9 cells by curcumin administration, and pretreatment with siRNAs for ikappaB significantly attenuated the reduction in cell viability after coadministration of erlotinib and curcumin. Furthermore, coadministration of erlotinib and/or curcumin augmentatively attenuated the growth of PC9 tumors in mice. These results suggested the existence of an augmentative tumor growth inhibitory effect between erlotinib and curcumin, and this effect was at least in part mediated by the increase in the expression of ikappaB induced by curcumin.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Erlotinib Hydrochloride; Humans; I-kappa B Proteins; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Quinazolines; RNA Interference

Curcumin exhibits growth-suppressive activity against a variety of cancer cells, but low bioavailability restricts its application in chemotherapeutic trials. Nowadays, a growing number of curcumin derivatives or analogs are known, hoping to replace curcumin and circumvent this problem. Hydrazinobenzoylcurcumin (HBC) has been synthesized and identified as a potent inhibitor of cell proliferation in previous reports.. This study presents a novel mechanism of cell autophagy induced by HBC in the human non-small lung epithelial carcinoma (A549) cells.. Cells were cultured and treated with HBC at different concentrations (10-80 μM) and at different time periods (1-24 h). Microscopic analysis was used to detect the morphology changes and autophagolysosomes of A549 cells. An acridine orange staining assay was conducted to evaluate the autophagolysosomes and autophagic vacuoles was analyzed by monodansylcadaverine (MDC) and GFP-LC3 transfection analysis. Western blotting was used to assess the conversion of microtubule-associated protein light chain 3 (LC3).. HBC could induce A549 cells autophagolysosomes formation in a dose and time-dependent manner and the inhibitory rate of HBC (80 μM) on the viability of A549 cells reached 76.68 ± 5.81% after 24 h of treatment. Autophagic vacuoles increased in a concentration-dependent manner in HBC-treated cell. Furthermore, conversion of LC3-I to LC3-II, accumulation of GFP-tagged LC3 positive intracellular vacuoles and increased fusion of autophagosomes with lysosomes suggested the occurrence of autophagy.. Our data indicate that HBC induced A549 cell autophagy, which is a novel cell death mechanism induced by curcumin derivatives.

Topics: Antineoplastic Agents; Autophagy; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Green Fluorescent Proteins; Humans; Lung Neoplasms; Lysosomes; Microtubule-Associated Proteins; Pyrazoles; Time Factors; Transfection

Curcumin, a natural phytochemical, exhibits potent anticancer activities. Here, we sought to determine the molecular mechanisms underlying the cytotoxic effects of curcumin against human non-small cell lung cancer (NSCLC) cells.. MTT assay and annexin-V/PI staining were used to analyze the effects of curcumin on the proliferation and apoptosis of A549 cells. The expression of microRNA-21 in curcumin-treated A549 cells was measured by quantitative real-time polymerase chain reaction assay. The protein level of phosphatase and tensin homolog (PTEN), a putative target of microRNA-21, was determined by Western blot analysis. Transfection of A549 cells with microRNA-21 mimic or PTEN small interfering RNA was performed to modulate the expression of microRNA-21 and PTEN under the treatment of curcumin.. Curcumin at 20-40 μM inhibited cell proliferation and induced apoptosis in A549 cells. Curcumin treatment produced a dose-dependent and significant (P < 0.05) suppression of microRNA-21 expression, compared to untreated A549 cells. Moreover, the protein level of PTEN, a putative target of microRNA-21, was significantly elevated in curcumin-treated A549 cells, as determined by Western blot analysis. Transfection of A549 cells with microRNA-21 mimic or PTEN small interfering RNA significantly (P < 0.05) reversed the growth suppression and apoptosis induction by curcumin, compared to corresponding controls.. Our data suggest a novel molecular mechanism in which inhibition of microRNA-21 and upregulation of PTEN mediate the anticancer activities of curcumin in NSCLC cells. Suppression of microRNA-21 may thus have therapeutic benefits against this malignancy.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Lung Neoplasms; MicroRNAs; PTEN Phosphohydrolase; Real-Time Polymerase Chain Reaction; Transfection

Inflammation is a key mediator in the development of malignant mesothelioma, which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anticarcinogenic properties through its anti-inflammatory effects. Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of proinflammatory cytokines, interleukin (IL)-1β and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of malignant mesothelioma cells. Using in vitro models with mouse and human malignant mesothelioma cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of high-mobility group box 1 (HMGB1) without processing of IL-1β and IL-18. Absence of IL-1β processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1β priming through inhibition of the NF-κB pathway. Furthermore, curcumin's cytotoxicity in malignant mesothelioma cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death. We also demonstrate that curcumin-mediated caspase-1 activation is oxidant dependent by using N-acetyl-L-cysteine (NAC) to inhibit pyroptosis. PCR array analysis using the human inflammasome template revealed that curcumin significantly downregulated levels of inflammasome-related gene expression involved in inflammation, e.g., NF-κB, toll-like receptors (TLR), and IL-1β. Our data indicate that curcumin has a double effect on malignant mesothelioma cells through induction of pyroptosis while subsequently protecting against inflammation.

Topics: Animals; Apoptosis; Carrier Proteins; Caspase 1; Curcumin; Cytokines; Humans; Inflammasomes; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction; Tumor Cells, Cultured

Curcumin, a natural and crystalline compound isolated from the plant Curcuma longa with low toxicity in normal cells, has been shown to protect against carcinogenesis and prevent tumor development. However, little is known about antimetastasis effects and mechanism of curcumin in lung cancer. Rac1 is an important small Rho GTPases family protein and has been widely implicated in cytoskeleton rearrangements and cancer cell migration, invasion and metastasis. In this study, we examined the influence of curcumin on in vitro invasiveness of human lung cancer cells and the expressions of Rac1. The results indicate that curcumin at 10 μM slightly reduced the proliferation of 801D lung cancer cells but showed an obvious inhibitory effect on epidermal growth factor or transforming growth factor β1-induced lung cancer cell migration and invasion. Meanwhile, we demonstrated that the suppression of invasiveness correlated with inhibition of Rac1/PAK1 signaling pathways and matrix metalloproteinase (MMP) 2 and 9 protein expression by combining curcumin treatment with the methods of Rac1 gene silence and overexpression in lung cancer cells. Laser confocal microscope also showed that Rac1-regulated actin cytoskeleton rearrangement may be involved in anti-invasion effect of curcumin on lung cancer cell. At last, through xenograft experiments, we confirmed the connection between Rac1 and the growth and metastasis inhibitory effect of curcumin in vivo. In summary, these data demonstrated that low-toxic levels of curcumin could efficiently inhibit migration and invasion of lung cancer cells through inhibition of Rac1/PAK1 signaling pathway and MMP-2 and MMP-9 expression, which provided a novel insight into the molecular mechanism of curcumin against lung cancer.

Topics: Cell Line, Tumor; Cell Movement; Curcumin; Humans; Lung Neoplasms; Neoplasm Invasiveness; p21-Activated Kinases; Phosphorylation; rac1 GTP-Binding Protein; Signal Transduction

Curcumin (diferuloylmethane) is a polyphenol natural product of the plant Curcuma longa, and has a diversity of antitumor activities. However, the clinical application of curcumin remains limited due to its poor pharmacokinetic characteristics. It is therefore critical to develop structural analogues of curcumin with increasing anticancer activity. T63, a new 4-arylidene curcumin analogue, was synthesized in our previous studies and exhibited higher in vitro and in vivo anti-tumor activities compared to curcumin. However, the precise molecular mechanism of its anti-tumor effects has not been well elucidated. Using a two-dimensional gel electrophoresis (2-DE)-based proteomic approach, we identified 66 differentially expressed proteins. Similarly to curcumin, T63 showed a diverse range of molecular targets. We proposed that induction of ROS generation and mitochondrial dysfunction, inhibition of proteasome, HSP90, and 14-3-3 proteins play important roles in T63-induced cell cycle arrest and apoptosis. These data indicate that the novel curcumin analogue T63 is a potent anti-tumor agent, which can induce cell cycle arrest and apoptosis, and also provided valuable resources for further study of the anti-tumor effects and molecular mechanisms of T63.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mitochondria; Oxidation-Reduction; Proteomics

The combination approach is the future of the war against cancer and the present study evaluated molecular mechanics behind the synergistic effects of curcumin and resveratrol during lung carcinogenesis.. The mice were segregated into five groups which included normal control, Benzo[a]pyrene[BP] treated, BP+curcumin treated, BP+resveratrol treated and BP+curcumin+resveratrol treated.. The morphological analyses of tumor nodules confirmed lung carcinogenesis in mice after 22 weeks of single intra-peritoneal[i.p] injection of BP at a dose of 100 mg/Kg body weight. The BP treatment resulted in a significant increase in the protein expressions of p53 in the BP treated mice. Also, a significant increase in the protein expression of phosphorylated p53[ser15] confirmed p53 hyper-phosphorylation in BP treated mice. On the other hand, enzyme activities of caspase 3 and caspase 9 were noticed to be significantly decreased following BP treatment. Further, radiorespirometric studies showed a significant increase in the 14C-glucose turnover as well as 14C-glucose uptake in the lung slices of BP treated mice. Moreover, a significant rise in the cell proliferation was confirmed indirectly by enhanced uptake of 3H-thymidine in the lung slices of BP treated mice. Interestingly, combined treatment of curcumin and resveratrol to BP treated animals resulted in a significant decrease in p53 hyper-phosphorylation, 14C glucose uptakes/turnover and 3H-thymidine uptake in the BP treated mice. However, the enzyme activities of caspase 3 and caspase 9 showed a significant increase upon treatment with curcumin and resveratrol.. The study, therefore, concludes that molecular mechanics behind chemo-preventive synergism involved modulation of p53 hyper-phosphorylation, regulation of caspases and cellular metabolism enzymes.

Topics: Analysis of Variance; Animals; Benzo(a)pyrene; Blotting, Western; Carbon Radioisotopes; Carcinogenesis; Curcumin; Drug Synergism; Immunohistochemistry; Lung Neoplasms; Mice; Phosphorylation; Resveratrol; Stilbenes; Tumor Suppressor Protein p53

Curcumin is a natural polyphenolic compound that exhibits strong antioxidant and anticancer activities; however, low bioavailability has restricted its application in chemotherapeutic trials. The present study aimed to investigate the anticancer effect of the novel curcumin derivative 2E,6E‑2‑(1H‑indol‑3‑yl) methylene)‑6‑(4‑hydroxy‑3‑methoxy benzylidene)‑cyclohexanone (IHCH) on A549 lung cancer cells. Cells were treated with IHCH at different concentrations (1‑40 µM) for different time periods (1‑36 h). Microscopic analysis revealed that IHCH inhibited A549 cell growth and induced the formation of characteristic autophagolysosomes in a dose‑ and time‑dependent manner. Furthermore, the inhibitory rate of IHCH (40 µM) on A549 cell viability was 77.34% after 36 h of treatment. Acridine orange staining revealed an increase in autophagic vacuoles in the IHCH‑treated A549 cells. Monodansylcadaverine staining was used to analyze autophagy rate. Immunocytochemistry revealed an increase in light chain (LC) 3 protein expression in the IHCH‑treated cells and western blot analysis detected the conversion of LC3‑I to LC3‑II, as well as the recruitment of LC3 to autophagosomes in the cytoplasmatic compartment, suggesting the occurrence of autophagy. These findings show that IHCH induced autophagy in A549 cells, which is a novel cell death mechanism induced by curcumin derivatives.

Topics: Androstadienes; Antifungal Agents; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Cyclohexanones; Humans; Indoles; Lung Neoplasms; Microtubule-Associated Proteins; Wortmannin

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality. Curcumin is involved in various biological pathways leading to inhibition of NSCLC growth. The purpose of this study was to evaluate the effect of curcumin on expression of nuclear factor κB-related proteins in vitro and in vivo and on growth and metastasis in an intralung tumor mouse model. H1975 NSCLC cells were treated with curcumin (0-50 μM) alone, or combined with gemcitabine or cisplatin. The effects of curcumin were evaluated in cell cultures and in vivo, using ectopic and orthotopic lung tumor mouse models. Twenty mice were randomly selected into two equal groups, one that received AIN-076 control diet and one that received the same food but with the addition of 0.6% curcumin 14 days prior to cell implantation and until the end of the experiment. To generate orthotopic tumor, lung cancer cells in Matrigel were injected percutaneously into the left lung of CD-1 nude mice. Western blot analysis showed that the expressions of IkB, nuclear p65, cyclooxygenase 2 (COX-2) and p-ERK1/2 were down-regulated by curcumin in vitro. Curcumin potentiated the gemcitabine- or cisplatin-mediated antitumor effects. Curcumin reduced COX-2 expression in subcutaneous tumors in vivo and caused a 36% decrease in weight of intralung tumors (P=.048) accompanied by a significant survival rate increase (hazard ratio=2.728, P=.036). Curcumin inhibition of COX-2, p65 expression and ERK1/2 activity in NSCLC cells was associated with decreased survival and increased induction of apoptosis. Curcumin significantly reduced tumor growth of orthotopic human NSCLC xenografts and increased survival of treated athymic mice. To evaluate the role of curcumin in chemoprevention and treatment of NSCLC, further clinical trials are required.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Curcumin; Cyclooxygenase 2; Humans; Lung Neoplasms; Mice, Nude; NF-kappa B; Xenograft Model Antitumor Assays

Drug-eluting medical implants are more common, particularly for fighting against cancers. FDA and other drug regulatory bodies have approved many nanoformulated devices eluting active pharmaceutical ingredients and thus there is growing demand for further value- added devices. Nanofibre membranes are known for its versatility of drug incorporation and sustained drug release. We intend to fabricate natural ingredient or extract, and their combination loaded polycaprolactone (PCL) nanofibre for usage as drug-eluting stents or implants for anticancer activity against lung and breast cancers. The fabricated nanofibre membranes were characterised by scanning electron microscope for morphology, FT-IR for chemical nature and tensile testing for mechanical strengths. Release of curcumin was studied with time to find the applicability of the device as drug-eluting implant. The activity of the nanofibre membranes was tested against human breast cancer (MCF7) and lung cancer (A459) cell lines in vitro. In both the cell lines tested, 1% aloe vera and 5% curcumin-loaded PCL nanofibre exhibited 15% more cytotoxicity in comparison with the commercial drug 1% cis-Platin-loaded PCL nanofibre after 24 h incubation.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Humans; Lung Neoplasms; Nanofibers; Plant Extracts; Polyesters

The aim of this study was to investigate the angiogenic effects of curcumin on an ischemia and lung cancer model. To induce ischemia combined with lung cancer models, unilateral femoral arteries of C57BL/6 mice were disconnected on one side of the mouse and Lewis lung carcinoma (LLC) cells were xenografted on the opposite side. Angiogenic effects and underlying mechanisms associated with curcumin were investigated. Molecular target(s), signaling cascades and binding affinities were detected by Western blot, two-dimensional gel electrophoresis (2-DE), computer simulations and surface plasmon resonance (SPR) techniques. Curcumin promoted post-ischemic blood recirculation and suppressed lung cancer progression in inbred C57BL/6 mice via regulation of the HIF1α/mTOR/VEGF/VEGFR cascade oppositely. Inflammatory stimulation induced by neutrophil elastase (NE) promoted angiogenesis in lung cancer tissues, but these changes were reversed by curcumin through directly reducing NE secretion and stimulating α1-antitrypsin (α1-AT) and insulin receptor substrate-1 (IRS-1) production. Meanwhile, curcumin dose-dependently influenced endothelial cells (EC) tube formation and chicken embryo chorioallantoic membrane (CAM) neovascularization. Curcumin had opposite effects on blood vessel regeneration under physiological and pathological angiogenesis, which was effected through negative or positive regulation of the HIF1α/mTOR/VEGF/VEGFR cascade. Curcumin had the promise as a new treatment modality for both ischemic conditions and lung cancer simultaneously in the clinic.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers; Blotting, Western; Carcinoma, Lewis Lung; Cell Movement; Cell Proliferation; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane; Computer Simulation; Curcumin; Electrophoresis, Gel, Two-Dimensional; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Hindlimb; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoenzyme Techniques; Immunoprecipitation; In Vitro Techniques; Ischemia; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Surface Plasmon Resonance; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Deregulation of STAT3 activation is a hallmark of many cancer cells, and the underlying mechanisms are subject to intense investigation. We examined the extent of PIAS3 expression in mesothelioma cells and human tumor samples and determined the functional effects of PIAS3 expression on STAT3 signaling.. We evaluated the expression of PIAS3 in mesothelioma tumors from patients and correlated the expression levels with the course of the disease. We also measured the effects of enhanced PIAS3 activity on STAT3 signaling, cellular growth, and viability in cultured mesothelioma cells.. Gene expression databases revealed that mesotheliomas have the lowest levels of PIAS3 transcripts among solid tumors. PIAS3 expression in human mesothelioma tumors is significantly correlated with overall survival intervals (P = 0.058). The high expression of PIAS3 is predictive of a favorable prognosis and decreases the probability of death within one year after diagnosis by 44%. PIAS3 expression is functionally linked to STAT3 activation in mesothelioma cell lines. STAT3 downregulation with siRNA or enhanced expression of PIAS3 both inhibited mesothelioma cell growth and induced apoptosis. Mesothelioma cells are sensitive to curcumin and respond by the induction of PIAS3. Corroborative evidence has been obtained from STAT3 inhibition experiments. Exposure of the cells to a peptide derived from the PIAS3 protein that interferes with STAT3 function resulted in apoptosis induction and the inhibition of cell growth.. These results suggest that PIAS3 protein expression impacts survival in patients with mesothelioma and that PIAS3 activation could become a therapeutic strategy. Clin Cancer Res; 20(19); 5124-32. ©2014 AACR.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Gene Expression; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Molecular Chaperones; Peptide Fragments; Prognosis; Protein Inhibitors of Activated STAT; RNA Interference; RNA, Messenger; RNA, Small Interfering; STAT3 Transcription Factor

Curcumin and its analogues have been reported to exert anti-cancer activity against a variety of tumors. Here, we reported A501, a new curcumin analogue. The effect of A501 on cell viability was detected by MTT assay, the result showed that A501 had a better inhibiting effect on the four non-small cell lung cancer (NSCLC) cells than that of curcumin. Moreover, Colony forming experiment showed A501 significant restrained cell proliferation. Flow cytometry displayed A501 can cause G2/M arrest and induce apoptosis. Western blotting showed that A501 decreased the expression of cyclinB1, cdc-2, bcl-2, while increased the expression of p53, cleaved caspase-3 and bax. In conclusion, curcumin analogues A501 played antitumor activity by inhibiting cell proliferation and inducing apoptosis of NSCLC cells. And it was likely to be a promising starting point for the development of curcumin-based anticancer drugs.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Non-Small-Cell Lung; Caspase 3; CDC2 Protein Kinase; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Cyclin B1; Cyclin-Dependent Kinases; Humans; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

Herbal compounds such as curcumin which decrease telomerase and gene expression have been considered as beneficial tools for lung cancer treatment. In this article, we compared the effects of pure curcumin and curcumin-loaded NIPAAm-MAA nanoparticles on telomerase and PinX1 gene expression in a lung cancer cell line.. A tetrazolium-based assay was used for determination of cytotoxic effects of curcumin on the Calu-6 lung cancer cell line and telomerase and pinX1 gene expression was measured with real-time PCR.. MTT assay showed that Curcumin-loaded NIPAAm-MAA inhibited the growth of the Calu-6 lung cancer cell line in a time and dose-dependent manner. Our q-PCR results showed that the expression of telomerase gene was effectively reduced as the concentration of curcumin-loaded NIPAAm-MAA increased while expression of the PinX1 gene became elevated.. The results showed that curcumin- loaded- NIPAAm-MAA exerted cytotoxic effects on the Calu-6 cell line through down-regulation of telomerase and stimulation of pinX1 gene expression. NIPPAm-MAA could be good carrier for such kinds of hydrophobic agent.

Topics: Acrylic Resins; Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle Proteins; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Methacrylates; Nanoparticles; Polymers; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spectroscopy, Fourier Transform Infrared; Telomerase; Tumor Cells, Cultured; Tumor Suppressor Proteins

To investigate the anticancer properties of a chemosynthetic curcumin analog, (1E,6E)-4-((furan-2-yl)methylene)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (C26H22O7, abbreviated MHMD) in A549 cells.. Inverted microscope was used to observe the alteration on cytomorphology. MTT assay was used to detect cell viability. Acridine-orange staining was used to measure autophagy, and AnnexinV/PI staining and Hoechst/PI staining to measure apoptosis and necrosis.. MTT assays showed that at 12 h, 24 h, 48 h, MHMD reduced cell viability with an IC50 of 27.46 µM, 18.86 µM, and 11.23 µM, respectively. Typical characteristics were observed in concert with cell death, including treated-cells getting brighter, rounder, and becoming non-adherent gradually. Additionally, acridine-orange staining suggested that autophagy didn't involve in MHMD-induced cell death. However, apoptosis and necrosis played important roles in MHMD-induced cell death by Hoechst33342/PI staining. It showed apoptosis was the main cause at low concentrations (≤ 4 µM), while with the concentrations rising, necrosis was the leading role. AnnexinV/PI staining again indicated the occurrence of apoptosis at 4 µM. Furthermore, the caspases inhibitor z-VAD-fmk could prevent MHMD-induced cell death, which showed much higher cell viability than those only treated with MHMD (4 µM). Moreover, MTT assay also demonstrated that MHMD did possess a greater anti-proliferative ability than curcumin.. The curcumin analog MHMD is able to induce A549 cell death in a time and dose-dependent manner via apoptosis and necrosis. And MHMD could be a more effective drug than curcumin.

Topics: Apoptosis; Autophagy; Cell Death; Cell Line, Tumor; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Humans; Lung Neoplasms

Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma Curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Recently, we found that the combined treatment of FUR with paclitaxel (TAX) showed synergetic anti-proliferative activities in 95-D lung cancer cells. Herein, we showed that FUR reduced the cell numbers distributed in mitosis phase induced by TAX while increased those in G1 phase. The protein levels of cyclin D1, cyclin B1, CDK6 and c-Myc were all down-regulated in the group of combined treatment. The dramatically down-regulated expression of integrin β4, focal adhesion kinase and paxillin might partially contribute to the synergic effect. Though FUR alone obviously induced endoplasmic reticulum stress, this signaling pathway may not contribute to the synergetic anti-proliferative effect as the protein expression of CHOP and BIP was similar in FUR alone and combined treatment group.

Topics: Cell Cycle; Cell Line, Tumor; Curcuma; Cyclin B1; Cyclin D1; Cyclin-Dependent Kinase 6; Drug Synergism; Drugs, Chinese Herbal; Endoplasmic Reticulum Stress; Focal Adhesion Kinase 1; Furans; Heterocyclic Compounds, 2-Ring; Humans; Integrin beta4; Lung Neoplasms; Paclitaxel; Paxillin; Proto-Oncogene Proteins c-myc; Signal Transduction

Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Herein, we systematically investigated the effects of FUR on the significant processes of tumor progression with the relatively low concentrations in 95-D lung cancer cells. FUR concentration-dependently inhibited cell proliferation and blocked the cell cycle progressions in G1 phase by down-regulating the protein levels of cyclin D1 and CDK6, and up-regulating those of p21 and p27 in 95-D cells. FUR also affected the signaling molecules that regulate apoptosis in 95-D cells revealed by the down-regulation of the protein levels of full PARP, pro-caspase-7, survivin, and Bcl-2, and the up-regulation of cleaved PARP. Further studies showed that FUR enhanced the expression of light chain 3-II (LC3-II) in the protein level, indicating that autophagy is involved in this process. Besides, the adhesion ability of 95-D cells to matrigel and fibronectin was slightly inhibited after FUR treatment for 1 h in our experimental condition. FUR also slightly suppressed cell migration and invasion in 95-D cells according to the data from wound healing and Transwell assays, respectively. Taken together, FUR activated the signal molecules regulating G1 cell cycle arrest, apoptosis and autophagy, while slightly affecting the key steps of cell metastasis in 95-D lung cancer cells in the relatively low concentrations.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Caspase 7; Curcuma; Dose-Response Relationship, Drug; Furans; G1 Phase Cell Cycle Checkpoints; Heterocyclic Compounds, 2-Ring; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Neoplasm Metastasis; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Rhizome; Survivin; Tumor Cells, Cultured

(1E,4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(5-methylfuran-2-yl)hepta-1,4,6-trien-3-one (2a), a novel curcumin analog, was previously synthesized in our laboratory as a potential thioredoxin reductase (TrxR) inhibitor with excellent growth inhibitory effects on several TrxR over-expressed cancer cells. In this study, our further studies show that 2a is able to inhibit the growth of cisplatin-resistant A549 (A549/CDDP) cells much more effectively in a dose-dependent manner than that of A549 cells in antiproliferative activity experiments. Moreover, 2a-pretreated A549/CDDP cells are sensitive to cisplatin treatment, which is accompanied by the inhibition of TrxR activity in A549/CDDP cells. As a consequence of targeting TrxR, 2a in turn remarkably up-regulates intracellular reactive oxygen species level, depletes glutathione (GSH), and reduces the GSH/GSSG ratio, suggesting that the intracellular redox balance is shifted to a more oxidative state. Consequently, concomitant with the cell growth inhibition of 2a, apoptosis is induced by 2a probably through increased oxidative stress in A549/CDDP cells. In conclusion, these observations demonstrated that TrxR inhibitors would be promising drugs to achieve a successful combinatory or single cancer chemotherapy.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Furans; Glutathione; Glutathione Disulfide; Humans; Lung Neoplasms; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase

Curcumin (Cum) has been reported to have potential chemo-preventive and chemotherapeutic activity through influencing various processes, inducing cell cycle arrest, differentiation and apoptosis in a series of cancers. However, the poor solubility of Cum limits its further applications in the treatment of cancer. We have previously reported Cum-loaded nanoparticles (Cum-NPs) prepared with amphilic methoxy poly(ethylene glycol)-polycaprolactone (mPEG-PCL) block copolymers. The current study demonstrated superior antitumor efficacy of Cum-NPs over free Cum in the treatment of lung cancer. In vivo evaluation further demonstrated superior anticancer effects of Cum-NPs by delaying tumor growth compared to free Cum in an established A549 transplanted mice model. Moreover, Cum-NPs showed little toxicity to normal tissues including bone marrow, liver and kidney at a therapeutic dose. These results suggest that Cum-NPs are effective to inhibit the growth of human lung cancer with little toxicity to normal tissues, and could provide a clinically useful therapeutic regimen. They thus merit more research to evaluate the feasibility of clinical application.

Topics: Animals; Antineoplastic Agents; Curcumin; Drug Carriers; Female; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Nanoparticles; Polyesters; Polyethylene Glycols; Xenograft Model Antitumor Assays

To prepare water soluble curcumin liposome and investigate its anti-tumour and antiangiogenic effects.. Liposomal curcumin was prepared by alcohol injection method. Proliferation inhibition to murin Lewis lung cancer cell line LL/2 of curcumin liposome was evaluated by MTT assay. Apoptosis and cell cycle arrest induced by liposomal curcumin were analysed by flow cytometry. Anti-tumour effects were investigated in a murine lung cancer model, and the anti-angiogenic effect was determined by aginate encapsulation assay.. In vitro, liposomal curcumin inhibits the proliferation of LL/2 cells and induces apoptosis and cell cycle arrest. In vivo, the systemic administration of liposomal curcumin resulted in the inhibition of tumour. Aginate encapsulation assay revealed angiogenesis was decreased by curcumin liposome.. The curcumin liposome treatment can significantly inhibit tumour growth in vivo.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Cell Line, Tumor; Curcumin; Liposomes; Lung Neoplasms; Mice; Neovascularization, Pathologic

Proteasome inhibitors have been suggested as potential anticancer agents in many clinical trials. Recent evidence indicates that proteasomal deubiquitinase (DUB) inhibitors, bearing a different mechanism from that of traditional proteasome inhibitors, would be appropriate candidates for new anticancer drug development. In the present study, we describe the deubiquitinase inhibition of 19S regulatory particles (19S RP) by AC17, a 4-arylidene curcumin analog synthesized in our laboratory. Although 4-arylidene curcumin analogs were reported to act as inhibitory κB (IκB) kinase (IKK) inhibitors, AC17 instead induced a rapid and marked accumulation of ubiquitinated proteins without inhibiting proteasome proteolytic activities. In contrast to its parent compound, curcumin, which is a proteasome proteolytic inhibitor, AC17 serves as an irreversible deubiquitinase inhibitor of 19S RP, resulting in inhibition of NF-κB pathway and reactivation of proapoptotic protein p53. In addition, in a murine xenograft model of human lung cancer A549, treatment with AC17 suppresses tumor growth in a manner associated with proteasome inhibition, NF-κB blockage, and p53 reactivation. These results suggest that 4-arylidene curcumin analogs are novel 19S deubiquitinase inhibitors with great potential for anticancer drug development.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Curcumin; Disease Models, Animal; Enzyme Activation; Enzyme Inhibitors; Female; Humans; Lung Neoplasms; NF-kappa B; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis; Tumor Burden; Tumor Suppressor Protein p53; Ubiquitin-Specific Proteases; Ubiquitination; Xenograft Model Antitumor Assays

(-)-Epigallocatechin gallate (EGCG) and curcumin are two naturally derived agents that have been widely investigated worldwide. They exhibit their anti-tumor effects in many types of cancers. In the current study, the effect of the combination of the two agents on non-small cell lung cancer (NSCLC) cells was investigated. The results revealed that at low concentrations, the combination of the EGCG and curcumin strongly enhanced cell cycle arrest. Flow cytometry analysis showed that the cells were arrested at G1 and S/G2 phases. Two main cell cycle related proteins cyclin D1 and cyclin B1 were significantly inhibited at the present of EGCG and curcumin. EdU (5-ethynyl-2'-deoxyuridine) fluorescence staining showed that the DNA replication was significantly blocked. A clonal growth assay also confirmed a marked repression of cell growth. In a lung cancer xenograft node mice model, combination of EGCG and curcumin exhibited protective effect against weight loss due to tumor burden. Tumor growth was strongly repressed by the combination of the two agents, without causing any serious side-effect. Overall, these results strongly suggest that EGCG in combination with curcumin could be a candidate for chemoprevention agent of NSCLC.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Catechin; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Clone Cells; Curcumin; Cyclin B1; Cyclin D1; DNA Replication; Female; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude

Curcumin (CM) has anticancer potential for several cancers and blocks several steps in the carcinogenesis process. However, the clinical application of CM is greatly limited due to its low effects in vivo resulted from its poor solubility and pharmacokinetics. This raises the possibility of taking CM as a novel model drug in a new nanoparticle-based delivery system. In this study, CM-loaded nanoparticles were prepared from three kinds of amphilic methoxy poly(ethylene glycol) (mPEG)-polycaprolactone (PCL) block copolymers. It was noted that CM-loaded nanoparticles prepared from mPEG10k-PCL30k showed not only the highest loading efficiency, but also the most sustained release pattern. In vitro studies showed that CM was effectively transported into A549 cells by nanoparticles and localized around the nuclei in the cytoplasm. In addition, the cytotoxicity of CM-loaded nanoparticles with mEPG10k-PCL30k as a drug carrier was in a dose- and time-dependent manner in A549 cells. Further apoptotic staining results demonstrated the superior pro-apoptotic effect of CM-loaded nanoparticles over free drug. Data in this study not only confirmed the potential of CM in treating lung cancer, but also offered an effective way to improve the anticancer efficiency of CM through the nano-drug delivery system.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Drug Carriers; Humans; Lung Neoplasms; Nanoparticles

Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Synergism; Humans; Lung Neoplasms; Mice; Sulindac; Xenograft Model Antitumor Assays

The aim of this paper is to compare the cytotoxicity and cellular uptake efficiency of three kinds of poly(b-benzyl-L-amino) block-poly(ethylene glycol) nanoparticles (PXA-PEG-NPs) using Calu-3 cells, and select one as a nasal drug delivery vector for curcumin (Cur). Poly(gamma-benzyl-L-glutamate) block-poly(ethylene glycol) nanoparticles (PBLG-PEG-NPs), poly(gamma-benzyl-L-lysine) block-poly(ethyleneglycol) nanoparticles (PZLL-PEG-NPs) and poly(gamma-benzyl-L-aspartate) block-poly(ethylene glycol) nanoparticles (PBLA-PEG-NPs) were prepared by emulsion-solvent evaporation method. MTT assays were used to evaluate the cytotoxicity of PXA-PEG-NPs against Calu-3 cells. The cellular uptake of nanoparticles was visualized by an inverted fluorescence microscope and quantified by a flow cytometer. The results indicated that even at high concentration of 2 mg x mL(-1) the three nanoparticles had no cytotoxicity on Calu-3 cells. Compared to the curcumin solution, the three curcumin-loaded PXA-PEG-NPs showed significantly higher cellular uptake efficiency on Calu-3 cells (at equal concentration of curcumin with 5 microg x mL(-1) Cur solution), PBLG-PEG-NPs group was the highest. The cellular uptake increased with incubation time, and has positive correlation with nanoparticle concentration. In brief, PXA-PEG-NPs are conducive to delivery Cur into cells, and PBLG-PEG-NPs might be provided as a good nasal drug delivery carrier.

Topics: Adenocarcinoma; Administration, Intranasal; Anti-Inflammatory Agents, Non-Steroidal; Aspartic Acid; Cell Line, Tumor; Cell Survival; Curcumin; Drug Carriers; Ethylene Glycol; Humans; Lung Neoplasms; Lysine; Nanoparticles; Particle Size; Polyethylene Glycols; Polyglutamic Acid

Curcumin is a major yellow pigment and active component of turmeric widely used as dietary spice and herbal medicine. This compound has been reported to be a promising antitumor agent, although the underlying molecular mechanisms are not fully understood yet. In this study, we reported that curcumin inhibited growth of lung adenocarcinoma cells, but had no cytotoxic activity to IMR-90 normal lung fibroblast cells. Curcumin induced autophagy in the A549 human lung adenocarcinoma cell line, evidenced by LC3 immunofluorescence analysis and immunoblotting assays on LC3 and SQSTM1. Moreover, the autophagy inhibitor 3-MA partly blocked the inhibitory effect of curcumin on the growth of A549 cells. Curcumin markedly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetylCoA carboxylase in A549 cells. At last, pharmacological blockade of the AMPK signaling pathway by compound C and genetic disruption of the AMPK signaling pathway with siRNA-mediated AMPKα1 knockdown impaired the autophagy-inducing effect of curcumin. Collectively, our data suggests that curcumin induces autophagy via activating the AMPK signaling pathway and the autophagy is important for the inhibiting effect of curcumin in lung adenocarcinoma cells.

Topics: Acetyl-CoA Carboxylase; Adenocarcinoma; AMP-Activated Protein Kinases; Antineoplastic Agents, Phytogenic; Autophagy; Cell Line, Tumor; Curcumin; Gene Knockdown Techniques; Humans; Lung Neoplasms; Phosphorylation; RNA, Small Interfering; Signal Transduction

Curcumin has shown promising therapeutic utilities for many diseases, including cancer; however, its clinical application is severely limited because of its poor stability under physiological conditions. Here we find that curcumin also loses its activity instantaneously in a reducing environment. Curcumin can exist in solution as a tautomeric mixture of keto and enol forms, and the enol form was found to be responsible for the rapid degradation of the compound. To increase the stability of curcumin, several analogues were synthesized in which the diketone moiety of curcumin was replaced by isoxazole (compound 2) and pyrazole (compound 3) groups. Isoxazole and pyrazole curcumins were found to be extremely stable at physiological pH, in addition to reducing atmosphere, and they can kill cancer cells under serum-depleted condition. Using molecular modeling, we found that both compounds 2 and 3 could dock to the same site of tubulin as the parent molecule, curcumin. Interestingly, compounds 2 and 3 also show better free radical scavenging activity than curcumin. Altogether, these results strongly suggest that compounds 2 and 3 could be good replacements for curcumin in future drug development.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; Flow Cytometry; Free Radical Scavengers; Humans; Isoxazoles; Ketones; Lung Neoplasms; Models, Chemical; Molecular Conformation; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Tubulin; Tumor Cells, Cultured

We intended to study the mechanism of the inhibitory action of curcumin on human non-small cell lung cancer A549 cell. The cell growth was determined by CCK-8 assay, and the results indicated that curcumin inhibited the cell proliferation in a concentration dependent manner. And to further confirm the relative anti-cancer mechanism of curcumin, RT-PCR was carried out to analysis the expression of relative apoptotic proteins Bax, Bcl-2. We found that curcumin could up-regulate the expression of Bax but down-regulate the expression of Bcl-2 in A549 cells. In addition, curcumin affect the mitochondrial apoptosis pathway. These results suggested that curcumin inhibited cancer cell growth through the regulation of Bcl-2/Bax and affect the mitochondrial apoptosis pathway.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Curcumin; Cytochromes c; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Proto-Oncogene Proteins c-bcl-2; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Multi-drug resistance (MDR) is an essential aspect of human lung cancer chemotherapy failure. Recent studies have shown that vinorelbine is involved in underlying processes in human tumors, reversing the MDR inseveral types of cancer cells. However, the roles and potential mechanism are not fully clear. In this study, we explored effects of vinorelbine in multi-drug resistance reversal of human lung cancer A549/DDP cells. We found that vinorelbine increased drug sensitivity to cisplatin and intracellular accumulation of rhodamine-123, while decreasing expression of P-glycoprotein (P-gp), multi-drug resistance-associated protein (MRP1) and glutathione-S-transferase Π (GST-Π) in A549/DDP cells. At the same time, we also established downregulation of p-Akt and decreased transcriptional activation of NF-κB and twist after vinorelbine treatment. The results indicated that vinorelbine might be used as a potential therapeutic strategy in human lung cancer.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Proliferation; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Glutathione; Glutathione S-Transferase pi; Humans; Lung Neoplasms; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Vinblastine; Vinorelbine

Curcumin was determined to have anticancer potency on several kinds of carcinoma. However, its medical application was limited because of its poor bioavailability, unsatisfying dispersity and rapid metabolism in vivo. In this study, curcumin was delivered by solid lipid nanoparticles (SLN) for lung cancer treatment. The physiochemical characters of SLN-curcumin were detected by HPLC, TEM, Zeta potential analysis and FTIR, and the anticancer efficiency on lung cancer was determined both in vitro and in vivo. SLN-curcumin was synthesized by sol-gel method with the size ranged from 20 to 80 nm. After being loaded in SLN, the IC50 of SLN-curcumin on A549 cells was 4 μM, only 1/20 of plain drug. The plasmid concentration of curcumin was highly increased in mice via i.p. after loaded with SLN. Furthermore, SLN-curcumin enhanced the targeting of curcumin to lung and tumor, which finally increased the inhibition efficiency of curcumin from 19.5% to 69.3%. The Flow Cytometry (FCM) analysis and immuno staining confirmed that the inhibition effect mostly came from apoptosis, but not necrosis. The tumor targeting and profound tumor inhibition effect of SLN-curcumin indicated its medical application on lung cancer treatment, and also provided a novel method for new anticancer agents' development.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Drug Carriers; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Lipids; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Transplantation, Heterologous

Systemic administration of chemotherapy for cancer often has toxic side effects, limiting the doses that can be used in its treatment. In this study, we developed methoxy poly(ethylene glycol)-poly(caprolactone) (MPEG-PCL) micelles loaded with curcumin and doxorubicin (Cur-Dox/MPEG-PCL) that were tolerated by recipient mice and had enhanced antitumor effects and fewer side effects. It was shown that these Cur-Dox/MPEG-PCL micelles could release curcumin and doxorubicin slowly in vitro. The long circulation time of MPEG-PCL micelles and the slow rate of release of curcumin and doxorubicin in vivo may help to maintain plasma concentrations of active drug. We also demonstrated that Cur-Dox/MPEG-PCL had improved antitumor effects both in vivo and in vitro. The mechanism by which Cur-Dox/MPEG-PCL micelles inhibit lung cancer might involve increased apoptosis of tumor cells and inhibition of tumor angiogenesis. We found advantages using Cur-Dox/MPEG-PCL micelles in the treatment of cancer, with Cur-Dox/MPEG-PCL achieving better inhibition of LL/2 lung cancer growth in vivo and in vitro. Our study indicates that Cur-Dox/MPEG-PCL micelles may be an effective treatment strategy for cancer in the future.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Curcumin; Doxorubicin; Female; Injections, Intravenous; Lung Neoplasms; Mice; Mice, Inbred C57BL; Micelles; Nanocapsules; Particle Size; Polyesters; Polyethylene Glycols; Treatment Outcome

Recent advances have highlighted the importance of the endoplasmic reticulum (ER) in cell death processes. Pharmacological interventions that effectively enhance tumor cell death through activating ER stress have attracted a great deal of attention for anti-cancer therapy.. A bio-evaluation on 113 curcumin analogs against four cancer cell lines was performed through MTT assay. Furthermore, real time cell assay and flow cytometer were used to evaluate the apoptotic induction of (1E,4E)-1,5-bis(5-bromo-2-ethoxyphenyl)penta-1,4-dien-3-one (B82). Western blot, RT-qPCR, and siRNA were then utilized to confirm whether B82-induced apoptosis is mediated through activating ER stress pathway. Finally, the in vivo anti-tumor effect of B82 was evaluated.. B82 exhibited strong anti-tumor activity in non-small cell lung cancer (NSCLC) H460 cells. Treatment with B82 significantly induced apoptosis in H460 cells in vitro and inhibited H460 tumor growth in vivo. Further studies demonstrated that the B82-induced apoptosis is mediated by activating ER stress both in vitro and in vivo.. A new monocarbonyl analog of curcumin, B82, exhibited anti-tumor effects on H460 cells via an ER stress-mediated mechanism. B82 could be further explored as a potential anticancer agent for the treatment of NSCLC.

Topics: Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Curcumin; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Transcription Factor CHOP; Xenograft Model Antitumor Assays

Non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR) are responsive to erlotinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of curcumin on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation was determined by MTT assay. Apoptosis was examined using TUNEL staining. Protein expression of genes was determined by Western blot. Tumor growth was assessed in a xenograft mouse model. Results showed that erlotinib had a stronger effect on the induction of apoptosis in erlotinib-sensitive PC-9 cells but showed a weaker effect on erlotinib-resistant H1975 and H1650 cells than cisplatin and curcumin. Furthermore, curcumin significantly increased the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, enhanced erlotinib-induced apoptosis, downregulated the expressions of EGFR, p-EGFR, and survivin, and inhibited the NF-κB activation in erlotinib-resistant NSCLC cells. The combination of curcumin and erlotinib exhibited the same effects on apoptosis as the combination of curcumin and cisplatin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of curcumin and erlotinib significantly inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that curcumin is a potential adjuvant for NSCLC patients during erlotinib treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Mice; Mice, Nude; Mutation; Quinazolines; Random Allocation; Survivin; Xenograft Model Antitumor Assays

Our study investigated the effects of dietary supplementation with curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] on spontaneous metastasis of Lewis lung carcinoma (LLC) in C57BL/6 mice. Mice were fed with the AIN93G control diet or with the diet supplemented with 2 or 4% curcumin for 5 weeks at which time they were injected subcutaneously with 2.5 × 10(5) viable LLC cells. The subcutaneous primary tumor was surgically removed when it reached ~ 8 mm in diameter, and the experiment was terminated 10 days after the surgery. There was no difference in pulmonary metastatic yield among the groups. Curcumin supplementation at either dietary level did not significantly increase the size of metastatic tumors; however, the combined data from both curcumin groups showed that curcumin treatment increased metastatic tumor cross-sectional area by 46% (p < 0.05) and volume by 70% (p < 0.05) compared to the controls. Curcumin supplementation increased plasma concentrations of angiogenic factors angiogenin (p < 0.05), basic fibroblast growth factor (p < 0.05) and vascular endothelial growth factor (p < 0.05), as well as inflammatory cytokines interleukin-1β (p < 0.05) and monocyte chemotactic protein-1 (p < 0.05), compared to the controls. These results demonstrate that curcumin does not prevent metastasis and indicate that it can enhance metastatic growth of LLC in mice, perhaps through upregulation of angiogenesis and inflammation.

Topics: Administration, Oral; Analysis of Variance; Angiogenic Proteins; Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Line, Tumor; Curcumin; Dietary Supplements; Drug Evaluation, Preclinical; Female; Inflammation Mediators; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Tumor Burden

Curcumin has been shown to have potent anticancer activities like inhibition of cell proliferation, induction of apoptosis, and suppression of angiogenesis. Transforming growth factor-β (TGF-β) signaling plays a complex role in tumor suppression and promotion depending on the tumor type and stage. However, the effect of curcumin on TGF-β signaling in cancer cells and the role of TGF-β signaling in curcumin-induced anticancer activities have not been determined. Here, we investigate the role of curcumin on TGF-β signaling, and whether TGF-β signaling is involved in the antitumor activities of curcumin.. Human non-small cell lung cancer (NSCLC) cell lines, ACC-LC-176 (without TGF-β signaling), H358, and A549 (with TGF-β signaling) were treated with curcumin to determine cell growth, apoptosis, and tumorigenicity. Antitumor activities of curcumin were determined using these cell lines and an in vivo mouse model. We also tested the effect of curcumin on TGF-β/Smad signaling by western blotting and by luciferase assays.. Curcumin inhibited cell growth and induced apoptosis of all three NSCLC cell lines in vitro and in vivo. It significantly reduced subcutaneous tumor growth by these three cell lines irrespective of TGF-β signaling status. Curcumin inhibited TGF-β-induced Smad2/3 phosphorylation and transcription in H358 and A549 cells, but not in ACC-LC-176 cells.. Curcumin reduces tumorigenicity of human lung cancer cells in vitro and in vivo by inhibiting cell proliferation and promoting apoptosis. These results suggest that TGF-β signaling is not directly involved in curcumin-mediated growth inhibition, induction of apoptosis, and inhibition of tumorigenicity.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Curcumin; Female; Flow Cytometry; Humans; Lung Neoplasms; Mice; Mice, Nude; Phosphorylation; Signal Transduction; Transforming Growth Factor beta; Tumor Cells, Cultured

The supermolecular curcumin (SMCCM) exhibiting remarkably improved solubility and release characteristics was fabricated to increase the oral bioavailability in rat as well as the antiproliferative and proapoptotic activities of curcumin (CCM) against human lung adenocarcinoma cell A549. SMCCM was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, morphology and structure, aqueous solubility, and release behavior in vitro. Computer modeling of the supermolecular structure was performed. The pharmacokinetics, antiproliferative and proapoptotic activities of SMCCM were evaluated. The mechanisms by which SMCCM inhibited proliferation and induced apoptosis were identified. The formation of SMCCM was testified and the supermolecular structure was studied by a computer modeling technique. Compared to free CCM, SMCCM with much higher aqueous solubility exhibited obviously enhanced release and more favorable pharmacokinetic profiles, and, furthermore, SMCCM showed higher anticancer efficacy, enhanced induction of G2/M-phase arrest and apoptosis in A549 cells, which might be involved with the increases in reactive oxygen species production and intracellular Ca(2+) accumulation, and a decrease in mitochondrial membrane potential. SMCCM remarkably enhanced not only the oral bioavailability but also the antiproliferative and proapoptotic activities of CCM along with improved solubility and release characteristics of CCM.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Calcium; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Lung; Lung Neoplasms; Male; Models, Molecular; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Solubility

This work aims to develop curcumin (Cur) loaded biodegradable self-assembled polymeric micelles (Cur-M) to overcome poor water solubility of Cur and to meet the requirement of intravenous administration. Cur-M were prepared by solid dispersion method, which was simple and easy to scale up. Cur-M had a small particle size of 28.2 ± 1.8 nm and polydisperse index (PDI) of 0.136 ± 0.050, and drug loading and encapsulation efficiency of Cur-M were 14.84 ± 0.11% and 98.91 ± 0.70%, respectively. Besides, in vitro release profile showed a significant difference between rapid release of free Cur and much slower and sustained release of Cur-M. Cytotoxicity study showed that the encapsulated Cur remained its potent anti-tumor effect. Furthermore, Cur-M were more effective in inhibiting tumor growth and spontaneous pulmonary metastasis in subcutaneous 4T1 breast tumor model, and prolonged survival of tumor-bearing mice. In addition, immunofluorescent and immunohistochemical studies also showed that tumors of Cur-M-treated mice had more apoptosis cells, fewer microvessels, and fewer proliferation-positive cells. In conclusion, polymeric micelles encapsulating Cur were developed with enhanced anti-tumor and anti-metastasis activity on breast tumor, and Cur-M is excellent water-based formulation of Cur which may serve as a candidate for breast cancer therapy.

Topics: Analysis of Variance; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Drug Carriers; Female; In Situ Nick-End Labeling; Lung Neoplasms; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Micelles; Neovascularization, Pathologic; Particle Size; Polyethylene Glycols; Solubility; Surface Properties

The purpose of this manuscript was to study the regulation effects of β-elemene combined with radiotherapy on three different gene expressions in lung adenocarcinoma A549 cell. mTOR gene, HIF-1α gene, Survivin gene were included in the gene group. Cell culture and RT-PCR were applied to finish this research. Hypoxia Control group, Hypoxia β-elemene group, Hypoxia β-elemene combined with irradiation group were set to compare the differences of three different gene expressions. The most active effects were found in the group of Hypoxia irradiation combined with β-elemene. In this group, the mTOR gene, HIF-1α gene, Survivin gene expressions were all down-regulated when compared with the single treatment groups, and there were significantly statistical differences.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Chemotherapy, Adjuvant; Curcuma; Down-Regulation; Gene Expression; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Phytotherapy; Plant Extracts; Reverse Transcriptase Polymerase Chain Reaction; Sesquiterpenes; Survivin; TOR Serine-Threonine Kinases

In this study, we report that the essential oil obtained from Curcuma zedoaria Roscoe, known as zedoary, possesses efficient cytotoxic effects on non-small cell lung carcinoma (NSCLC) cells and causes cell apoptosis. Zedoary essential oil increased the sub-G1 population and the level of annexin-V binding and induced cleavage and activation of caspase-3, -8, and -9 and poly(ADP ribose) polymerase. Decreases in the levels of Bcl-2 and Bcl-xL and an increase in the Bax/Bcl-2 ratio were also observed following zedoary essential oil treatment. Notably, zedoary essential oil led to the release of AIF, endonuclease G, and cytochrome c into the cytosol and increased levels of p53 in H1299 cells. Our results indicate that zedoary essential oil slightly inhibited the phosphorylation of ERK1/2 and enhanced the phosphorylation of JNK1/2 and p38. Zedoary essential oil also inhibited AKT/NF-κB signaling pathways in H1299 cells. Moreover, intraperitoneal administration of zedoary essential oil significantly suppressed the growth of H1299 cells in vivo. In addition, potential active compounds were detected using gas chromatography and mass spectrometry. 8,9-Dehydro-9-formyl-cycloisolongifolene, 6-ethenyl-4,5,6,7-tetrahydro-3,6-dimethyl-5-isopropenyl-trans-benzofuran, eucalyptol, and γ-elemene were found in zedoary essential oil. In summary, our findings provide insight into the molecular mechanisms underlying zedoary essential oil-induced apoptosis in NSCLC cells that are worthy of further study.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Cell Proliferation; Curcuma; Drug Screening Assays, Antitumor; Lung Neoplasms; Mice; Mice, Inbred BALB C; Oils, Volatile

The present study demonstrates that curcumin acts as pro-oxidant and sensitizes human lung adenocarcinoma epithelial cells (A549) to apoptosis via intracellular redox status mediated pathway. Results indicated that curcumin induced cell toxicity (light microscopy and MTT assay) and apoptosis (AnnexinV-FITC/PI labeling and caspase-3 activity) in these cells. These events seem to be mediated through generation of reactive oxygen species (ROS) and superoxide radicals (SOR) and enhanced levels of lipid peroxidation. These changes were accompanied by increase in oxidized glutathione (GSSG), reduced glutathione (GSH) and gamma-glutamylcysteine synthetase (gamma-GCS) activity, but decrease in GSH/GSSG ratio. The induction of apoptosis and decrease in GSH/GSSG ratio was also accompanied by sustained phosphorylation and activation of p38 mitogen activated protein kinase (MAPK). On the other hand, addition of N-acetyl cysteine (NAC), an antioxidant, blocked the curcumin-induced ROS production and rescued malignant cells from curcumin-induced apoptosis through caspase-3 deactivation. However, L-buthionine sulfoximine (BSO), a GSH synthesis blocking agent, further enhanced curcumin-induced ROS production and apoptosis in A549 cells. Decreased GSH/GSSG ratio seems to be a crucial factor for the activation of MAPK signaling cascade by curcumin. The study therefore, provides an insight into the molecular mechanism involved in sensitization of lung adenocarcinoma cells to apoptosis by curcumin.

Topics: Acetylcysteine; Adenocarcinoma; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Buthionine Sulfoximine; Caspase 3; Cell Line, Tumor; Curcumin; Drug Screening Assays, Antitumor; Enzyme Activation; Enzyme Induction; Glutamate-Cysteine Ligase; Glutathione; Humans; Lipid Peroxidation; Lung Neoplasms; MAP Kinase Signaling System; Oxidants; Oxidation-Reduction; Phosphorylation; Protein Processing, Post-Translational; Reactive Oxygen Species; RNA, Messenger; RNA, Neoplasm; Superoxides

CLEFMA or 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] is a curcuminoid being developed as an anticancer drug. We recently reported that it potently inhibits proliferation of various cancer cells. In this project, we investigated the effect of CLEFMA on gene expression profile in H441 lung adenocarcinoma cells, and studied its mechanism of action. In microarray data, we observed a deregulation of genes involved in redox and glutamate metabolism. Based on the affected ontologies, we hypothesized that antiproliferative activity of CLEFMA could be a result of the induction of reactive oxygen species (ROS). We tested this hypothesis by determining the levels of glutathione (GSH) and ROS in H441 cells treated with CLEFMA. We observed a rapid depletion of intracellular GSH/GSSG ratio. Using a cell-permeable fluorogenic substrate, we found that CLEFMA significantly induced ROS in a time- and dose-dependent manner (p < 0.05). Flow-cytometry with a mitochondria-selective fluorescent reporter of ROS indicated that the CLEFMA-induced ROS was of mitochondrial origin. In contrast to the cancer cells, the normal lung fibroblasts (CCL-151) did not show any increase in ROS and were resistant to CLEFMA-induced cell death. Furthermore, the addition of antioxidants, such as catalase, superoxide dismutase and N-acetylcysteine, rescued cancer cells from CLEFMA-induced cell death. Gene expression pathway analysis suggested that a transcription factor regulator Nrf2 is a pivotal molecule in the CLEFMA-induced deregulation of redox pathways. The immunoblotting of Nrf2 showed that CLEFMA treatment resulted in phosphorylation and nuclear translocation of Nrf2 in a time-dependent fashion. Based on these results, we conclude that induction of ROS is critical for the antiproliferative activity of CLEFMA and the Nrf2-mediated oxidative stress response fails to salvage H441 cells.

Topics: Active Transport, Cell Nucleus; Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Antioxidants; Benzylidene Compounds; Blotting, Western; Cell Death; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glutathione; Humans; Lung Neoplasms; NF-E2-Related Factor 2; Oligonucleotide Array Sequence Analysis; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Piperidones; Reactive Oxygen Species; Time Factors

Curcumin (diferuloylmethane), an active component of the spice turmeric, induces apoptosis in several types of malignancies. However, little is known about its anticancer activity in small cell lung cancer (SCLC). SCLC represents a highly malignant and particularly aggressive form of cancer, with early and widespread metastases and a poor prognosis. In this study, we found that curcumin does not activate caspase-8 cleavage or alter the expression of apoptotic receptors FAS and TRAIL in NCI-H446 cells, suggesting that curcumin-induced apoptosis is not associated with death receptor-mediated pathways in these cells. Instead, curcumin caused apoptosis by increasing Bax expression while decreasing the expression of Bcl-2 and Bcl-xL. Curcumin induced a rapid decrease in mitochondrial membrane potential and the release of cytochrome c into the cytosol, followed by activation of caspase-9 and caspase-3. In addition, curcumin-induced apoptosis was accompanied by an increase of intracellular reactive oxygen species (ROS) level. These results indicated that a ROS-mediated mitochondrial pathway played an important role in the process of curcumin-induced apoptosis of human SCLC NCI-H446 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Microscopy, Electron, Transmission; Mitochondria; Reactive Oxygen Species; Receptors, Death Domain; Signal Transduction; Small Cell Lung Carcinoma

Cancer cells exhibit de-regulation of multiple cellular signalling pathways and treatments of various types of cancers with polyphenols are promising. We recently reported the synthesis of a series of 33 novel divanillic and trivanillic polyphenols that displayed anticancer activity, at least in vitro, through inhibiting various kinases. This study revealed that minor chemical modifications of a trivanillate scaffold could convert cytotoxic compounds into cytostatic ones. Compound 13c, a tri-chloro derivative of trivanillic ester, displayed marked inhibitory activities against FGF-, VEGF-, EGF- and Src-related kinases, all of which are implicated not only in angiogenesis but also in the biological aggressiveness of various cancer types. The pan-anti-kinase activity of 13c occurs at less than one-tenth of its mean IC(50) in vitro growth inhibitory concentrations towards a panel of 12 cancer cell lines. Of the 26 kinases for which 13c inhibited their activity by >75%, eight (Yes, Fyn, FGF-R1, EGFR, Btk, Mink, Ret and Itk) are implicated in control of the actin cytoskeleton organization to varying degrees. Compound 13c accordingly impaired the typical organization of the actin cytoskeleton in human U373 glioblastoma cells. The pan-anti-kinase activity and actin cytoskeleton organization impairment provoked by 13c concomitantly occurs with calcium homeostasis impairment but without provoking MDR phenotype activation. All of these anticancer properties enabled 13c to confer therapeutic benefits in vivo in a mouse melanoma pseudometastatic lung model. These data argue in favour of further chemically modifying trivanillates to produce novel and potent anticancer drugs.

Topics: Actin Cytoskeleton; Animals; Antineoplastic Agents; Apoptosis; Calcium; Cell Line, Tumor; Curcumin; Cytostatic Agents; Female; Glioblastoma; Inhibitory Concentration 50; Lung Neoplasms; Male; Mice; Microscopy, Fluorescence; Microscopy, Video; Mitosis; Phosphotransferases; Polyphenols

We previously reported that curcumin inhibited lung cancer A549 cells growth and promoted cell apoptosis in vitro. In this study, we further examined the apoptosis-related parameters, including lysosomal damage and cathepsin activation, in A549 cells exposed to curcumin. We found that curcumin caused lysosomal membrane permeabilization (LMP) and cytosolic relocation of cathepsin B (cath B) and cathepsin D (cath D). However, only Z-FA-fmk (a cath B inhibitor) but not pepstatin A (a cath D inhibitor) inhibited curcumin-induced cell apoptosis, mitochondrial membrane potential loss, and cytochrome c release. The antioxidant N-acetylcysteine and glutathione attenuated LMP, suggesting that lysosomal destabilization was dependent on the elevation of reactive oxygen species and which precedes mitochondrial dysfunction. These findings indicated a novel pathway for curcumin regulation of ROS-lysosomal-mitochondrial pathway and provided the key mechanism of regulation of LMP in cell apoptosis, which may be exploited for cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; Cathepsin B; Cathepsin D; Cell Line, Tumor; Curcumin; Cytochromes c; Humans; Intracellular Membranes; Lung Neoplasms; Lysosomes; Membrane Potential, Mitochondrial; Mitochondria; Permeability; Reactive Oxygen Species

Curcumin (diferuloylmethane), a phenolic compound obtained from the rhizome of Curcuma longa, has been found to inhibit cell proliferation in various human cancer cell lines, including non-small cell lung cancer (NSCLC). Thymidine phosphorylase (TP) is considered an attractive therapeutic target, because increased TP expression can suppress cancer cell death induced by DNA-damaging agents. Mitomycin C (MMC), a chemotherapeutic agent used to treat NSCLC, inhibits tumour growth through DNA cross-linking and breaking. Whether MMC can affect TP expression in NSCLC is unknown. Therefore, in this study, we suggested that curcumin enhances the effects of MMC-mediated cytotoxicity by decreasing TP expression and ERK1/2 activation. Exposure of human NSCLC cell lines H1975 and H1650 to curcumin decreased MMC-elicited phosphorylated MKK1/2-ERK1/2 protein levels. Moreover, curcumin significantly decreased MMC-induced TP protein levels by increasing TP mRNA and protein instability. Enhancement of ERK1/2 activation by constitutively active MKK1/2 (MKK1/2-CA) increased TP protein levels and cell viability in curcumin- and MMC-co-treated cells. In contrast, U0126, a MKK1/2 inhibitor, augmented the cytotoxic effect and the down-regulation of TP by curcumin and MMC. Specific inhibition of TP by siRNA significantly enhanced MMC-induced cell death and cell growth inhibition. Our results suggest that suppression of TP expression or administration of curcumin along with MMC may be a novel lung cancer therapeutic modality in the future.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Curcuma; Curcumin; Down-Regulation; Drug Synergism; Humans; Lung Neoplasms; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mitomycin; Phosphorylation; Thymidine Phosphorylase

Curcumin (Cum), the principal polyphenolic curcuminoid, obtained from the turmeric rhizome Curcuma longa, is recently reported to have potential antitumor effects in vitro and in vivo. Docetaxel (Doc) is considered as first-line chemotherapy for the treatment of non-small cell lung cancer. Here we report for the first time that Cum could synergistically enhance the in vitro and in vivo antitumor efficacy of Doc against lung cancer. In the current study, combination index (CI) is calculated in both in vitro and in vivo studies to determine the interaction between Cum and Doc. In the in vitro cytotoxicity test, media-effect analysis clearly indicated a synergistic interaction between Cum and Doc in certain concentrations. Moreover, in vivo evaluation further demonstrated the superior anticancer efficacy of Cum + Doc compared with Doc alone by intravenous delivery in an established A549 transplanted xenograft model. Results showed that Cum synergistically increased the efficacy of Doc immediately after 4 days of the initial treatment. Additionally, simultaneous administration of Cum and Doc showed little toxicity to normal tissues including bone marrow and liver at the therapeutic doses. Therefore, in vitro and in vivo evaluations demonstrated the satisfying synergistic antitumor efficacy of Cum and Doc against lung cancer and the introduction of Cum in traditional chemotherapy is a most promising way to counter the spread of non-small cell lung cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Docetaxel; Drug Synergism; Female; Humans; Lung Neoplasms; Male; Medicine, Chinese Traditional; Mice; Mice, Nude; Taxoids; Xenograft Model Antitumor Assays

Multiple studies from independent groups find evidence for signal transducer and activator of transcription 3 (Stat3) activation in nearly 50% of lung cancers, suggesting a functional role for this target in subsets of lung cancer. On the basis of the existing evidence, we hypothesized that bioavailable curcuminoid complex may modulate lung carcinogenesis, primarily by inhibiting Stat3 activation. With the safety of this being botanically well established, the objective of these studies was to test our hypothesis in vitro and in vivo in an effort to inform the design of a phase II chemoprevention trial in former smokers. We treated non-tumor-derived, normal (but immortalized) human bronchial epithelial cells (AALE) (Lundberg et al., 2002; Pillai et al., 2011) and lung adenocarcinoma-derived cells (H441) with bioactive curcumin C3 complex. Asynchronous cells in each case were treated with curcumin for 24 h, followed by immunoblotting for Stat3 and activated Stat3-P, prior signal of which was used for normalization. We also completed a preclinical trial in which 12 mice were randomly divided into three groups and subjected to 3 days or 9 days of curcumin intraperitoneal injections, followed by analysis of lung tissues for Stat3-P changes and growth suppressive effects of the curcumin. The growth suppressive effects were measured using Cyclin D1 and the replicative helicase subunit, Mcm2, as surrogates for the proliferative capacity of the tissues. In-vitro studies with curcuminoid complex demonstrated that the activity of Stat3 in both normal bronchoepithelial cells and lung cancer-derived cells is sensitive to curcumin exposure. In a dose-dependent manner, curcumin treatment resulted in significant suppression of Stat3 phosphorylation and reduction in the proliferative capacity of both cell types. In the preclinical trial with rodent models, curcumin reduced Stat3-P and the proliferative markers CycD1 and Mcm2 in mice lung tissues in vivo. These culture and preclinical studies indicate that the activity of the Stat3 pathway can be suppressed by curcumin treatment, concomitant with a reduction in cell proliferation, supporting our hypothesis that inhibition of the Stat3 pathway represents at least one important mechanism by which curcumin elicits its effects on the bronchoepithelium. These data provide a rationale for the use of curcumin as a promising chemopreventive agent in high-risk populations such as former smokers.

Topics: Animals; Cell Line; Curcumin; Enzyme Inhibitors; Female; Humans; Lung Neoplasms; Mice; Mice, Nude; Random Allocation; STAT3 Transcription Factor

Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for the development of therapeutic drugs for cancer treatment. Curcumin, a dietary phytochemical, exhibits growth-suppressive activity against cancer cells via multitarget mechanisms. However, the low stability and poor pharmacokinetics significantly limit its clinical applications. Thus, we designed and synthesized a novel monocarbonyl analog of curcumin, 1,5-bis(2-methoxyphenyl) penta-1,4-dien-3-one (B63). This compound exhibited a higher chemical stability in cultural medium and a better intracellular profile than curcumin. Treatment with B63 potently induced apoptosis of human non-small cell lung cancer (NSCLC) cells in a dose-responsive manner, while exhibiting no cytotoxicity in normal lung fibroblast cells. Its antitumor effect was associated with the ER stress-mediated apoptotic pathway and, ultimately, the activation of the caspase cascades. However, curcumin at the same concentrations did not cause ER stress in H460 cells. Further, C/EBP homologous protein knockdown by siRNA attenuated B63-induced cell apoptosis, indicating that the apoptotic pathway is ER stress-dependent. In vivo, the volume and weight of the tumor were reduced significantly by pretreating the H460 tumor cells with B63 before implantation. Taken together, these insights on the novel compound B63, from both chemical and biological perspectives, may provide a novel anticancer candidate for the treatment of NSCLC.

Topics: Animals; Anisoles; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Endoplasmic Reticulum Stress; Humans; Ketones; Lung Neoplasms; Mice; Mice, Inbred BALB C

Cdc42, a Rho GTPase family member, is involved in cell transformation, proliferation, survival, invasion and metastasis of human cancer cells. Overexpression of Cdc42 has been reported in several types of human cancer. However, the underlying mechanisms are not well understood. The present study showed that Cdc42 was overexpressed in 80 of 110 primary lung cancer patients, and overexpression of Cdc42 was significantly associated with high TNM stage and lymph node metastasis. Moreover, RNAi-mediated suppression of Cdc42 expression reduced actin filopodia formation, migration and invasion potential of a highly metastatic lung cancer cell line, 801D. In parallel, 801D cells were treated with curcumin and the effect on the expression of the Cdc42 gene at the transcriptional and translational levels was analyzed by RT-PCR and Western blotting. Curcumin inhibited cell migration, invasion and downregulated Cdc42 gene and Cdc42-related target gene expression in 801D cells. It also induced rearrangements of the actin cytoskeleton. These effects mimicked those of Cdc42 knockdown. Furthermore, xenograft experiments confirmed the suppression of tumor growth and invasion in vivo, which was due to the effect of curcumin and the inhibition of Cdc42 by curcumin. Our results showing the downregulation of Cdc42 expression by curcumin in lung cancer cells taken together with the clinical data suggest a potential therapeutic role for curcumin in inducing Cdc42-mediated inhibition of invasion of lung cancer cells.

Topics: Actin Cytoskeleton; Analysis of Variance; Animals; Antineoplastic Agents, Phytogenic; Blotting, Western; cdc42 GTP-Binding Protein; Cell Line, Tumor; Cell Movement; Chi-Square Distribution; Curcumin; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lung Neoplasms; Lymphatic Metastasis; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Polymerase Chain Reaction; RNA Interference; RNA, Messenger; Transcriptional Activation; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

Recent understanding on cancer therapy indicated that targeting metastatic signature or angiogenic switch could be a promising and rational approach to combat cancer. Advancement in cancer research has demonstrated the potential role of various tumor suppressor proteins in inhibition of cancer progression. Current studies have shown that axonal sprouting inhibitor, semaphorin 3A (Sema 3A) acts as a potent suppressor of tumor angiogenesis in various cancer models. However, the function of Sema 3A in regulation of melanoma progression is not well studied, and yet to be the subject of intense investigation.. In this study, using multiple in vitro and in vivo approaches we have demonstrated that Sema 3A acts as a potent tumor suppressor in vitro and in vivo mice (C57BL/6) models. Mouse melanoma (B16F10) cells overexpressed with Sema 3A resulted in significant inhibition of cell motility, invasiveness and proliferation as well as suppression of in vivo tumor growth, angiogenesis and metastasis in mice models. Moreover, we have observed that Sema 3A overexpressed melanoma clone showed increased sensitivity towards curcumin and Dacarbazine, anti-cancer agents.. Our results demonstrate, at least in part, the functional approach underlying Sema 3A mediated inhibition of tumorigenesis and angiogenesis and a clear understanding of such a process may facilitate the development of novel therapeutic strategy for the treatment of cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Apoptosis; Blotting, Western; Case-Control Studies; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Curcumin; Dacarbazine; Human Umbilical Vein Endothelial Cells; Humans; Immunoenzyme Techniques; Liver Neoplasms; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Phosphorylation; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Semaphorin-3A; Wound Healing

Curcumin, a yellow pigment derived from Curcuma longa Linn, has been favored by the Eastern as dietary ingredients for centuries. During the past decade, extensive investigations have revealed curcumin sensitized various chemotherapeutic agents in human breast, colon, pancreas, gastric, liver, brain and hematological malignant disorders in vivo and in vitro. Several pathways and specific targets including NF-κB, STAT3, COX-2, Akt and multidrug resistant protein have been identified to facilitate curcumin as a chemosensitizer. Recent studies suggest HIF-1α participated in the development of drug resistance in cancer cells and targeting HIF-1α either by RNAi or siRNA successfully overcame chemotherapeutic resistance. To investigate the mechanism basis of curcumin as a chemosensitizer in lung cancer, we examined curcumin's effects on HIF-1α in cis-platin (DDP) sensitive A549 and resistant A549/DDP cell lines by RT-PCR and Western blot. HIF-1α in A549/DDP cells was found to be overexpressed at both mRNA and protein levels together with a poor response to DDP. Results from transient transfection and flow cytometry showed the HIF-1α abnormality contributed to DDP resistance in A549/DDP lung cancer cells. Combined curcumin and DDP treatment markedly inhibited A549/DDP cells proliferation, reversed DDP resistance and triggered apoptotic death by promoting HIF-1α degradation and activating caspase-3, respectively. Expression of HIF-1α-dependent P-gp also seemed to decrease as response to curcumin in a dose-dependent manner. Our findings shed light on drug resistant reversing effect of curcumin in lung cancer cells by inhibiting HIF-1α expression and activating caspase-3.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms

Lung carcinogenesis is a complex process in an unregulated inflammatory environment. Curcumin has been extensively investigated as a multi-target anti-tumor and anti-inflammation compound. In this paper, we demonstrate a novel inflammation-related mechanism for curcumin-induced inhibition of lung tumor growth. We found that neutrophil elastase, an important regulator of inflammatory processes, directly triggered tumor cell proliferation in human lung adenocarcinoma A549 cells, and curcumin could completely suppress the excess tumor proliferation induced by neutrophil elastase. α1-antitrypsin is synthesized by tumor cells and is the natural inhibitor of neutrophil elastase. We found that curcumin counteracted the decrease of α1-antitrypsin induced by neutrophil elastase by inducing the promoter activity of α1-antitrypsin and promoting its expression in A549 cells. The inhibition of neutrophil elastase-induced proliferation by curcumin was dependent on the PI3K/Akt pathway. Knockdown of α1-antitrypsin by siRNA further enhanced the tumor cell proliferation induced by neutrophil elastase and significantly blocked the anti-proliferation effect of curcumin against neutrophil elastase. Curcumin remarkably inhibited the primary tumor growth of Lewis lung carcinoma (LLC) in C57BL/6 mice. We further showed that curcumin upregulated the level of α1-antitrypsin in primary tumor tissue by promoting its local expression, and the protein level of neutrophil elastase in tumor tissue was obviously decreased in mice treated with curcumin. Overall, our results suggest that neutrophil elastase and α1-antitrypsin play important roles in modulating lung tumor proliferation in inflammatory microenvironment and curcumin inhibits neutrophil elastase-induced tumor proliferation via upregulating α1-antitrypsin expression in vitro and in vivo.

Topics: alpha 1-Antitrypsin; Animals; Carcinoma, Lewis Lung; Cell Line, Tumor; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Leukocyte Elastase; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; Up-Regulation

The present study attempted to explore the efficacy of curcumin and resveratrol in modulating mitotic catastrophe and apoptosis during lung carcinogenesis. The mice were segregated into five groups, which included normal control, benzo(a)pyrene (BP)-treated, BP + curcumin (C)-treated, BP + resveratrol (R)-treated and BP + C + R-treated groups. The BP treatment resulted in a significant increase in the formation of micronuclei as well as in the protein expression of bcl-2 in the lungs of mice. On the other hand, a significant decrease was observed in the number of apoptotic cells and protein expression of bax in the lungs of BP-treated mice. Supplementation of curcumin and resveratrol individually to BP-treated animals resulted in a decrease in the micronuclei formation; however, it was not statistically significant. Interestingly, combination of curcumin and resveratrol resulted in a statistically significant decrease in micronuclei formation. Moreover, phytochemicals in combination significantly reduced the protein expression of bcl-2 in BP-treated mice. Furthermore, supplementation of phytochemicals in combination brought a noticeable improvement in the number of apoptotic cells as well as in the protein expression of bax. The present study, therefore, concludes that the combined treatment with curcumin and resveratrol modulates mitotic catastrophe by stimulating apoptosis in BP-treated mice.

Topics: Animals; Antimutagenic Agents; Apoptosis; Benzo(a)pyrene; Carcinogens; Curcumin; Disease Models, Animal; Drug Therapy, Combination; Lung; Lung Neoplasms; Male; Mice; Micronuclei, Chromosome-Defective; Micronucleus Tests; Mitosis; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Stilbenes

The present study attempted to explore the efficacy of curcumin and resveratrol in modulating premature mitochondria senescence and ultrastructural changes during lung carcinogenesis. The mice were segregated into 5 groups, which included normal control, benzo[a]pyrene (BP) treated, BP + curcumin (C) treated, BP + resveratrol (R) treated, and BP + C + R treated groups. Animals were given a single ip injection of benzo[a]pyrene in corn oil at a dose level of 100 mg/kg body weight. Treatments of curcumin and resveratrol were given orally in drinking water at a dose level of 60 mg/kg body weight and 5.7 µg/mL drinking water, respectively, 3 times a week for a total duration of 22 weeks. Ultrastructure of BP-treated mice revealed disruptions in cellular integrity along with nuclear deformation and premature mitochondrial senescence. Interestingly, supplementation of curcumin and resveratrol individually resulted in improvement of ultrahistoarchitecture of BP-treated mice but the improvement was much greater with combined supplementation of phytochemicals. Further, benzo[a]pyrene treatment revealed alterations in lung histoarchitecture, which, however, was improved appreciably following combined supplementation with curcumin and resveratrol. The present study concludes that combined supplementation with curcumin and resveratrol effectively modulates histoarchitecture as well as ultrahistoarchitecture during benzo[a]pyrene-induced lung carcinogenesis in mice. Cancer is a public health problem worldwide. Lung cancer is a major cause of mortality throughout the world and is responsible for the deaths of more than one million people annually. Phytochemicals have shown great potential in preventing the occurrence of cancer and other chronic diseases that result from oxidative stress induced by free radicals. Phytochemicals are nonnutritive products of plants and, being nontoxic, are presently being studied the world over for their chemopreventive actions in controlling various diseases, including cancer. In the present study, curcumin and resveratrol are the phytochemicals of interest. Curcumin, a polyphenol, has been reported to have anti-invasive properties. Further, curcumin has been shown to activate apoptotic machinery in patients with lung cancer. On the other hand, resveratrol (trans-3,4,5- thihydroxystibene) is a phytoalexin that is present naturally in grapes as well as in a variety of medicinal plants and has been shown to exhibit antioxidant activity wit

Topics: Animals; Anticarcinogenic Agents; Benzo(a)pyrene; Carcinogens; Cellular Senescence; Curcumin; Disease Models, Animal; Drug Therapy, Combination; Lung Neoplasms; Male; Mice; Mitochondria; Pulmonary Alveoli; Resveratrol; Stilbenes

Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development. However, little is known about its anti-tumor mechanism in small cell lung cancer (SCLC). In this study, we found that curcumin can inhibit SCLC cell proliferation, cell cycle, migration, invasion and angiogenesis through suppression of the STAT3. SCLC cells were treated with curcumin (15 µmol/L) and the results showed that curcumin was effective in inhibiting STAT3 phosphorylation to downregulate of an array of STAT3 downstream targets ,which contributed to suppression of cell proliferation, loss of colony formation, depression of cell migration and invasion. Curcumin also suppressed the expression of proliferative proteins (Survivin, Bcl-X(L) and Cyclin B1), and invasive proteins (VEGF, MMP-2, MMP-7 and ICAM-1). Knockdown of STAT3 expression by siRNA was able to induce anti-invasive effects in vitro. In contrast, activation of STAT3 upstream of interleukin 6 (IL-6) leads to the increased cell proliferation ,cell survival, angiogenesis, invasion, migration and tumor growth. Our findings illustrate the biologic significance of IL-6/JAK/STAT3 signaling in SCLC progression and provide novel evidence that the pathway may be a new potential target for therapy of SCLC. It was concluded that curcumin is a potent agent in the inhibition of STAT3 with favorable pharmacological activity,and curcumin may have translational potential as an effective cancer therapeutic or preventive agent for SCLC.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Cyclin B1; Humans; Interleukin-6; Janus Kinases; Lung Neoplasms; Matrix Metalloproteinases; Neovascularization, Pathologic; RNA Interference; Signal Transduction; Small Cell Lung Carcinoma; STAT3 Transcription Factor

Radiation pneumonitis (RP) is an important dose-limiting toxicity during thoracic radiotherapy. Previous investigations have shown that curcumin is used for the treatment of inflammatory conditions and cancer, suggesting that curcumin may prevent RP and sensitize cancer cells to irradiation. However, the clinical advancement of curcumin is limited by its poor water solubility and low bioavailability after oral administration. Here, a water-soluble liposomal curcumin system was developed to investigate its prevention and sensitizing effects by an intravenous administration manner in mice models. The results showed that liposomal curcumin inhibited nuclear factor-κB pathway and downregulated inflammatory factors including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and transforming growth factor-β induced by thoracic irradiation. Furthermore, the combined treatment with liposomal curcumin and radiotherapy increased intratumoral apoptosis and microvessel responses to irradiation in vivo. The significantly enhanced inhibition of tumor growth also was observed in a murine lung carcinoma (LL/2) model. There were no obvious toxicities observed in mice. The current results indicate that liposomal curcumin can effectively mitigate RP, reduce the fibrosis of lung, and sensitize LL/2 cells to irradiation. This study also suggests that the systemic administration of liposomal curcumin is safe and deserves to be investigated for further clinical application.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Analysis of Variance; Animals; Carcinoma, Lewis Lung; Cell Line, Tumor; Combined Modality Therapy; Curcumin; Cytokines; Histocytochemistry; Liposomes; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Radiation Pneumonitis; Radiation-Sensitizing Agents; Radiography, Thoracic

Some phytochemicals with the characteristics of cytotoxicity and anti-metastasis has generated intense interest among the invasive cancer study. Curcumin, one of these anti-cancer phytochemicals, has been reported to induce the cytoprotective enzyme heme oxygenase-1 expression. Since heme oxygenase-1 has been suggested to enhance cancer cell invasion, we investigated the anti-invasive effect of curcumin when heme oxygenase-1 was knocked down in vitro, and the heme oxygenase-1 expression after curcumin treatment in vivo. Curcumin inhibited cell viability and the MMP-2/9 activities of human bladder cancer cells. At 10 μM, curcumin inhibited cell viability and cell invasive activity by 15% and 40%, respectively. Ten micrometer curcumin increased the intracellular reactive oxygen species concentration and heme oxygenase-1 protein and mRNA expression in bladder cancer cells. The anti-invasive activity of curcumin was elevated when heme oxygenase-1 was knocked down by siRNA or inhibited by pharmacological inhibitor. In vivo, curcumin induced heme oxygenase-1 protein expression in the lung tissue of murine lung metastasis tumor model and in the bladder tissue of murine orthotopic bladder tumor model. Taken together, our data suggest that curcumin-induced heme oxygenase-1 attenuates the anti-invasive effect of curcumin in cancer therapy, and co-treatment by heme oxygenase-1 inhibitor enhances the anti-invasive activity of curcumin.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Curcumin; Female; Gene Expression Regulation, Enzymologic; Gene Knockdown Techniques; Heme Oxygenase-1; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mice, Nude; Neoplasm Invasiveness; Reactive Oxygen Species; Urinary Bladder Neoplasms

Overall clinical outcome for advanced lung cancer remains very disappointing despite recent advances in treatment. Curcumin has been reported as potentially active against cancer.. Owing to poor curcumin solubility, we have used cyclodextrins (CD) as an excipient allowing a considerable increase of aqueous solubility and bioavailability of curcumin. The effects of solubilised curcumin have been evaluated in cell cultures as well as in an in vivo orthotopic lung tumour mouse model.. Cell proliferation was reduced while apoptosis rates were increased when lung epithelial tumour cells were cultured in the presence of curcumin-CD complexes. For in vivo experiments, cells were grafted into lungs of C57Bl/6 mice treated by an oral administration of a non-soluble form of curcumin, CDs alone or curcumin-CD complexes, combined or not with gemcitabine. The size of orthotopically implanted lung tumours was reduced upon curcumin complex administration as compared with treatments with placebo or non-solubilised curcumin. Moreover, curcumin potentiated the gemcitabine-mediated antitumour effects.. Our data demonstrate that curcumin, when given orally in a CD-solubilised form, reduces lung tumour size in vivo. In vitro experiments show impaired tumour cell proliferation and increased cell apoptosis. Moreover, our data underline a potential additive effect of curcumin with gemcitabine thus providing an efficient therapeutic option for antilung cancer therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Curcumin; Cyclodextrins; Deoxycytidine; Drug Synergism; G2 Phase; Gemcitabine; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Tumor Cells, Cultured

Curcumin (diferuloylmethane) is a natural polyphenol product of the plant Curcuma longa and has a diversity of antitumor activities. T63, a new 4-arylidene curcumin analogue, was reported to inhibit proliferation of lung cancer cells. However, its precise molecular antitumor mechanisms have not been well elucidated. Here, we showed that T63 could significantly inhibit the proliferation of A549 and H460 human lung cell lines via induction of G0/G1 cell cycle arrest and apoptosis. We found that the reactive oxygen species (ROS)-activated FOXO3a cascade plays a central role in T63-induced cell proliferation inhibition. Mechanistically, enhancement of ROS production by T63 induced FOXO3a expression and nuclear translocation through activation of p38MAPK and inhibition of AKT, subsequently elevating the expression of FOXO3a target genes, including p21, p27, and Bim, and then increased the levels of activated caspase-3 and decreased the levels of cyclin D1. Moreover, the antioxidant N-acetylcysteine markedly blocked the above effects, and small interfering RNA-mediated knockdown of FOXO3a also significantly decreased T63-induced cell cycle arrest and apoptosis. In vivo experiments showed that T63 significantly suppressed the growth of A549 lung cancer xenograft tumors, associated with proliferation suppression and apoptosis induction in tumor tissues, without inducing any notable major organ-related toxicity. These data indicated that the novel curcumin analogue T63 is a potent antitumor agent that induces cell cycle arrest and apoptosis and has significant therapeutic potential for lung cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Catalase; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Forkhead Box Protein O3; Forkhead Transcription Factors; Glutathione; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase; Transcriptional Activation; Tumor Burden; Xenograft Model Antitumor Assays

Endoplasmic reticulum (ER) stress-induced cancer cell apoptosis has become a novel signaling target for development of cancer therapeutic drugs. Curcumin exhibits growth-suppressive activity against a variety of cancer cells. We previously synthesized a series of monocarbonyl analogues of curcumin with strong cytotoxicity against tumor cells. In this study, we found that only compound 19 [(1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one] can induce C/EBP-homologous protein (CHOP) expression in human lung cancer H460 cells. Treatment with 19 induced H460 cell apoptosis in a dose-responsive manner, and this effect was associated with corresponding increases in a series of key components in ER stress-mediated apoptosis pathway, followed by caspase cleavage and activation. However, curcumin at the same concentrations does not display such properties. CHOP knockdown by specific siRNA attenuated 19-induced cell apoptosis, further indicating that the apoptotic pathway is ER stress-dependent. In vivo, 19 showed a dramatic 53.5% reduction in H460 xenograft tumor size after 22 days of treatment. Taken together, these mechanistic insights on the novel compound 19, with nontoxicity, may provide us with a novel anticancer candidate.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Proliferation; Curcumin; Endoplasmic Reticulum; Female; Humans; Lentivirus; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Molecular Targeted Therapy; Oxidative Stress; RNA, Small Interfering; Signal Transduction; Transcription Factor CHOP; Xenograft Model Antitumor Assays

The p53 tumor suppressor gene plays an essential role in tumorigenesis, and the chromosomal region maintenance 1 (CRM1) has been suggested to export p53 protein from the nucleus to the cytoplasm. The objectives of the present study were to evaluate p53 expression and subcellular localization as well as CRM1 expression using immunohistochemistry in our established bitransgenic mouse lung tumor model. In this model, expression of the mutant human Ki-rasG12C allele was regulated in a doxycycline (DOX)-inducible, lung-specific manner. Following treatment with curcumin, we found that although overall p53 expression levels were not significantly changed among the three groups, lung lesions in mice treated with DOX alone had the highest proportion of N>C (nucleus predominant) p53 staining (46±7%), followed by lung lesions in mice co-treated with DOX and curcumin (31±12%) and controls (17±4%). CRM1 expression was dramatically inhibited in lung lesions in mice treated with DOX (0±0) as compared to controls (90±17, P=0.001), and could be partially reversed after curcumin treatment (47±21, P=0.028, DOX vs. DOX+curcumin). Collectively, the results from this study demonstrated that p53 accumulated in the nucleus in lung lesions in mice expressing the mutant Ki-rasG12C transgene as a result of down-regulation of CRM1. Furthermore, these alterations could be partially reversed by curcumin treatment. p53 subcellular localization resulting from CRM1 alterations may play an important role in lung tumorigenesis.

Topics: Alleles; Animals; Cell Nucleus; Curcumin; Doxycycline; Exportin 1 Protein; Gene Expression Regulation, Neoplastic; Genes, p53; Karyopherins; Lung Neoplasms; Mice; Mice, Transgenic; Models, Genetic; Mutation; Receptors, Cytoplasmic and Nuclear; Transgenes; Tumor Suppressor Protein p53

We investigated the inhibition of pulmonary tumor formation through treatment with curcumin in transgenic mice.. In this study, a strain of transgenic mice carrying human vascular endothelial growth factor A₁₆₅ (hVEGF-A₁₆₅) gene to induce pulmonary tumor was used as an in vivo cancer therapy model. We found that curcumin significantly reduced hVEGF-A₁₆₅ overexpression to normal, specifically in Clara cells of the lungs of transgenic mice, and suppressed the formation of tumors. In addition, we demonstrated a relationship between curcumin treatment and the expression of VEGF, EGFR, ERK2, and Cyclin A at the transcriptional and translational levels. We also noticed a reduction of Cyclin A and Cyclin B after curcumin treatment that had an effect on the cell cycle. Curcumin-induced inhibition of Cyclin A and Cyclin B likely results in decreased progression through S and G2/M phases. These results demonstrated that the expression of proteins involved in the S to M phase transition in transgenic mice is suppressed by curcumin.. A Data suggest that a blockade of the cell cycle may be a critical mechanism for the observed effects on vasculogenesis and angiogenesis following treatment with curcumin.

Topics: Animals; Blotting, Western; Cell Cycle; Curcumin; Cyclin A; Cyclin B; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Genes, erbB-1; Genetic Markers; Humans; Lung Neoplasms; Mice; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Vascular Endothelial Growth Factor A

This study explored the efficacy of curcumin and resveratrol in maintaining adequate zinc levels to regulate p21 and cyclooxygenase-2 (cox-2) during benzo[a]pyrene (BP)-induced lung carcinogenesis. The mice were segregated into five groups, which included normal control, BP treated, BP plus curcumin treated, BP plus resveratrol treated, and BP plus curcumin plus resveratrol-treated groups. BP treatment resulted in a significant decrease in the zinc levels and protein expression of p21. On the contrary, the enzyme activity of cox-2 showed a significant increase in the BP-treated mice. Interestingly, combined supplementation of curcumin and resveratrol to BP-treated mice resulted in an appreciable improvement in the zinc levels and protein expression of p21. In contrast, synergistic supplementation with phytochemicals resulted in a significant decrease in the enzyme activities of cox-2 in BP-treated mice. This study, therefore, concludes that combined treatment with curcumin and resveratrol maintains adequate zinc levels and regulates inflammation by cox-2 and cell cycle arrest by p21 during lung carcinogenesis in mice.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzo(a)pyrene; Blotting, Western; Body Weight; Carcinogens; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Cyclooxygenase 2; Disease Progression; Drug Synergism; Immunoenzyme Techniques; Lung Neoplasms; Male; Mice; Organ Size; Resveratrol; Stilbenes; Zinc

Curcumin (diferuloylmethane), a major active component of turmeric (Curcuma longa), has been reported to suppress the proliferation of a wide variety of tumor cells. Rad51 is a key protein in the homologous recombination (HR) pathway of DNA double-strand break repair, and HR represents a novel target for cancer therapy. A high expression of Rad51 has been reported in chemo- or radio-resistant carcinomas. Therefore, in the current study, we will examine whether curcumin could enhance the effects of mitomycin C (MMC), a DNA interstrand cross-linking agent, to induce cytotoxicity by decreasing Rad51 expression. Exposure of two human non-small lung cancer (NSCLC) cell lines (A549 and H1975) to curcumin could suppress MMC-induced MKK1/2-ERK1/2 signal activation and Rad51 protein expression. Enhancement of ERK1/2 activation by constitutively active MKK1/2 (MKK1/2-CA) increased Rad51 protein levels in curcumin and MMC co-treated human lung cells. Moreover, the synergistic cytotoxic effect induced by curcumin combined with MMC was decreased by MKK1-CA-mediated enhancement of ERK1/2 activation by a significant degree. In contrast, MKK1/2 inhibitor, U0126 was shown to augment the cytotoxicity of curcumin and MMC through downregulation of ERK1/2 activation and Rad51 expression. Depletion of endogenous Rad51 expression by siRad51 RNA transfection significantly enhanced MMC and/or curcumin induced cell death and cell growth inhibition. In contrast, an overexpression of Rad51 protected lung cancer cells from synergistic cytotoxic effects induced by curcumin and MMC. We concluded that Rad51 inhibition may be an additional action mechanism for enhancing the chemosensitization of MMC by curcumin in NSCLC.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Cytotoxins; Down-Regulation; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases; Mitomycin; Rad51 Recombinase; RNA, Small Interfering

The purpose of the study is to design and evaluate curcumin loaded gelatin microspheres (C-GMS) for effective drug delivery to the lung. C-GMS was prepared by the emulsification-linkage technique and the formulation was optimized by orthogonal design. The mean encapsulation efficiency and drug loading of the optimal C-GMS were 75.5 ± 3.82 % and 6.15 ± 0.44%, respectively. The C-GMS presented a spherical shape and smooth surface with a mean particle diameter of 18.9 μm. The in vitro drug release behavior of C-GMS followed the first-order kinetics. The tissue distribution showed that the drug concentrations at lung tissue for the C-GMS suspension were significantly higher than those for the curcumin solution, and the Ce for lung was 36.19. Histopathological studies proved C-GMS was efficient and safe to be used as a passive targeted drug delivery system to the lung. Hence, C-GMS has a great potential for the targeted delivery of curcumin to the lung.

Topics: Animal Structures; Animals; Biological Availability; Calorimetry, Differential Scanning; Curcumin; Drug Delivery Systems; Emulsions; Formaldehyde; Gelatin; Glutaral; Hexoses; Injections, Intravenous; Lung; Lung Neoplasms; Microscopy, Electron, Scanning; Microspheres; Mineral Oil; Particle Size; Powders; Rabbits; Rheology; Surface Properties; Surface-Active Agents; Tissue Distribution; Transition Temperature

Non-small cell lung cancer (NSCLC) patients with L858R or exon 19 deletion mutations in epidermal growth factor receptor (EGFR) have good responses to the tyrosine kinase inhibitor (TKI), gefitinib. However, patients with wild-type EGFR and acquired mutation in EGFR T790M are resistant to gefitinib treatment. Here, we showed that curcumin can improve the efficiency of gefitinib in the resistant NSCLC cells both in vitro and in vivo models.. After screening 598 herbal and natural compounds, we found curcumin could inhibit cell proliferation in different gefitinib-resistant NSCLC cell lines; concentration-dependently down-regulate EGFR phosphorylation through promoting EGFR degradation in NSCLC cell lines with wild-type EGFR or T790M EGFR. In addition, the anti-tumor activity of gefitinib was potentiated via curcumin through blocking EGFR activation and inducing apoptosis in gefitinib-resistant NSCLC cell lines; also the combined treatment with curcumin and gefitinib exhibited significant inhibition in the CL1-5, A549 and H1975 xenografts tumor growth in SCID mice through reducing EGFR, c-MET, cyclin D1 expression, and inducing apoptosis activation through caspases-8, 9 and PARP. Interestingly, we observed that the combined treatment group represented better survival rate and less intestinal mucosal damage compare to gefitinib-alone therapy. We showed that curcumin attenuated the gefitinib-induced cell proliferation inhibition and apoptosis through altering p38 mitogen-activated protein kinase (MAPK) activation in intestinal epithelia cell.. Curcumin potentiates antitumor activity of gefitinib in cell lines and xenograft mice model of NSCLC through inhibition of proliferation, EGFR phosphorylation, and induction EGFR ubiquitination and apoptosis. In addition, curcumin attenuates gefitinib-induced gastrointestinal adverse effects via altering p38 activation. These findings provide a novel treatment strategy that curcumin as an adjuvant to increase the spectrum of the usage of gefitinib and overcome the gefitinib inefficiency in NSCLC patients.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; ErbB Receptors; Gefitinib; Humans; Intestinal Mucosa; Intestines; Lung Neoplasms; Mice; Mice, SCID; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Quinazolines; Ubiquitination; Xenograft Model Antitumor Assays

Hypermethylation of the Wnt inhibitory factor-1 (WIF-1) promoter has been implicated in the overactivation of the Wnt pathway in human lung cancer. Curcuminoids exert anti-cancer effects and have been reported to act as hypomethylating agents. Previously, we have investigated and compared the demethylation effects of three curcuminoids and observed that bisdemethoxycurcumin exhibited the strongest demethylation potency. In this study, we used lung cancer cell lines with WIF-1 promoter hypermethylated as a model to study the demethylating effect of bisdemethoxycurcumin on WIF-1 restoration, Wnt signaling activity and cell death. Bisdemethoxycurcumin directly suppressed the activity of DNA methyltransferase-1 (DNMT1) but did not influence DNMT1 expression. In addition, it induced WIF-1 promoter demethylation and protein re-expression. WIF-1 restoration in lung cancer cells down-regulated nuclear β-catenin and the canonical Wnt cascade. Furthermore, we also showed that down-regulation of Wnt signaling by WIF-1 was required for bisdemethoxycurcumin-induced apoptosis in certain lung cancer cell types. This report is the first to show that bisdemethoxycurcumin induces apoptosis by reactivating WIF-1 from a silenced state. Our results provide new insights into the anti-cancer actions of bisdemethoxycurcumin.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Base Sequence; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Diarylheptanoids; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; Mice, SCID; Molecular Sequence Data; Promoter Regions, Genetic; Repressor Proteins; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Curcuma zedoaria (Berg.) Rosc., a traditional Chinese herb, was used widely but absolutely prohibited for the pregnant in clinic. Based on that there is abundant angiogenesis in endometrium and placenta during gestation period, we hypothesized that some components from it could inhibit angiogenesis and then damaged the supply of oxygen and nutrition to the embryo, which finally led to gestation failure.. This study was set to demonstrate whether essential oil, major components of Curcuma zedoaria had anti-angiogenic effect.. Essential oil of Curcuma zedoaria (EO-CZ) was abstracted by steam distillation extraction. Cell proliferation assay and two angiogenic models, rat aortic ring assay and chick embryo chorioallantoic membrane assay were presented. Furthermore, melanoma growth and experimental lung metastasis assay in mice were performed to evaluate its anti-angiogenesis effect in vivo. Immunohistochemical analysis and enzyme-linked immunosorbent assay (ELISA) were used to respectively detect the expression of CD34 and matrix metalloproteinases (MMPs).. EO-CZ exhibited anti-proliferative effect on B16BL6 and SMMC-7721 cells, the IC(50), respectively was 41.8 μg/ml and 30.7 μg/ml, and on HUVEC (Human Umbilical Vein Endothelial Cells) cells with IC(50) of far more than 120 μg/ml. Both 20 μg/ml and 40 μg/ml EO-CZ indicated significant suppression on sprouting vessels of aortic ring and formation of microvessels in chick embryo chorioallantoic membrane in vitro. Moreover, solid melanoma grown in left oxter of mice was obviously inhibited after oral intake of 100 and 200 mg/kg of EO-CZ a day for 28 days, and CD34 expression indicating angiogenesis in melanoma reduced significantly compared with control; melanoma metastatic nodules in lung were detected to be inhibited, as well as MMP-2 and MMP-9 expression in serum.. Essential oil, a fat-soluble fraction of Curcuma zedoaria, presented anti-angiogenic activity in vitro and in vivo, resulting in suppressing melanoma growth and lung metastasis. And this was associated with down-regulating MMPs.

Topics: Angiogenesis Inhibitors; Animals; Aorta, Thoracic; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane; Curcuma; Endothelial Cells; Humans; In Vitro Techniques; Liver Neoplasms; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Neovascularization, Pathologic; Neovascularization, Physiologic; Oils, Volatile; Phytotherapy; Plant Extracts; Rats; Rhizome

The emergence of multidrug resistance (MDR) is a big challenge to cancer chemotherapy. Plant-derived agents have great potential to prevent onset or delay progression of the carcinogenic process, and enhance the efficacy of mainstream antitumor agents. In this study, fractionated extracts of Curcuma wenyujin and Chrysanthemum indicum were tested for their potential to modulate the MDR phenotype and function of P-gp in MCF-7/ADR and A549/Taxol cells in vitro. Fractions C. wenyujin C10, E10 from Curcuma wenyujin, and C. indicum E10 from Chrysanthemum indicum, exhibited significant effects in sensitization of these resistant cancer cells at non-toxic concentration to doxorubicin and docetaxel by MTT method. They also increased the intracellular doxorubicin accumulation and retention in MCF-7/ADR cells. In mechanism study, an increase of Rh123 accumulation and a decrease of Rh123 efflux were observed in MCF-7/ADR cells treated with these fractions, indicating a blockage of the activity of P-gp. Furthermore, C. wenyujin C10 had the ability to down-regulate the expression of P-gp. All these fractions could enhance the apoptosis induced by doxorubicin in MCF-7/ADR cells, and restore the effect of docetaxel on the induction of G2/M arrest in A549/Taxol cells. C. wenyujin C10 and E10 also owned the ability to induce S phase arrest. These results showed the therapeutic value of the three fractions as potential MDR-reversing agents and warranted further investigations.

Topics: Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Division; Cell Survival; Chrysanthemum; Curcuma; Doxorubicin; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; G2 Phase; Humans; Lung Neoplasms; Medicine, Chinese Traditional; Paclitaxel; Phytotherapy; Plant Extracts

δ-Elemene, an antitumor component, is a chemical compound isolated from Curcuma wenyujin, a Chinese traditional herb. We examined whether δ-elemene could affect apoptosis in human lung carcinoma mucoepidermoid NCI-H292 cells, and test whether and how the over-expression of B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma extra large (Bcl-xL) could off-set the effect of δ-elemene on cell growth. The result demonstrated that δ-elemene significantly induced apoptosis of NCI-H292, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, DNA fragmentation measurement, Annexin V (AnV) binding of externalized phosphatidylserine and the mitochondrial probe JC-1 using flow cytometry. Treatment of NCI-H292 with δ-elemene increased both p38 mitogen-activated protein kinase (MAPK) and inducible nitric oxide synthese (iNOS) levels, suggesting these two molecules maybe relate to the apoptotic effect of δ-elemene. The cells with Bcl-2 or Bcl-xL over-expression showed an elevation of nuclear factor kappa B (NF-kappa B) activity, accompanying a significant reduction of δ-elemene-induced apoptosis. Furthermore, inhibition of NF-kappa B by IkBαSR, which is a powerful inhibitor of NF-kappa B, restored the ability of δ-elemene to induce apoptosis in the cells transfected with Bcl-2. These data strongly indicated that the apoptotic effect of δ-elemene on NCI-H292 was closely associated with the activity of NF-kappa B, which was up-regulated by Bcl-2 and Bcl-xL. In conclusion, δ-elemene induced apoptosis in NCI-H292 cells. The apoptotic effect of δ-elemene could be significantly offset by over-expression of either Bcl-2 or Bcl-xL. Bcl-2 and Bcl-xL were able to increase the activity of NF-kappa B, which was a known anti-apoptotic molecule in human lung cancer cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-X Protein; Carcinoma, Mucoepidermoid; Cell Line, Tumor; Curcuma; DNA Fragmentation; Drugs, Chinese Herbal; Flow Cytometry; Humans; Lung Neoplasms; NF-kappa B; Nitric Oxide Synthase Type II; p38 Mitogen-Activated Protein Kinases; Phytotherapy; Proto-Oncogene Proteins c-bcl-2; Sesquiterpenes; Signal Transduction

Pokemon, which stands for POK erythroid myeloid ontogenic factor, can regulate expression of many genes and plays an important role in tumorigenesis. Curcumin, a natural and non-toxic yellow compound, has capacity for antioxidant, free radical scavenger, anti-inflammatory properties. Recent studies shows it is a potential inhibitor of cell proliferation in a variety of tumour cells. To investigate whether curcumin can regulate the expression of Pokemon, a series of experiments were carried out. Transient transfection experiments demonstrated that curcumin could decrease the activity of the Pokemon promoter. Western blot analysis suggested that curcumin could significantly decrease the expression of the Pokemon. Overexpression of Sp1 could enhance the activity of the Pokemon promoter, whereas knockdown of Sp1 could decrease its activity. More important, we also found that curcumin could decrease the expression of the Pokemon by suppressing the stimulation of the Sp1 protein. Therefore, curcumin is a potential reagent for tumour therapy which may target Pokemon.

Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Chromatin Immunoprecipitation; Curcumin; DNA Primers; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Humans; Luciferases; Lung Neoplasms; Promoter Regions, Genetic; Protein Binding; Sp1 Transcription Factor; Transcription Factors

Curcumin, a polyphenolic compound, is the active component of Curcuma longa and has been extensively investigated as an anticancer drug that modulates multiple pathways. Eukaryotic initiation factors (eIFs) have been known to play important roles in translation initiation, which controls cell growth and proliferation. Little is known about the effects of curcumin on eIFs in lung cancer. The objective of this study was to exam the curcumin cytotoxic effect and modulation of two major rate-limiting translation initiation factors, including eIF2α and eIF4E protein expression levels in lung adenocarcinoma epithelial cell line A549. Cytotoxicity was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and protein changes were determined by Western blot. A549 cells were treated with 0-240 μM curcumin for 4-96 h. The inhibitory effects of curcumin on cytotoxicity were dose- and time-dependent (P < 0.001). The 50% inhibitory curcumin concentrations (IC50s) at 24, 48, 72, and 96 h were 93, 65, 40, and 24 μM, respectively. Protein expressions of eIF2α, eIF4E, Phospho-4E-BP1 were down-regulated, while Phospho-eIF2α and Phospho-eIF4E were up-regulated after A549 cells were treated with 20 and 40 μM curcumin for 24 h. In addition, the effects of curcumin on these protein expression changes followed a significant dose-response (P < 0.05, trend test). These findings suggest that curcumin could reduce cell viability through prohibiting the initiation of protein synthesis by modulating eIF2α and eIF4E.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Cell Cycle Proteins; Cell Death; Cell Line, Tumor; Curcumin; Epithelial Cells; Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-4E; Eukaryotic Initiation Factors; Humans; Lung Neoplasms; Phosphoproteins; Phosphorylation

The aim of the present study is to explore the chemopreventive potential of curcumin and resveratrol during promotional phase of benzo(a)pyrene (BP) induced lung carcinogenesis in mice. The mice were segregated into five groups which included normal control, BP-treated, BP+curcumin-treated, BP+resveratrol-treated and BP+curcumin+resveratrol-treated groups. The BP treatment resulted in a significant increase in the levels of lipid peroxidation (LPO). On the other hand, reduced glutathione (GSH) levels and the activities of superoxide dismutase (SOD) were found to be significantly decreased following BP treatment. Administration of curcumin to BP-treated mice decreased the levels of LPO significantly. Further, treatment of resveratrol to BP-treated mice significantly elevated the activities of SOD. Combined treatment of curcumin and resveratrol, kowever, showed significant improvement in LPO and GSH levels as well as in the activities of SOD. Histo-architectural studies showed well-differentiated signs of lung carcinogenesis following BP administration to mice. Although treatments with resveratrol and curcumin given separately to BP-treated mice showed appreciable improvement in the histo-architecture of the lung, combined treatment resulted in a noticeable improvement in the lung histo-architecture.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Benzopyrenes; Curcumin; Drug Therapy, Combination; Glutathione; Lipid Peroxidation; Lung Neoplasms; Male; Mice; Mice, Inbred Strains; Phytotherapy; Plant Extracts; Resveratrol; Stilbenes; Superoxide Dismutase

Several studies have shown that curcumin can induce apoptosis and inhibit growth in human A549 lung adenocarcinoma cells. However, the mechanism is not completely understood yet. The present study was designed to investigate the effects of curcumin on A549 cells to better understand its apoptosis and apoptosis-related factors in vitro. The apoptosis induction, intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were examined by confocal fluorescence microscope and flow cytometry. The MAPK protein expression was examined by Western blot analysis. After treatment with curcumin, apoptosis were observed. Curcumin-induced apoptosis was accompanied by an increase of intracellular ROS level and a loss of MMP. In addition, induction of apoptosis was also accompanied by sustained phosphorylation and activation of JNK, p38 and ERK. However, pretreatment with MAPK inhibitors had no effect upon curcumin-induced apoptosis. GSH and NAC, an anti-oxidant agent, blocked the curcumin-induced ROS production, MMP loss and rescued cells from curcumin-induced apoptosis. Our results indicated that curcumin induced apoptosis in A549 cells through a reactive oxygen species-dependent mitochondrial signaling pathway and independent of MAPK signaling pathway.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Curcumin; Drug Evaluation, Preclinical; Humans; Lung Neoplasms; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species; Signal Transduction

Anoikis, an apoptosis triggered by loss of cell anchorage, has been shown to be a principal mechanism of inhibition of tumor metastasis. Recently, anti-apoptotic Bcl-2 and Cav-1 proteins have been demonstrated to be highly associated with tumor metastasis and apoptosis resistance. Curcumin, a major active component of turmeric, Curcuma longa, has been shown to inhibit neoplastic evolution and tumor progression; however, the underlying mechanisms are unclear. In this study, we investigated the effect of curcumin on cell anoikis as a possible mechanism of anti-tumorigenic action of curcumin, and evaluated the potential role of Bcl-2 and Cav-1 in this process. Our results showed that ectopic expression of either Bcl-2 or Cav-1 induced anoikis resistance of lung carcinoma H460 cells. Curcumin downregulated Bcl-2 protein during anoikis and sensitized the cells to detachment-induced apoptosis, whereas it had no significant effect on Cav-1 protein expression. Bcl-2 down-regulation as well as anoikis enhancement by curcumin were inhibited by superoxide anion scavenger, Mn(III)tetrakis(4-benzoic acid) porphyrin chloride, but were unaffected by other ROS scavengers including catalase and deferoxamine, suggesting that superoxide anion is a key player in the downregulation of Bcl-2 by curcumin. Furthermore, we provided evidence that curcumin decreased Bcl-2 level through ubiquitin-proteasomal degradation which sensitized cells to detachment-induced apoptosis. These findings indicate a novel pathway for curcumin regulation of Bcl-2 and provide a key mechanism of anoikis regulation that may be exploited for metastatic cancer treatment.

Topics: Animals; Anoikis; Carcinoma, Non-Small-Cell Lung; Caveolin 1; Cell Line, Tumor; Curcumin; Down-Regulation; Humans; Lung Neoplasms; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Superoxides; Ubiquitin

Curcumin is a natural compound that has been extensively observed due to its potential as an anticancer drug. Curcumin restrains cancer cell progression via telomerase activity suppression. However, the exact mechanism is still unknown. In this study, we demonstrate that the effects of curcumin on cell viability and telomerase activity can be blunted by reactive oxygen species (ROS) inhibitor N-acetyl cysteine (NAC). The ROS induced by curcumin in A549 cells was detected by flow cytometry. Using Western blot and RT-PCR, human telomerase reverse transcriptase (hTERT) decreased in the presence of curcumin. Sp1 is one of the important transcription factors in hTERT expression. Our data showed that curcumin decreases the expression of Sp1 through proteasome pathway. In addition, NAC blunted the Sp1 reduction and hTERT downregulation by curcumin. Further, reporter assay and DNA affinity precipitation assay confirmed the influence of curcumin on Sp1 in hTERT regulation. This is the first study to demonstrate that curcumin induces ROS production resulting in Sp1 binding activity inhibition and hTERT downregulation.

Topics: Acetylcysteine; Adenocarcinoma; Cell Line, Tumor; Cell Shape; Cell Survival; Curcumin; Down-Regulation; Humans; Lung Neoplasms; Reactive Oxygen Species; Sp1 Transcription Factor; Telomerase

Several studies have shown that curcumin can induce apoptosis and inhibit growth in human tumor cell lines. However, the mechanism is not completely understood yet. The present studies were designed to investigate the effects of curcumin on human A549 lung adenocarcinoma cells lines to better understand its effect on apoptosis and apoptosis-related genes in vitro. Apoptosis induction, mitochondria membrane potential, mitochondria structure, and apoptotic associated gene expression were examined by flow cytometric assay, confocal microscopy, Western blotting and electron microscopy. After treatment with curcumin, percentage of apoptotic cells increased dose- and time-dependently, and morphology observation revealed typical apoptotic features. Our data further indicated that the expression of Bax proteins in A549 cells was increased in a dose-dependent manner, whereas the expression of Bcl-2 was significantly decreased, thus the ratio of Bax/Bcl-2 was increased. The apoptotic process was accompanied by the change of mitochondrial function and structure which led to release of the cytochrome c, and activation of caspase-9 and caspase-3. Furthermore, curcumin also induced a dose-dependent cleavage of PARP. Caspases activation during the course of curcumin-induced apoptosis was additionally confirmed by using a broad-spectrum caspases inhibitor, Z-VAD-fmk. As expected, the inhibitor was able to decrease curcumin-induced apoptosis on A549 cells. These results suggested that mitochondria played an important role in the curcumin-induced apoptosis, and mitochondria membrane potential loss initiated apoptosis via the activation of caspases.

Topics: Adenocarcinoma; Amino Acid Chloromethyl Ketones; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Shape; Curcumin; Cysteine Proteinase Inhibitors; Cytochromes c; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Microscopy, Confocal; Microscopy, Electron, Transmission; Mitochondria; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Time Factors

Curcumin, a phenolic compound isolated from the plant Curcuma longa (Linn), is ingested every day in the Indian subcontinent and is well reported to possess cancer-preventive activity. To achieve effective cancer prevention with curcumin, we need to find a new method to enhance the effects of curcumin in the diet. Based on our evidence that (-)-epicatechin (EC), an inert catechin, enhances the cancer-preventive activity of green tea catechins, we studied the enhancing effects of EC on inductions of growth inhibition and apoptosis in human lung cancer cell lines PC-9 and A549 with curcumin. The combination of curcumin with EC significantly increased the inhibition of cell growth compared with curcumin or EC alone. The combination similarly increased both apoptosis and expression of GADD153 and GADD45 genes, associated with their enhanced protein production. Knockdown of GADD153 or GADD45 by small interfering RNA abrogated the apoptosis induction and growth inhibition induced by the combination, indicating the crucial role of their upregulation. Treatments of PC-9 cells with c-Jun-NH(2)-kinase inhibitor SP600125, with p38 mitogen-activated protein kinase inhibitor SB202190 and with PD98059 (extracellular signal-regulated kinase 1/2 inhibitor) all increased the upregulation of GADD153 and GADD45 genes by the combination. Because EC was previously shown to enhance the incorporation of EGCG into PC-9 cells, we think that EC has similar effects on curcumin. This report is the first report on the enhancing effects of EC on curcumin, and the data suggest that EC plays a significant role in the enhancement of the cancer-preventive activity of curcumin in the diet.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Non-Small-Cell Lung; Catechin; Cell Cycle Proteins; Cell Growth Processes; Cell Line, Tumor; Curcumin; Down-Regulation; Drug Evaluation, Preclinical; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Nuclear Proteins; Protein Kinase Inhibitors; RNA, Small Interfering; Transcription Factor CHOP

Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186 * in A549/DDP. In addition, transfection of cells with a miR-186 * inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186 * significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186 * may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; MicroRNAs; Signal Transduction

It has been reported that curcumin inhibited various types of cancer cells in vitro and in vivo. However, mechanisms of curcumin-inhibited cell growth and -induced apoptosis in human non-small cell lung cancer cells (NCI-H460) still remain unclear. In this study, NCI-H460 cells were treated with curcumin to determine its anticancer activity. Different concentrations of curcumin were used for different durations in NCI-H460 cells and the subsequent changes in the cell morphology, viability, cell cycle, mRNA and protein expressions were determined. Curcumin induced apoptotic morphologic changes in NCI-H460 cells in a dose-dependent manner. After curcumin treatment, BAX and BAD were up-regulated, BCL-2, BCL-X(L) and XIAP were down-regulated. In addition, reactive oxygen species (ROS), intracellular Ca(2+) and endoplasmic reticulum (ER) stress were increased in NCI-H460 cells after exposure to curcumin. These signals led to a loss of mitochondrial membrane potential (Delta Psi(m)) and culminated in caspase-3 activation. Curcumin-induced apoptosis was also stimulated through the FAS/caspase-8 (extrinsic) pathway and ER stress proteins, growth arrest- and DNA damage-inducible gene 153 (GADD153) and glucose-regulated protein 78 (GRP78) were activated in the NCI-H460 cells. Apoptotic cell death induced by curcumin was significantly reversed by pretreatment with ROS scavenger or caspase-8 inhibitor. Furthermore, the NCI-H460 cells tended to be arrested at the G(2)/M cell cycle stage after curcumin treatment and down-regulation of cyclin-dependent kinase 1 (CDK1) may be involved. In summary, curcumin exerts its anticancer effects on lung cancer NCI-H460 cells through apoptosis or cell cycle arrest.

Topics: Antineoplastic Agents; Apoptosis; Calcium; Carcinoma, Non-Small-Cell Lung; Caspase Inhibitors; Caspases; Cell Cycle; Cell Line, Tumor; Curcumin; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Fluorescent Antibody Technique; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Reactive Oxygen Species

Curcumin, a natural compound, is derived from the rthizom of Curcuma longa. In vitro and in vivo preclinical studies have shown its anti-inflammatory, antioxidant, anticancer activities and so on. miR-186*, which was found by microarray technology, was highly expressed in lung carcinoma cells A549/DDP. The aim of this study is to illustrate whether Curcumin could promote the apoptosis of A549/DDP cells through regulating the expression of miR-186*.. An oligonucleotide microarray chip was used to profile microRNA (miRNA) expressions in A549/DDP cells treated with and without Curcumin. The significantly differentially expressed miRNA, which was selected from microarray chip, validated by quantitative real-time PCR. Ultimately, the remarkably expressed miRNA modulated the apoptosis assaying by flow cytometry expriments and the survival rate was measured by MTT method.. The microarray chip results demonstrated: Curcumin altered the expression level of miRNAs compared with untreated control in A549/DDP cell line, miR-186* was significantly down-regulated after Curcumin treatment, which confirmed by quantitative real-time PCR. Down-regulation of miR-186* expression by curcumin elevated the apoptosis, and the survival rate of A549/DDP cells decreased; but up-regulation of miR-186* expression by transfection its mimics restrained the apoptosis, the survival rate of A549/DDP cells increased, which were assayed by flow cytometry expriments and MTT method.. Modulation of miRNAs expression may be an important mechanism underlying the biological roles of Curcumin.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; MicroRNAs

The expression of "growth arrest and DNA damage inducible genes 45 and 153" is related to apoptotic induction of cells. GADD45 is an effector gene of the tumor suppressor p53, and GADD153 is associated with cellular function of cancer prevention. Curcumin, isolated from the plant Curcuma longa (LINN), has been investigated as a promising cancer preventive in food because curcumin, a phenolic and coloring compound, is widely ingested in the Indian subcontinent. However, the exact mechanisms of action of curcumin have not yet been clearly elucidated. Based on our successful results with green tea catechins as cancer preventive, we studied the relationship between the expression of GADD45 and 153 and apoptotic induction in human lung cancer cell line PC-9. In our study curcumin increased the expression of GADD45 and 153 in a p53-independent manner. Curcumin also inhibited the growth of PC-9 cells and induced G(1)/S arrest of the cell-cycle followed by strong induction of apoptosis. Treatment with GADD45 and 153 small interfering RNAs (siRNAs) inhibited the apoptotic induction in PC-9 cells by curcumin. Moreover, curcumin induced the expression of cyclin dependent kinase inhibitor genes p21 and p27, while it inhibited the expression of numerous genes, including Bcl-2, cyclin D1, CDK2, CDK4 and CDK6. All the results with PC-9 cells suggest that the up-regulation of GADD45 and 153 by curcumin is a prime mechanism in the anticancer activity of curcumin.

Topics: Anticarcinogenic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Curcumin; DNA Damage; Flow Cytometry; Gene Expression Regulation; Humans; Lung Neoplasms; Nuclear Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Transcription Factor CHOP; Transfection; Up-Regulation

Lung cancer is the most lethal cancer and almost 90% of lung cancer is due to cigarette smoking. Even though nicotine, one of the major ingredients of cigarette smoke and the causative agent for addiction, is not a carcinogen by itself, several investigators have shown that nicotine can induce cell proliferation and angiogenesis. We observed that the proliferative index of nicotine is different in the lung cancer cell lines H1299 (p53-/-) and A549 (p53+/+) which indicates that the mode of up-regulation of survival signals by nicotine might be different in cells with and without p53.. While low concentrations of nicotine induced activation of NF-κB, Akt, Bcl2, MAPKs, AP1 and IAPs in H1299, it failed to induce NF-κB in A549, and compared to H1299, almost 100 times higher concentration of nicotine was required to induce all other survival signals in A549. Transfection of WT-p53 and DN-p53 in H1299 and A549 respectively, reversed the mode of activation of survival signals. Curcumin down-regulated all the survival signals induced by nicotine in both the cells, irrespective of their p53 status. The hypothesis was confirmed when lower concentrations of nicotine induced NF-κB in two more lung cancer cells, Hop-92 and NCI-H522 with mutant p53 status. Silencing of p53 in A549 using siRNA made the cells susceptible to nicotine-induced NF-κB nuclear translocation as in A549 DN-p53 cells.. The present study reveals a detrimental role of nicotine especially in lung cancer patients with impaired p53 status and identifies curcumin as a potential chemopreventive.

Topics: Cell Line, Tumor; Cell Proliferation; Curcumin; Cyclin D1; Cyclooxygenase 2; Down-Regulation; Humans; Lung Neoplasms; Nicotine; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Transcription Factor AP-1; Tumor Suppressor Protein p53

Lung cancer is one of the leading causes of cancer-related death worldwide. Curcumin has been reported to have an antitumor effect by inducing apoptosis and suppressing growth of tumor cells. However, the mechanism by which curcumin exerts its anti-cancer effect needs further research. The purpose of the present study was to identify a miRNA-mediated mechanism which plays a role in the anti-cancer effects of curcumin. Alterations in miRNA expression were seen in curcumin-treated A549 cells, including significant downregulation of miRNA-186* expression by microarray analysis and real-time PCR. The miRNA-186* functions by overexpression or inhibition were investigated using biological assays in A549 cells. Additionally, caspase-10 was identified as a target of miRNA-186* using dual luciferase reporter assays and western blot analysis. These results demonstrate that curcumin induces A549 cell apoptosis through a miRNA pathway. Also, miRNA-186* could serve as a potential gene therapy target in curcumin treatment. furthermore, caspase-10 was shown to be a target of miR-186* regulation.

Topics: 3' Untranslated Regions; Adenocarcinoma; Antineoplastic Agents; Apoptosis; Base Sequence; Caspase 10; Cell Growth Processes; Cell Line, Tumor; Curcumin; Down-Regulation; Humans; Lung Neoplasms; Microarray Analysis; MicroRNAs; Signal Transduction

A series of curcumin analogues including new 4-arylidene curcumin analogues (4-arylidene-1,7-bisarylhepta-1,6-diene-3,5-diones) were synthesized. Cell growth inhibition assays revealed that most 4-arylidene curcumin analogues can effectively decrease the growth of a panel of lung cancer cells at submicromolar and low micromolar concentrations. High content analysis technology coupled with biochemical studies showed that this new class of 4-arylidene curcumin analogues exhibits significantly improved NF-κB inhibition activity over the parent compound curcumin, at least in part by inhibiting IκB phosphorylation and degradation via IKK blockage; selected 4-arylidene curcumin analogues also reduced the tumorigenic potential of cancer cells in a clonogenic assay.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Nucleus; Curcumin; Humans; Inhibitory Concentration 50; Lung Neoplasms; Magnetic Resonance Spectroscopy; NF-kappa B; Signal Transduction; Tumor Necrosis Factor-alpha

Several studies have shown that curcumin can induce apoptosis and inhibit growth in human A549 lung adenocarcinoma cells. However, the mechanism is not completely understood yet. In the present study, we investigated the in vitro effect of curcumin on cell viability, apoptosis and disorganization of the actin cytoskeleton in A549 cells. Our results showed that curcumin significantly inhibited the viability of A549 cells in a dose- and time-dependent manner by induced apoptosis. The apoptotic process was associated with a disorganization of the architecture of actin microfilaments and a decrease in the levels of F-actin. DMSO-treated control cells exhibited a well-defined F-actin network that was mainly organized into stress fibers. The actin fibers in cells treated with curcumin or the positive control drug cytochalasin B were disorganized, disassembled, or disrupted, however, the disorganization of actin fibers and apoptosis could be prevented by phalloidin, an F-actin stabilizing compound. Thus, these results demonstrated that actin filament disorganization might play a central role in the curcumin-induced apoptosis of A549 cells.

Topics: Actin Cytoskeleton; Actins; Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Survival; Curcuma; Curcumin; Cytochalasin B; Cytoskeleton; Dose-Response Relationship, Drug; Humans; Lung Neoplasms; Phalloidine; Phytotherapy; Plant Extracts; Poisons

The purpose of this study was to investigate the sensitizing effect of curcumin on cisplatin-induced apoptosis in non-small cell lung cancer (NSCLC) H460 cells. Curcumin was shown to induce superoxide anion generation, down-regulate anti-apoptotic Bcl-2 protein, and subsequently sensitize cells to cisplatin-induced apoptosis. Co-treatment of the cells with curcumin and cisplatin resulted in increased apoptosis and reversal of Bcl-2-mediated cisplatin resistance. The mechanism by which curcumin down-regulates Bcl-2 and sensitizes cells to cisplatin-induced apoptosis involves proteasomal degradation of Bcl-2. These findings indicate a novel pathway for curcumin regulation of Bcl-2, which could benefit the development of a cisplatin sensitizing agent.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cisplatin; Curcumin; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2; Superoxides; Time Factors; Transfection

Curcumin exhibits anti-inflammatory and antitumor activity and is being tested in clinical trials as a chemopreventive agent for colon cancer. Curcumin's chemopreventive activity was tested in a transgenic mouse model of lung cancer that expresses the human Ki-ras(G12C) allele in a doxycycline (DOX) inducible and lung-specific manner. The effects of curcumin were compared with the lung tumor promoter, butylated hydroxytoluene (BHT), and the lung cancer chemopreventive agent, sulindac. Treatment of DOX-induced mice with dietary curcumin increased tumor multiplicity (36.3 +/- 0.9 versus 24.3 +/- 0.2) and progression to later stage lesions, results which were similar to animals that were co-treated with DOX/BHT. Microscopic examination showed that the percentage of lung lesions that were adenomas and adenocarcinomas increased to 66% in DOX/BHT, 66% in DOX/curcumin and 49% in DOX/BHT/curcumin-treated groups relative to DOX only treated mice (19%). Immunohistochemical analysis also showed increased evidence of inflammation in DOX/BHT, DOX/curcumin and DOX/BHT/curcumin mice relative to DOX only treated mice. In contrast, co-treatment of DOX/BHT mice with 200 p.p.m. [DOSAGE ERROR CORRECTED] of sulindac inhibited the progression of lung lesions and reduced the inflammation. Lung tissue from DOX/curcumin-treated mice demonstrated a significant increase (33%; P = 0.01) in oxidative damage, as assessed by the levels of carbonyl protein formation, relative to DOX-treated control mice after 1 week on the curcumin diet. These results suggest that curcumin may exhibit organ-specific effects to enhance reactive oxygen species formation in the damaged lung epithelium of smokers and ex-smokers. Ongoing clinical trials thus may need to exclude smokers and ex-smokers in chemopreventive trials of curcumin.

Topics: Animals; Anticarcinogenic Agents; Butylated Hydroxytoluene; Cell Transformation, Neoplastic; Curcumin; Doxycycline; Genes, ras; Lung Neoplasms; Mice; Mice, Transgenic; Organ Specificity; Reactive Oxygen Species; Sulindac

Turmeric, an essential ingredient of culinary preparations of Southeast Asia, contains a major polyphenolic compound, named curcumin or diferuloylmethane, which eliminates cancer cells derived from a variety of peripheral tissues. Although in vitro experiments have addressed its anti-tumor property, no in vivo studies have explored its anti-cancer activity in the brain. Oral delivery of this food component has been less effective because of its low solubility in water.We show that a soluble formulation of curcumin crosses the blood–brain barrier but does not suppress normal brain cell viability. Furthermore, tail vein injection, or more effectively, intracerebral injection through a cannula, blocks brain tumor formation in mice that had already received an intracerebral bolus of mouse melanoma cells (B16F10).While exploring the mechanism of its action in vitro we observed that the solubilized curcumin causes activation of proapoptotic enzymes caspase 3/7 in human oligodendroglioma (HOG) and lung carcinoma (A549) cells, and mouse tumor cells N18(neuroblastoma), GL261 (glioma), and B16F10. A simultaneous decrease in cell viability is also revealed by MTT [3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide]assays. Further examination of the B16F10 cells showed that curcumin effectively suppresses Cyclin D1, P-NF-kB, BclXL, P-Akt, and VEGF, which explains its efficacy in blocking proliferation, survival, and invasion of the B16F10 cells in the brain. Taken together,solubilized curcumin effectively blocks brain tumor formation and also eliminates brain tumor cells. Therefore, judicious application of such injectable formulations of curcumin could be developed into a safe therapeutic strategy for treating brain tumors.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Survival; Curcumin; Glioma; Humans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neuroblastoma; Oligodendroglioma

It is well known that matrix metalloproteinases (MMPs) act an important role in the invasion, metastasis and angiogenesis of cancer cells. Agents suppressed the MMPs could inhibited the cancer cells migration and invasion. Numerous evidences had shown that curcumin (the active constituent of the dietary spice turmeric) has potential for the prevention and therapy of cancer. Curcumin can inhibit the formation of tumors in animal models of carcinogenesis and act on a variety of molecular targets involved in cancer development. There is however, no available information to address the effects of curcumin on migration and invasion of human lung cancer cells. The anti-tumor invasion and migration effects of lung cancer cells induced by curcumin were examined. Here, we report that curcumin suppressed the migration and invasion of human non-small cell lung cancer cells (A549) in vitro. Our findings suggest that curcumin has anti-metastatic potential by decreasing invasiveness of cancer cells. Moreover, this action was involved in the MEKK3, p-ERK signaling pathways resulting in inhibition of MMP-2 and -9 in human lung cancer A549 cells. Overall, the above data shows that the anticancer effect of curcumin is also exist for the inhibition of migration and invasion in lung cancer cells.

Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Movement; Curcumin; Humans; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Neoplasm Invasiveness; Signal Transduction; Vascular Endothelial Growth Factor A

Recent studies have demonstrated that K-ras mutations in lung epithelial cells elicit inflammation that promotes carcinogenesis in mice (intrinsic inflammation). The finding that patients with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer after controlling for smoking suggests a further link between lung cancer and extrinsic inflammation. Besides exposure to cigarette smoke, it is thought that airway inflammation in COPD is caused by bacterial colonization, particularly with non-typeable Hemophilus influenzae (NTHi). Previously, we have shown that NTHi-induced COPD-like airway inflammation promotes lung cancer in an airway conditional K-ras-induced mouse model. To further test the role of inflammation in cancer promotion, we administered the natural anti-inflammatory agent, curcumin, 1% in diet before and during weekly NTHi exposure. This significantly reduced the number of visible lung tumors in the absence of NTHi exposure by 85% and in the presence of NTHi exposures by 53%. Mechanistically, curcumin markedly suppressed NTHi-induced increased levels of the neutrophil chemoattractant keratinocyte-derived chemokine by 80% and neutrophils by 87% in bronchoalveolar lavage fluid. In vitro studies of murine K-ras-induced lung adenocarcinoma cell lines (LKR-10 and LKR-13) indicated direct anti-tumoral effects of curcumin by reducing cell viability, colony formation and inducing apoptosis. We conclude that curcumin suppresses the progression of K-ras-induced lung cancer in mice by inhibiting intrinsic and extrinsic inflammation and by direct anti-tumoral effects. These findings suggest that curcumin could be used to protract the premalignant phase and inhibit lung cancer progression in high-risk COPD patients.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemokines; Curcumin; Female; Genes, ras; Haemophilus Infections; Haemophilus influenzae; Inflammation; Lung Neoplasms; Male; Mice; Neutrophils; Pulmonary Disease, Chronic Obstructive

Furanodiene is a sesquiterpene extracted from the essential oil of the rhizome of Curcuma wenyujin Y.H. Chen et C. Ling (Wen Ezhu). Furanodiene is the primary component in Wen Ezhu's essential oil, accounting for more than 20% by weight. In vitro, MTT assay was used to compare the inhibitory effects of furanodiene and Wen Ezhu's essential oil on 11 human cancer cell lines. Compared to the essential oil, furanodiene showed stronger growth inhibitions on Hela, Hep-2, HL-60, PC3, SGC-7901 and HT-1080 cells with IC(50) between 0.6-4.8 microg/ml. In vivo, furanodiene was also found to exhibit inhibitory effects on the growth of uterine cervical (U14) and sarcoma 180 (Sl80) tumors in mice. Our data suggests that furanodiene, an active component from the essential oil of Wen Ezhu, possesses efficacy against uterine cervical cancer.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Division; Curcuma; Drugs, Chinese Herbal; Female; Fibrosarcoma; Furans; HeLa Cells; Heterocyclic Compounds, 2-Ring; HL-60 Cells; Humans; K562 Cells; Leukemia; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred Strains; Organ Size; Sesquiterpenes; Spleen; Thymus Gland; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

Curcumin, a major component of the Curcuma species, is known to have antioxidant, anti-inflammatory properties and induce apoptosis of cancer cells, however, the precise molecular mechanisms of apoptosis in vitro are unclear. In this study, we showed that curcumin, a plant product containing the phenolic phytochemical, caused DNA damage and endoplasmic reticulum (ER) stress and mitochondrial-dependent-induced apoptosis through the activation of caspase-3 at a treatment concentration of 30 microM in human lung cancer A-549 cells. In contrast, treatment with 5-10 microM of curcumin did not induce significant apoptosis, but rather induced G2/M-phase arrest in A-549 cells. Flow cytometric analysis indicated that curcumin directly increased intracellular oxidative stress based on the cell permeable dye, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) acting as an indicator of reactive oxygen species (ROS) generation. GADD153 and GRP78 were increased by curcumin which was indicative of ER stress. Curcumin increased Ca(2+) levels and the mitochondrial membrane potential (DeltaPsi(m)), was decreased in A-549 cells. Overall, our results demonstrated that curcumin treatment causes cell death by activating pathways inducing G2/M-phase arrest and apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Calcium; Caspases; Cell Cycle; Cell Line, Tumor; Cell Survival; Curcumin; DNA Damage; Egtazic Acid; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Enzyme Activation; Humans; Lung Neoplasms; Mitochondria; Reactive Oxygen Species

Curcumin (diferuloylmethane) is an active component of the spice turmeric and has a diversity of antitumor activities. In this study, we found that curcumin can inhibit cancer cell invasion and metastasis through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). Human lung adenocarcinoma cells (CL1-5) treated with curcumin (1-20 mumol/L) showed a concentration-dependent reduction in cell migration, invasion, and metastatic ability, and this was associated with increased HLJ1 expression. Knockdown of HLJ1 expression by siRNA was able to reverse the curcumin-induced anti-invasive and antimetastasis effects in vitro and in vivo. The HLJ1 promoter and enhancer in a luciferase reporter assay revealed that curcumin transcriptionally up-regulates HLJ1 expression through an activator protein (AP-1) site within the HLJ1 enhancer. JunD, one of the AP-1 components, was significantly up-regulated by curcumin (1-20 mumol/L) in a concentration- and time-dependent manner. Knockdown of JunD expression could partially reduce the curcumin-induced HLJ1 activation and diminish the anti-invasive effect of curcumin, indicating that JunD would seem to be involved in curcumin-induced HLJ1 expression. Curcumin was able to induce c-Jun NH(2)-kinase (JNK) phosphorylation, whereas the JNK inhibitor (SP-600125) could attenuate curcumin-induced JunD and HLJ1 expression. Activation of HLJ1 by curcumin further leads to up-regulation of E-cadherin and a suppression of cancer cell invasion. Our results show that curcumin induces HLJ1, through activation of the JNK/JunD pathway, and inhibits lung cancer cell invasion and metastasis by modulating E-cadherin expression. This is a novel mechanism and supports the application of curcumin in anti-cancer metastasis therapy.

Topics: Adenocarcinoma; Animals; Cadherins; Cell Line, Tumor; Cell Movement; Curcumin; HSP40 Heat-Shock Proteins; Humans; Lung Neoplasms; MAP Kinase Kinase 4; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Proto-Oncogene Proteins c-jun; Random Allocation; Signal Transduction; Transcription Factor AP-1; Transfection; Up-Regulation

Multidrug resistance (MDR) is the main obstacle to a successful chemotherapy of lung cancer. We tested the potential of sulfinosine and curcumin, alone and in combination, for modulating MDR in the human resistant, non-small cell lung carcinoma cell line (NCI-H460/R). First, we determined the mutational status of the p53 gene in NCI-H460/R cells by PCR-SSCP and DNA sequencing and identified mutations which could at least partially contribute to the development of the MDR phenotype. The effects of sulfinosine and curcumin were studied, both separately and in combination, at the level of cytotoxicity, cell cycle distribution and gene expression. Sulfinosine displayed dose-dependent growth inhibition in both resistant and control sensitive cell lines, whereas curcumin considerably inhibited their growth only at relatively high doses. When sulfinosine was combined with a low dose of curcumin the drugs exerted a synergistic cytotoxic effect in NCI-H460/R cells. The expression of MDR-related genes mdr1, gst-pi and topo IIalpha, was altered by sulfinosine and curcumin. The most pronounced effect was observed when the agents were applied together. Sulfinosine and curcumin caused perturbations in cell cycle distribution in the NCI-H460/R cell line. The combination of the two drugs induced a more pronounced cell cycle arrest in S and G(2)/M in NCI-H460/R cells. Our results show that sulfinosine and curcumin overcome MDR in non-small cell lung carcinoma cell line (NSCLC), especially in combination despite the presence of a mutated p53 gene.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Exons; Genes, p53; Humans; Lung Neoplasms; Mutation; Phenotype; Purine Nucleosides

Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitroand in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA-MB-231 cells in correlation with reduced activation of the survival pathway NFkappaB, as a consequence of diminished IotakappaB and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NFkappa B activity and transcriptional downregulation of AP-1. NFkappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NFkappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NFkappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Female; Flavonoids; Forkhead Transcription Factors; Humans; I-kappa B Proteins; Lung Neoplasms; Matrix Metalloproteinases; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; NF-kappa B; Phenols; Phosphorylation; Polyphenols; Transcription Factor AP-1; Transfection; Xenograft Model Antitumor Assays

Exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concentrations of doxorubicin resulted in the appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin. Slight cross-resistance to two MDR-unrelated drugs 8-Cl-cAMP and sulfinosine was observed. Flow cytometry analysis showed that the accumulation of doxorubicin in the resistant cells was 88.4% lower than in the parental cells. Also, verapamil significantly decreased the efflux rate in NCI-H460 and NCI-H460/R cells, whereas curcumin inhibited the efflux in NCI-H460 cells only. Gene expression data confirmed the induction of mdr1 (P-gp), as judged by the observed 15-fold increase in its mRNA concentration in doxorubicin-resistant NCI-H460/R cells. In contrast, mrp1 and lrp expression was unaffected by the doxorubicin resistance. Further work should develop a rationale for a novel treatment of NSCLC with appropriate modulators of resistance aimed at improving the outcome of the acquired drug resistance.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Curcumin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Glutathione Transferase; Humans; Lung Neoplasms; Multidrug Resistance-Associated Proteins; Paclitaxel; Rhodamines; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured; Verapamil; Vinblastine

The current study demonstrates that COX-2 expression is positively regulated by IFN-alpha, which is mediated by activation of STAT1 in A549 cells. The IFN-alpha-induced COX-2 expression and STAT1 activation were markedly inhibited by the addition of curcumin to the IFN-alpha-pretreated cells. While IFN-alpha or COX-2 inhibitors alone did not result in growth inhibition of A549 cells, the combination of IFN-alpha and celecoxib or curcumin resulted in a significant growth inhibition of A549 cells, which was associated with down-regulation of CDK2, 4, and 6 and up-regulation of p27. We demonstrate that the expression of COX-2 was induced by IFN-alpha possibly via STAT1 activation in the A549 human non-small cell lung cancer cell line, which may partly account for its IFN-alpha resistance. The addition of curcumin or celecoxib to the IFN-alpha-pretreated A549 cells altered the IFN-alpha sensitivity of cell growth inhibition.

Topics: Carcinoma, Non-Small-Cell Lung; Curcumin; Cyclooxygenase 2; DNA, Neoplasm; Drug Interactions; Drug Resistance, Neoplasm; Enzyme Induction; Humans; Interferon-alpha; Lung Neoplasms; Membrane Proteins; Phosphorylation; RNA, Messenger; STAT1 Transcription Factor

Elderly lung cancer patients and those with poor performance status/co-morbid conditions are deprived of chemotherapy because of high toxicity of multidrug regimens. Human squamous cell lung carcinoma H520 cells treated with Curcumin were sensitized to the cytotoxicity caused by chemotherapeutic agent, Vinorelbine. Both caused apoptosis by increasing the protein expression of Bax and Bcl-xs while decreasing Bcl-2 and Bcl-X(L), releasing apoptogenic cytochrome c, and augmenting the activity of caspase-9 and caspase-3. Expression of Cox-2, NF-kappaB, and AP-1 was also affected. 23.7% apoptosis was induced in the H520 cells by treatment with Curcumin while Vinorelbine caused 38% apoptosis. Pre-treatment with Curcumin enhanced the Vinorelbine induced apoptosis to 61.3%. The findings suggest that Curcumin has the potential to act as an adjuvant chemotherapeutic agent and enhance chemotherapeutic efficacy of Vinorelbine in H520 cells in vitro. Thus, Curcumin offers the prospect of being beneficial in the above-mentioned patient groups.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspase 3; Caspase 9; Caspases; Cell Line, Tumor; Curcumin; Down-Regulation; Drug Synergism; Humans; Lung Neoplasms; Mitochondria; NF-kappa B; Transcription Factor AP-1; Vinblastine; Vinorelbine

The A549 cells, non-small cell lung cancer cell line from human, were resistant to interferon (IFN)-alpha treatment. The IFN-alpha-treated A549 cells showed increase in protein expression levels of NF-kappaB and COX-2. IFN-alpha induced NF-kappaB binding activity within 30 min and this increased binding activity was markedly suppressed with inclusion of curcumin. Curcumin also inhibited IFN-alpha-induced COX-2 expression in A549 cells. Within 10 min, IFN-alpha rapidly induced the binding activity of a gamma-(32)P-labeled consensus GAS oligonucleotide probe, which was profoundly reversed by curcumin. Taken together, IFN-alpha-induced activations of NF-kappaB and COX-2 were inhibited by the addition of curcumin in A549 cells.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Curcumin; Cyclooxygenase 2; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Interferon-alpha; Lung Neoplasms; Membrane Proteins; NF-kappa B; Prostaglandin-Endoperoxide Synthases

Currently, there is no effective therapy for metastatic breast cancer after surgery, radiation, and chemotherapy have been used against the primary tumor. Because curcumin suppresses nuclear factor-kappaB (NF-kappaB) activation and most chemotherapeutic agents activate NF-kappaB that mediates cell survival, proliferation, invasion, and metastasis, we hypothesized that curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis. We tested this hypothesis using paclitaxel (Taxol)-resistant breast cancer cells and a human breast cancer xenograft model. As examined by electrophoretic mobility gel shift assay, paclitaxel activated NF-kappaB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of IkappaBalpha kinase activation and IkappaBalpha phosphorylation and degradation. Curcumin also suppressed the paclitaxel-induced expression of antiapoptotic (XIAP, IAP-1, IAP-2, Bcl-2, and Bcl-xL), proliferative (cyclooxygenase 2, c-Myc, and cyclin D1), and metastatic proteins (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1). It also enhanced apoptosis. In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-kappaB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-kappaB and NF-kappaB-regulated gene products.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; Cyclooxygenase 2; Drug Synergism; Female; Gene Expression; Humans; Immunohistochemistry; Ki-67 Antigen; Lung Neoplasms; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 9; Mice; Mice, Nude; NF-kappa B; Paclitaxel; Promoter Regions, Genetic; Signal Transduction; Xenograft Model Antitumor Assays

Xanthorrhizol is a sesquiterpenoid compound isolated from the rhizome of Curcuma xanthorrhiza. In this study, the anti-metastatic activity of xanthorrhizol was evaluated by using an in vivo mouse lung metastasis model and a tumor mass formation assay. Interestingly, xanthorrhizol dramatically inhibited the formation of tumor nodules in the lung tissue and the intra-abdominal tumor mass formation. Next, to examine the mechanism of the anti-metastatic action of xanthorrhizol in the mouse lung metastasis, expression patterns of the several intracellular signaling molecules were evaluated using the lung tissues with tumor nodules. Higher expression levels of cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and phosphorylated extracellular signal-regulated kinase (ERK) were observed in the metastatic group compared with control, but these were attenuated by the treatment of xanthorrhizol. In conclusion, xanthorrhizol exerts anti-metastatic activity in vivo and this effect could be highly linked to the metastasis-related multiplex signal pathway including ERK, COX-2, and MMP-9.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Curcuma; Dose-Response Relationship, Drug; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms, Experimental; Phenols; Phytotherapy; Plant Extracts; Treatment Outcome

The inhibitory effect of Curcuma zedoaria Roscoe (WE-CZ) on experimental pulmonary metastasis of B16 melanoma cells was investigated. The intake of WE-CZ at doses of 250 and 500 mg/kg for 6 weeks from 2 weeks before tumor inoculation significantly reduced the number of metastatic surface nodules in the lung, resulting in an extended life span. When the duration of WE-CZ intake was examined, survival time was not affected by pre-intake before B16 melanoma cell inoculation and was slightly extended by post-intake after B16 melanoma cell inoculation, although the life span was prolonged by intake throughout the experiment. To address the mechanism underlying the anti-metastatic effect of WE-CZ, we examined the issue of whether WE-CZ modulated macrophage function, which is involved in killing tumor cells. The intake of WE-CZ for 6 weeks increased nitric oxide (NO) production by macrophages following stimulation with lipopolysaccharide in a dose-dependent manner. The elevated NO was found to serve as a cytotoxic mediator against B16 melanoma cells in co-culture with macrophages. On the contrary, B16 melanoma-conditioned medium reduced NO production by macrophages. However, WE-CZ treatment significantly reversed the reduction in NO production by the conditioned medium. These findings indicate that WE-CZ possesses anti-migratory effects on B16 melanoma cells and that the macrophage function-modulating activity by WE-CZ appears to underlie its anti-metastatic activity, which leads to a decrease in the number of lung metastatic surface nodules and the extension of life span. These results suggest that WE-CZ may play important roles in the inhibition of cancer metastasis.

Topics: Animals; Curcuma; Dose-Response Relationship, Drug; Lung Neoplasms; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nitric Oxide; Phytotherapy; Plant Extracts

Cell migration is essential for invasive and metastatic phenotypes of cancer cells. Potential chemopreventive agents of cancer-sulindac sulfide, caffeic acid phenethyl ester (CAPE), curcumin, and (+)-catechin-have been reported to interfere with several types of intracellular signaling. In this study, we examined the effects of these agents on transforming growth factor-beta(TGF-beta)-induced motility and Akt phosphorylation in A549 cells. Judged by gold particle phagokinesis assay, sulindac sulfide, CAPE, and curcumin suppressed the motility of A549 cells promoted by TGF-beta. LY294002, a specific inhibitor of phosphatidylinositol 3-kinase(PI3K)/Akt signaling, also suppressed TGF-beta-induced motility and Akt phosphorylation. Sulindac sulfide and CAPE, but not curcumin, suppressed TGF-beta-induced Akt phosphorylation. We conclude that sulindac sulfide and CAPE suppress the motility promoted by TGF-beta in lung adenocarcinoma cells through the suppression of Akt. Our observations raise the possibility that these agents, except for (+)-catechin, can be applied not only as chemopreventive agents but also as anti-metastatic therapy.

Topics: Adenocarcinoma; Antineoplastic Agents; Caffeic Acids; Catechin; Cell Movement; Curcumin; Humans; Lung Neoplasms; Neovascularization, Pathologic; NF-kappa B; Phenylethyl Alcohol; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Sulindac; Transforming Growth Factor beta; Tumor Cells, Cultured

Curcumin has been reported to exhibit anti-invasive and/or antimetastatic activities, but the mechanism remains unclear. In this study, microarray analysis of gene expression profiles were used to characterize the anti-invasive mechanisms of curcumin in highly invasive lung adenocarcinoma cells (CL1-5). Results showed that curcumin significantly reduces the invasive capacity of CL1-5 cells in a concentration range far below its levels of cytotoxicity (20 microM) and that this anti-invasive effect was concentration dependent (10.17 +/- 0.76 x 10(3) cells at 0 microM; 5.67 +/- 1.53 x 10(3) cells at 1 microM; 2.67 +/- 0.58 x 10(3) cells at 5 microM; 1.15 +/- 1.03 x 10(3) cells at 10 microM; P < 0.05) in the Transwell cell culture chamber assay. Using microarray analysis, 81 genes were down-regulated and 71 genes were up-regulated after curcumin treatment. Below sublethal concentrations of curcumin (10 microM), several invasion-related genes were suppressed, including matrix metalloproteinase 14 (MMP14; 0.65-fold), neuronal cell adhesion molecule (0.54-fold), and integrins alpha6 (0.67-fold) and beta4 (0.63-fold). In addition, several heat-shock proteins (Hsp) [Hsp27 (2.78-fold), Hsp70 (3.75-fold), and Hsp40-like protein (3.21-fold)] were induced by curcumin. Real-time quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry confirmed these results in both RNA and protein levels. Curcumin (1 to 10 microM) reduced the MMP14 expression in both mRNA and protein levels and also inhibited the activity of MMP2, the down-stream gelatinase of MMP14, by gelatin zymographic analysis. Based on these data, it can be concluded that curcumin might be an effective antimetastatic agent with a mechanism of anti-invasion via the regulation of certain gene expressions.

Topics: Antineoplastic Agents; Blotting, Western; Cell Survival; Curcumin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lung Neoplasms; Matrix Metalloproteinase 2; Neoplasm Invasiveness; NF-kappa B; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic; Tumor Cells, Cultured

Curcumin, a phenolic compound from the rhizome of the plant Curcuma longa has anti-inflammatory, antioxidant and anti-cancer activities. Although the precise mode of action of this compound is not yet elucidated, studies have shown that chemo-preventive action of curcumin might be due to its ability to induce apoptosis and to arrest cell cycle. This study investigated the cellular and molecular changes induced by curcumin leading to the induction of apoptosis in human lung cancer cell lines-A549 and H1299. A549 is p53 proficient and H1299 is p53 null mutant. The lung cancer cells were treated with curcumin (0-160 microM) for 12-72 h. Curcumin inhibited the growth of both the cell lines in a concentration dependent manner. Growth inhibition of H1299 cell lines was both time and concentration dependent. Curcumin induced apoptosis in both the lung cancer cell lines. A decrease in expression of p53, bcl-2, and bcl-X(L) was observed after 12 h exposure of 40 microM curcumin. Bak and Caspase genes remained unchanged up to 60 microM curcumin but showed decrease in expression levels at 80-160 microM. The data also suggest a p53 independent induction of apoptosis in lung cancer cells.

Topics: Adenocarcinoma; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Genes, myc; Humans; Lung Neoplasms; Poly(ADP-ribose) Polymerases; Tumor Suppressor Protein p53

To investigate the mechanism of anti-tumor effects of curcumin on human lung cancer cell (A549).. MTT colorimetry method, fluoroscope, FCM combine PI and Annexin V-FITC double pigmentation method and Western blot method were used.. Under the effect of the curcumin, cell grew against the wall and suspended in the culture liquid, the A549 cell nucleolus were found fragmentated into different size of apoptosis body under fluoroscopy. The cell proliferation were obvious suppressed after treated with different concentration curcumin for 72 hours. The IC50 were 18 micromol/L by using linear regression. The apoptosis induced by curcumin of A549 cell is concentration dependent. With curcumin increased from 5 micromol/L to 30 micromol/L, Annexin-FITC single positive cell (early apoptosis cell) increased from 3.4% to 59.1%. When curcumin concentration reached 40 micromol/L, PI and Annexin V-FITC double positive cell (secondary apoptosis necrosis cell) became major part of cells, and the cell showed G2 phase block. Observed with western blot method, with the increase of curcumin concentration to 10 micromol/L, the expression of PARP increased simultaneously.. Curcumin can interfere cell growth cycle of A549 cell and suppress cell growth. The suppression effect is concentration dependent. The effect depends not only from the nonspecific cytotoxic but also from induced cell apoptosis.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Flow Cytometry; Humans; Lung Neoplasms; Poly(ADP-ribose) Polymerases; Tumor Cells, Cultured

Curcumin (diferuloyl methane), the major pigment from the rhizome of Curcuma longa L., has been widely studied for its tumor-inhibiting properties. Recent studies indicate that curcumin can modify cell receptor binding, it also affects intracellular signalling reactions. Curcumin-treated B16F10 melanoma cells formed eight-fold fewer lung metastases in C57BL6 mice. In the cell adhesion assays, curcumin-treated cells showed a dose-dependent reduction in their binding to four extracellular matrix (ECM) proteins. The binding to fibronectin, vitronectin, and collagen IV decreased by over 50% in 24 hours, and by 100% after 48 hours of curcumin treatment, it persisted at this level even after 15 days of cultivating cells in curcumin-free medium. Curcumin-treated cells showed a marked reduction in the expression of alpha5beta1 and alpha(v)beta3 integrin receptors. In addition, curcumin treatment inhibited pp125 focal adhesion kinase (FAK), tyrosine phosphorylation of a 120 kD protein, and collagenase activity. Curcumin enhances the expression of antimetastatic proteins, tissue inhibitor metalloproteinase (TIMP)-2, nonmetastatic gene 23 (Nm23), and E-cadherin. In this article we report on the effect of curcumin on the expression of integrin, TIMP-2, Nm23, E-cadherin, adhesion, and metalloproteinase activity.

Topics: Animals; Antineoplastic Agents; Cadherins; Cell Adhesion; Collagenases; Curcumin; Dose-Response Relationship, Drug; Integrins; Lung Neoplasms; Melanoma; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Signal Transduction; Skin Neoplasms; Tissue Inhibitor of Metalloproteinase-3; Tumor Cells, Cultured

It is well known that N-acetyltransferase (NAT) plays an important role in the arylamine metabolism. We analysed the response of A549 human lung cancer cells for N-acetylation of 2-aminofluorene (AF) to curcumin. After curcumin treatment, the NAT activity was examined by HPLC, AF-DNA adduct formation was examined by HPLC, and NAT gene expression by polymerase chain reaction were detected. The NAT activity in the human A549 cells and cytosols was suppressed by curcumin in a dose-dependent manner. The results also demonstrated that gene expression (NAT1 mRNA) in human lung A549 tumor cells was inhibited and decreased by curcumin. After the incubation of human lung A549 tumor cells with AF with or without curcumin co-treatment, the cells were recovered and DNA was prepared and hydrolyzed to nucleotides. The adducted nucleotides were extracted into butanol and analyzation of AF-DNA adducts was done by HPLC. The results also demonstrated that curcumin decreases AF-DNA adduct formation in the human lung A549 tumor cells.

Topics: Acetylation; Antineoplastic Agents; Arylamine N-Acetyltransferase; Base Sequence; Curcumin; DNA Adducts; Enzyme Inhibitors; Fluorenes; Humans; Lung Neoplasms; Molecular Sequence Data; Tumor Cells, Cultured

Cigarette smoke (CS) is a major cause of a variety of malignancies including cancers of the larynx, oral cavity and pharynx, esophagus, pancreas, kidney, bladder and lung. The signal transduction pathway that mediates the effects of CS is not well understood but nuclear factor-kappa B (NF-kappaB) is probably involved. The gas phase of CS contains free radicals such as superoxide radicals, hydroxyl radicals and hydrogen peroxide, which potentially can activate NF-kappaB. Benzo[a]pyrene, another potent carcinogen of CS, can also activate NF-kappaB, but by an as yet unknown mechanism. Various other agents that activate NF-kappaB are either tumor initiators or tumor promoters, and NF-kappaB activation can block apoptosis, promote proliferation and mediate tumorigenesis. Therefore, NF-kappaB is an ideal target for preventing CS-induced lung carcinogenesis. Thus, agents that abrogate NF-kappaB activation have the potential to suppress lung carcinogenesis. Because curcumin, a diferuloylmethane, is anticarcinogenic, we investigated the effect of this phytochemical on CS-induced NF-kappaB activation and NF-kappaB-regulated gene expression in human non-small cell lung carcinoma cells. Exposure of cells to CS induced persistent activation of NF-kappaB, and pre-treatment with curcumin abolished the CS-induced DNA-binding of NF-kappaB, IkappaBalpha kinase activation, IkBalpha phosphorylation and degradation, p65 nuclear translocation and CS-induced NF-kappaB-dependent reporter gene expression. The inhibition of NF-kappaB activation correlated with suppression of CS-induced NF-kappaB-dependent cyclin D1, cyclooxygenase-2 and matrix metalloproteinase-9 expression. Overall our results indicate that CS-induced NF-kappaB activation and NF-kappaB-regulated gene expression in human non-small cell lung carcinoma cells is suppressed by curcumin through suppression of IkappaBalpha kinase.

Topics: Antineoplastic Agents; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cells, Cultured; Curcumin; Cyclin D1; Cyclooxygenase 2; DNA Primers; Down-Regulation; Epithelial Cells; Humans; I-kappa B Kinase; Isoenzymes; Luciferases; Lung Neoplasms; Matrix Metalloproteinase 9; Membrane Proteins; NF-kappa B; Phosphorylation; Prostaglandin-Endoperoxide Synthases; Protein Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Smoking; Transfection

We examined the ability of adenoviral-mediated expression of the melanoma differentiation associated gene-7 (Ad-mda-7), to radiosensitize non-small cell lung cancer (NSCLC) cell lines (A549 (wt-TP53/wt-RB1) and H1299 (del-TP53/wt-RB1)), and normal human lung fibroblast (NHLF) lines (CCD-16 and MRC-9). Results of clonogenic assays indicated that Ad-mda7 enhanced the radiosensitivity of the NSCLC cells independent of their TP53 gene status. On the other hand, the NHLF cell lines seemed to be relatively resistant to the cytotoxic effects of Ad-mda7 and were not radiosensitized compared with the NSCLC cells. We further examined the basis for this difference in the ability of Ad-mda7 to radiosensitize NSCLC cells compared with normal cells. Radiation-induced apoptosis was restored in the NSCLC lines, but not in the normal lines. Western blot analysis revealed that Ad-mda7 enhances radiosensitivity independently of any ability to upregulate the expression of Fas or Bax in NSCLC cells. Further analysis indicated that phosphorylated c-Jun expression was increased by Ad-mda7 in both A549 and H1299 cells, but not in CCD-16 cells. These results support the use of gene replacement with Ad-mda7 in combination with radiotherapy for the treatment of NSCLC.

Topics: Adenoviridae; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Curcumin; Dose-Response Relationship, Radiation; Enzyme Inhibitors; fas Receptor; G2 Phase; Gene Transfer Techniques; Genes, Tumor Suppressor; Humans; Interleukins; Lung Neoplasms; Mitosis; Nocodazole; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-jun; Radiation Tolerance; Transfection; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Up-Regulation

Flavonoids are a class of polyphenolic compounds widely distributed in the plant kingdom, which display a variety of biological activities, including chemoprevention and tumor growth inhibition. Our aim was to investigate the effects of several polyphenols on the growth and metastatic potential of B16-BL6 melanoma cells in vivo. Intraperitoneal administration of quercetin, apigenin, (-)-epigallocathechin-3-gallate (EGCG), resveratrol, and the anti-estrogen tamoxifen, at the time of i.m. injection of B16-BL6 cells into syngeneic mice, resulted in a significant, dose-dependent delay of tumor growth, without toxicity. The relative descending order of potency was EGCG > apigenin = quercetin = tamoxifen > resveratrol > control. Furthermore, polyphenols significantly potentiated the inhibitory effect of a non-toxic dose of cisplatin. When tested for the ability to inhibit lung colonization, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the number of B16-BL6 colonies in the lungs in a dose-dependent manner, with quercetin and apigenin being more effective than tamoxifen. Interestingly, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the invasion of B16-BL6 cells in vitro, with quercetin and apigenin being more effective than tamoxifen. This suggests that anti-invasive activity is one of the mechanisms underlying inhibition of lung colonization by quercetin and apigenin. In conclusion, quercetin and apigenin inhibit melanoma growth and invasive and metastatic potential; therefore, they may constitute a valuable tool in the combination therapy of metastatic melanoma.

Topics: Animals; Anticarcinogenic Agents; Apigenin; Catechin; Cell Division; Curcumin; Female; Flavonoids; Growth Inhibitors; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Transplantation; Quercetin; Resveratrol; Stilbenes; Tamoxifen; Tumor Cells, Cultured

Orthotopic implantation of a metastatic cell line of Lewis lung carcinoma (LLC-MLN), which was isolated by an in vivo selection method, resulted in greater metastatic growth in mediastinal lymph nodes as compared with that of the original LLC cells. LLC-MLN cells also had increased invasive ability and activator protein-1 (AP-1) transcriptional activity as compared with the original LLC cells. This is well consistent with the previously reported finding that overexpression of AP-1 is associated with lymphatic metastasis in lung cancer patients. Oral administration of curcumin, which downregulates AP-1 transcription, significantly inhibited the mediastinal lymph node metastasis of orthotopically implanted LLC cells in a dose-dependent manner, but did not affect the tumor growth at the implantation site. Combined treatment with curcumin and an anti-cancer drug, cis-diamine-dichloroplatinum (CDDP), resulted in a marked inhibition of tumor growth at the implanted site and of lymphatic metastasis, and a significant prolongation of the survival time. The downregulation of transcriptional AP-1 activity by curcumin as seen in the dual luciferase assay caused inhibition of LLC cell invasion through the repression of expression of the mRNAs for urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR). Inhibition of AP-1 transcriptional activity may offer improved therapeutic efficacy for lung cancer patients with lymphatic metastasis.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Division; Cisplatin; Curcumin; Dose-Response Relationship, Drug; Female; Kinetics; Lung Neoplasms; Lymphatic Metastasis; Mediastinal Neoplasms; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; RNA, Neoplasm; Transcription Factor AP-1; Urokinase-Type Plasminogen Activator

The potential activities of butylated hydroxyanisole (BHA), myo-inositol, curcumin, esculetin, resveratrol and lycopene-enriched tomato oleoresin (LTO) as chemopreventive agents against lung tumor induction in A/J mice by the tobacco smoke carcinogens benzo[a]pyrene (BaP) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were evaluated. Groups of 20 A/J mice were treated weekly by gavage with a mixture of BaP and NNK (3 micromol each) for 8 weeks, then sacrificed 26 weeks after the first carcinogen treatment. Mice treated with BHA (20 or 40 micromol) by gavage 2 h before each dose of BaP and NNK had significantly reduced lung tumor multiplicity. Treatment with BHA (20 or 40 micromol) by gavage weekly or with dietary BHA (2000 ppm), curcumin (2000 ppm) or resveratrol (500 ppm) from 1 week after carcinogen treatment until termination had no effect on lung tumor multiplicity. Treatment with dietary myo-inositol (30,000 ppm) or esculetin (2000 ppm) from 1 week after carcinogen treatment until termination significantly reduced lung tumor multiplicity, with the effect of myo-inositol being significantly greater than that of esculetin. Treatment with dietary LTO (167, 1667 or 8333 ppm) from 1 week before carcinogen treatment until termination had no effect on lung tumor multiplicity. The results of this study demonstrate that BHA is an effective inhibitor of BaP plus NNK-induced lung tumorigenesis in A/J mice when administered during the period of carcinogen treatment and that, among the compounds tested, myo-inositol is most effective after carcinogen treatment.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Benzo(a)pyrene; Butylated Hydroxyanisole; Carotenoids; Curcumin; Female; Inositol; Lung Neoplasms; Lycopene; Mice; Mice, Inbred A; Nitrosamines; Resveratrol; Stilbenes; Umbelliferones

The inhibitory effects of curcumin and catechin on lung metastasis induced by B16F-10 melanoma cells were studied in female C57BL/6 mice. Curcumin and catechin significantly (P < 0.001) inhibited lung tumour formation (89.3% and 82.2%, respectively) and significantly increased the life span (143.9% and 80.8%, respectively). Moreover, lung collagen hydroxyproline and serum sialic acid levels were found to be significantly (P < 0.001) lower in treated animals compared to the untreated controls. Curcumin and catechin treatment (10 microg/ml) significantly inhibited the invasion of B16F-10 melanoma cells across the collagen matrix of the Boyden chamber. Gelatin zymographic analysis of the trypsin-activated B16F-10 melanoma cells sonicate revealed that curcumin- and catechin-treated zymograms did not show any metalloproteinase activity. Curcumin and catechin treatment did not inhibit the motility of B16F-10 melanoma cells across a polycarbonate filter in vitro. These findings suggest that curcumin and catechin inhibit the invasion of B16F-10 melanoma cells by inhibition of metalloproteinases, thereby inhibiting lung metastasis.

Topics: Animals; Antineoplastic Agents; Catechin; Cell Adhesion; Cell Movement; Collagen; Curcumin; Female; Gelatin; Hydroxyproline; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; N-Acetylneuraminic Acid; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Survival Rate; Tumor Cells, Cultured

The modifying effects of the naturally occurring antioxidants n-tritriacontane-16,18-dione (TTAD), curcumin, dihydroguaiaretic acid (DHGA), chlorophyllin, tannic acid and phytic acid on the initiation stage in a rat multi-organ carcinogenesis model were examined in male F344 rats. Animals were initiated with two i.p. injections of 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN), followed by two i.g. administrations of N-ethyl-N-hydroxyethylnitrosamine (EHEN), and then three s.c. injections of 3,2'-methyl-4-aminobiphenyl (DMAB) during the first 3 weeks. Starting 1 day before the first carcinogen application, groups of rats received diet containing one of the antioxidants (0.2% TTAD, the others at 1% each) until 1 week after the last carcinogen exposure. Surviving animals were killed and complete autopsies were performed at the end of week 36. Histological examination revealed no inhibitory effects in terms of the multiplicities and/or incidences of neoplastic lesions in any of the organs examined, other than a significant increase in seminal vesicle atypical hyperplasia observed in rats treated with tannic acid. Thus, the antioxidants, with the exception of tannic acid, did not show any modifying effects on the initiation stage in the present multi-organ carcinogenesis model and at the present dose levels applied.

Topics: Aminobiphenyl Compounds; Animals; Antimutagenic Agents; Antineoplastic Agents; Antioxidants; Carcinogens; Chlorophyllides; Curcumin; Diethylnitrosamine; Guaiacol; Hydrolyzable Tannins; Lignans; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms, Experimental; Nitrosamines; Paraffin; Phytic Acid; Precancerous Conditions; Rats; Rats, Inbred F344

Experiments were conducted by using scrape-loading and dye transfer (SLDT) method to study the gap junction intercellular communication (GJIC) of Chinese hamster lung cells (V79), mouse fibrous cells (Balb/c-3T3), rat liver cells (WB) and human embryonal lung cells (2BS). We also observed the inhibition of the GJIC by TPA and the antagonistic effect of Curcumin derivatives on TPA. The results indicated that V79, WB, 3T3 and 2BS normal cells showed medium level of GJIC, and TPA could inhibit the GJIC to some extents. Curcumin derivatives (91022, 91022-S) could counteract the inhibition of TPA-induced GJIC. It was also found that human lung adenocarcinoma cell (A549) and GLC lacked GJIC, and 91022 could improve the GJIC of A549 cell. It may be related to its anticancer activity.

Topics: 3T3 Cells; Adenocarcinoma; Animals; Antineoplastic Agents; Carcinogens; Cell Communication; Cells, Cultured; Cricetinae; Curcumin; Fetus; Gap Junctions; Humans; Liver; Lung; Lung Neoplasms; Mice; Rats; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Several polyphenolic compounds were tested for the inhibition of lung metastasis induced by B16F10 melanoma cells in mice. Oral administration of polyphenols such as curcumin and catechin at concentrations of 200 nmol/kg body weight were found to inhibit the lung metastasis maximally as seen by the reduction in the number of lung tumor nodules (80%). Other polyphenols which inhibited the lung tumor nodule formation were rutin (71.2%), epicatechin (61%), naringin (27.2%) and naringenin (26.1%). The polyphenols which did not inhibit lung tumor nodule formation were quercetin, morin and ellagic acid. Consequent to the inhibition of the lung tumor nodules, the life span of animals treated with polyphenols was also found to be increased. Curcumin (143.85%), catechin (80.81%) and rutin (63.59%) had maximal increase in life span. The results indicate a possible use of these compounds in arresting the metastatic growth of tumor cells.

Topics: Animals; Catechin; Cell Survival; Curcumin; Female; Flavonoids; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Phenols; Polymers; Rutin; Survival Analysis