curcumin and Cell-Transformation--Neoplastic

Oral submucous fibrosis (OSF) is a chronic debilitating disease that has a high risk of malignant transformation. Management of OSF is quite challenging, with no definitive cure being available. This systematic review assessed the available evidence for using curcumin for pain alleviation and clinical improvement in patients with OSF.. A comprehensive search of PubMed/Medline, Scopus, and ISI Web of Science databases was conducted to identify all relevant clinical trials comparing patients receiving curcumin treatment to active and/or nonactive controls for the treatment of OSF.. Six clinical trials comprising 298 patients were included. All studies found curcumin to be effective in the management of OSF. Three studies found significantly higher improvement in burning sensation in the curcumin group compared with controls, whereas 3 other studies found comparable results. With regard to clinical signs, 2 studies showed better improvement in mouth opening in the curcumin group; 3 studies reported no differences in effectiveness; and only 1 study found curcumin to be inferior to conventional therapy.. The available evidence remains inconclusive but suggests that curcumin is a promising effective treatment option for the management of patients with OSF. Further well-designed clinical trials with large sample sizes and adequate follow-up periods are warranted.

Topics: Antineoplastic Agents; Cell Transformation, Neoplastic; Curcumin; Humans; Oral Submucous Fibrosis; Randomized Controlled Trials as Topic; Treatment Outcome

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

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

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

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

Type II topoisomerases are essential enzymes that modulate DNA under- and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase II poisons) in clinical use. Topoisomerase II poisons kill cells by increasing levels of covalent enzyme-cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use also is associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase II-active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type II topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential.

Topics: Animals; Antineoplastic Agents; Catechin; Cell Transformation, Neoplastic; Chromosome Breakage; Curcumin; DNA Topoisomerases, Type II; Genistein; Humans; Infant; Leukemia; Neoplasms, Second Primary; Translocation, Genetic

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

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

Melanoma is the most dangerous type of skin cancer. Despite the rise of public awareness, the incidence rate among the white population has been rising constantly for several decades. Systematic improvement in knowledge about the biology of pigment cells and molecular mechanisms of their neoplastic transformation has enhanced the possibility of melanoma chemoprevention. Hence, chemopreventive agents that prevent, inhibit, or reverse melanoma development are being investigated intensively. Among synthetic compounds, especially well studied are lipid-lowering drugs and cyclooxygenase inhibitors. Substances found in everyday diet, such as genistein, apigenin, quercetin, resveratrol, and curcumin may also have potential chemopreventive qualities. However, studies examining the chemopreventive activity of these compounds have shown widely varying results. Early reports on the possible chemopreventive activity of statins and fibrates were not proved by the results of randomized clinical trials. Similarly, case-control studies examining the influence of NSAIDs on the risk of melanoma do not confirm the antitumor activity of cyclooxygenase inhibitors. Further clinical trials involving carefully selected target populations as well as the identification of specific biomarkers of prognostic and predictive value seem to be essential for the evaluation of the chemopreventive activity of the studied substances.

Topics: Aminoquinolines; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Cell Line, Tumor; Cell Transformation, Neoplastic; Chemoprevention; Curcumin; Flavonoids; Humans; Imiquimod; Melanoma; Melanoma, Cutaneous Malignant; Pigmentation; Randomized Controlled Trials as Topic; Resveratrol; Retinoids; Risk; Skin; Skin Neoplasms; Stilbenes; Tea; Treatment Outcome; Vitamin D

Oral squamous cell carcinoma (OSCC) is a growing global public health problem for which standard therapeutic strategies have failed to contribute significantly to improve the survival rates that have remained around 50% over the past three decades. Therefore, there is a pressing need for new therapeutic strategies. Curcumin is a natural dietary compound with known anti-neoplastic activities, hence its classification as a nutraceutical agent. This review presents the current in vitro and in vivo studies in which curcumin has been examined for its anti-cancer potential in treating OSCC. Its mechanisms of action are also beginning to become unveiled. The available studies have been focusing on the impact of curcumin on epithelial malignant cells, but overlooking the components of the tumor microenvironment. Curcumin has been emerging as a promising therapeutic agent in oral cancer, either alone or in combination with standard therapeutic agents, and will probably become of practical use once its route of administration has overcome its poor bioavailability.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Curcumin; Dietary Supplements; Epithelial Cells; Humans; Mouth Neoplasms; Tumor Microenvironment

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

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

Pancreatic cancer has a poor prognosis and is often diagnosed at an advanced stage, which makes it difficult to treat. The low survival rate of patients with pancreatic cancer points towards an increased need for novel therapeutic and chemopreventive strategies and also early detection of this disease. Increased consumption of fruits and vegetables has been associated with a reduced risk of pancreatic cancer. Synthetic and natural, diet-derived bioactive compounds have been evaluated as pancreatic cancer chemopreventive agents and have demonstrated various degrees of efficacy in cellular and in vivo animal models. Some chemopreventive agents (for example, curcumin or resveratrol) have also been reported to sensitize pancreatic cancer cells to standard chemotherapeutic drugs (for example, gemcitabine or erlotinib), which suggests that chemopreventive agents could potentially be used as potentiators of standard chemotherapy. Few clinical trials of pancreatic cancer chemopreventive agents have been completed and some are in early phases. Further development of pancreatic cancer chemopreventive agents may prove to be tremendously valuable for individuals at high risk of developing pancreatic cancer and patients who present with premalignant lesions. This Review discusses the current state of the pancreatic cancer chemoprevention field and highlights the challenges ahead.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; beta Carotene; Camellia sinensis; Celecoxib; Cell Transformation, Neoplastic; Chemoprevention; Curcumin; Cyclooxygenase 2 Inhibitors; Deoxycytidine; Disease Models, Animal; Down-Regulation; Drug Synergism; Gemcitabine; Humans; Isothiocyanates; Pancreatic Neoplasms; Phototherapy; Pyrazoles; Sulfonamides; Tea; Vitamin D; Vitamin E

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

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

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

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

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

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

A wide variety of phenolic substances derived from spice possess potent antimutagenic and anticarcinogenic activities. Examples are curcumin, a yellow colouring agent, contained in turmeric (Curcuma longa L., Zingiberaceae), [6]-gingerol, a pungent ingredient present in ginger (Zingiber officinale Roscoe, Zingiberaceae) and capsaicin, a principal pungent principle of hot chili pepper (Capsicum annuum L, Solanaceae). The chemopreventive effects exerted by these phytochemicals are often associated with their antioxidative and anti-inflammatory activities. Cyclo-oxygenase-2 (COX-2) has been recognized as a molecular target of many chemopreventive as well as anti-inflammatory agents. Recent studies have shown that COX-2 is regulated by the eukaryotic transcription factor NF-kappaB. This short review summarizes the molecular mechanisms underlying chemopreventive effects of the aforementioned spice ingredients in terms of their effects on intracellular signaling cascades, particularly those involving NF-kappaB and mitogen-activated protein kinases.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antimutagenic Agents; Antioxidants; Capsaicin; Catechols; Cell Transformation, Neoplastic; Curcumin; Cyclooxygenase 2; Fatty Alcohols; Humans; Isoenzymes; Membrane Proteins; Mutagens; NF-kappa B; Prostaglandin-Endoperoxide Synthases; Spices

Topics: Administration, Oral; Administration, Topical; Allyl Compounds; Animals; Anticarcinogenic Agents; Antioxidants; Carcinogens; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cocarcinogenesis; Curcumin; Female; Flavonoids; Humans; Male; Mice; Mice, Inbred SENCAR; Neoplasms, Radiation-Induced; Papilloma; Phenols; Phytotherapy; Plants, Medicinal; Polymers; Reactive Oxygen Species; Resveratrol; Silymarin; Skin Neoplasms; Stilbenes; Sulfides; Tea; Ultraviolet Rays; Zingiber officinale

Breast cancer is a complex multifactorial disease and polymorphisms in nucleotide excision repair pathway are associated with the potential risk of breast cancer. Pathological processes linked to breast cancer are associated with oxidative stress. Catalase plays an essential role in cell defense against oxidative stress. Curcumin has antioxidant activity that can significantly reduce oxidative stress levels. The aims of this study were to determine ERCC5 rs751402 polymorphism was associated with oxidative stress in breast carcinogenesis. The impact of curcumin on catalase activity for inhibiting breast cancer progression was also studied.. The effect of ERCC5 rs751402 polymorphism on oxidative stress was studied with different H2O2 concentrations in HCC 1937 cell line for 24 h and then analysed by MTT assay. The impact of curcumin on catalase activity was studied in MCF-7 cell line treated with different curcumin concentrations for 24 h and then analysed by trypan blue exclusion assay and catalase activity assay.. It showed that this polymorphism involved in oxidative stress (p < 0.05) and curcumin caused the antiproliferative effect by the catalase activity increase (p < 0.05).. Our study indicated that ERCC5 rs751402 polymorphism may contribute to the etiology of breast carcinogenesis about the failure of oxidative stress protection and lead to breast carcinogenesis. The antiproliferative effect of curcumin may be associated with catalase activity and protect breast carcinogenesis.

Topics: Antioxidants; Breast Neoplasms; Carcinoma, Hepatocellular; Catalase; Cell Transformation, Neoplastic; Curcumin; DNA-Binding Proteins; Endonucleases; Female; Humans; Hydrogen Peroxide; Liver Neoplasms; MCF-7 Cells; Nuclear Proteins; Oxidative Stress; Polymorphism, Genetic; Transcription Factors

Multicomponent therapy has gained interest for its potential to synergize and subsequently lower the effective dose of each constituent required to reduce colon cancer risk. We have previously showed that rapidly cycling Lgr5 stem cells are exquisitely sensitive to extrinsic dietary factors that modulate colon cancer risk. In the present study, we quantified the dose-dependent synergistic properties of dietary n-3 polyunsaturated fatty acids (PUFA) and curcumin (Cur) to promote targeted apoptotic deletion of damaged colonic Lgr5 stem cells. For this purpose, both heterogeneous bulk colonocytes and Lgr5 stem cells were isolated from Lgr5-EGFP-IRES-CreER knock-in mice injected with azoxymethane (AOM). Isolated cells were analyzed for DNA damage (γH2AX), apoptosis (cleaved caspase-3), and targeted apoptosis (both γH2AX and cleaved caspase-3) at 12 h post-AOM injection. Comparison of the percentage of targeted apoptosis in Lgr5 stem cells (GFP) across a broad bioactive dose-range revealed an ED50 of 16.0 mg/day n-3 PUFA + 15.9 mg/day Cur. This corresponded to a human equivalent dose of 3.0 g n-3 PUFA + 3.0 g Cur. In summary, our results provide evidence that a low dose (n-3 PUFA + Cur) combination diet reduces AOM-induced DNA damage in Lgr5 stem cells and enhances targeted apoptosis of DNA-damaged cells, implying that a lower human equivalent dose can be utilized in future human clinical trials.

Topics: Animals; Apoptosis; Azoxymethane; Carcinogens; Cell Proliferation; Cell Transformation, Neoplastic; Colon; Colonic Neoplasms; Curcumin; Dietary Supplements; Dose-Response Relationship, Drug; Fatty Acids, Omega-3; Female; Gene Knock-In Techniques; Humans; Intestinal Mucosa; Male; Mice; Mice, Transgenic; Neoplasms, Experimental; Neoplastic Stem Cells; Receptors, G-Protein-Coupled

Tobacco smoke (TS) is the most important single risk factor for bladder cancer. Epithelial-mesenchymal transition (EMT) is a transdifferentiation process, involved in the initiation of TS-related cancer. Cancer stem cells (CSCs) have an essential role in the progression of many tumors including TS-related cancer. However, the molecular mechanisms of TS exposure induced urocystic EMT and acquisition of CSCs properties remains undefined. Wnt/β-catenin pathway is critical for EMT and the maintenance of CSCs. The aim of our present study was to investigate the role of Wnt/β-catenin pathway in chronic TS exposure induced urocystic EMT, stemness acquisition and the preventive effect of curcumin. Long time TS exposure induced EMT changes and the levels of CSCs' markers were significant upregulated. Furthermore, we demonstrated that Wnt/β-catenin pathway modulated TS-triggered EMT and stemness, as evidenced by the findings that TS elevated Wnt/β-catenin activation, and that TS-mediated EMT and stemness were attenuated by Wnt/β-catenin inhibition. Treatment of curcumin reversed TS-elicited activation of Wnt/β-catenin, EMT and CSCs properties. Collectively, these data indicated the regulatory role of Wnt/β-catenin in TS-triggered urocystic EMT, acquisition of CSCs properties and the chemopreventive effect of curcumin.

Topics: Cell Line, Tumor; Cell Transdifferentiation; Cell Transformation, Neoplastic; Curcumin; Epithelial-Mesenchymal Transition; Humans; Neoplastic Stem Cells; Risk Factors; Tobacco Smoking; Urinary Bladder Neoplasms; Wnt Signaling Pathway

Breast cancer is a major cause of global mortality in women. Curcumin exerts anti-proliferative, anti-migratory and apoptotic effects. The aim of this study was to evaluate gene expression involved in epithelial-mesenchymal transition (EMT). An in vitro model was developed with the MCF-10F immortalized breast epithelial cell line exposed to low radiation doses of high LET (linear energy transfer) α-particles (150 keV/µm) and cultured in the presence of 17β-estradiol (estrogen). The following cell lines were used: i) MCF-10F, normal; ii) Alpha5, pre-tumorigenic, and iii) Tumor2 derived from Alpha5 injected into the nude mice. Our previous results have shown that Alpha5 and Tumor2 increased cell proliferation, anchorage independency, invasive capabilities and tumor formation in nude mice in comparison to control. Results indicated that curcumin decreased expression of EMT-related genes in Tumor2 cell line when compared to its counterpart as E-cadherin, N-cadherin, ZEB2, Twist1, Slug, Axl, vimentin, STAT-3, fibronectin; and genes p53 and caveolin-1, as well as apoptotic genes caspase-3, caspase-8, and others such as cyclin D1 and NFκB. All these changes induced a decrease in migratory and invasive capabilities of such a cell line. Thus, it seems that curcumin may impinge upon apoptosis and metastatic properties of the malignant cells exerting antitumor activity in breast cancer cells transformed by low doses of α-particles and estrogen in vitro.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Line; Cell Movement; Cell Transformation, Neoplastic; Curcumin; Epithelial-Mesenchymal Transition; Estrogens; Female; Gene Expression Regulation, Neoplastic; Humans; Mice

To develop injectable formulation and improve the stability of curcumin (Cur), Cur was encapsulated into monomethyl poly (ethylene glycol)-poly (ε-caprolactone)-poly (trimethylene carbonate) (MPEG-P(CL-co-TMC)) micelles through a single-step solid dispersion method. The obtained Cur micelles had a small particle size of 27.6 ± 0.7 nm with polydisperse index (PDI) of 0.11 ± 0.05, drug loading of 14.07 ± 0.94%, and encapsulation efficiency of 96.08 ± 3.23%. Both free Cur and Cur micelles efficiently suppressed growth of CT26 colon carcinoma cells in vitro. The results of in vitro anticancer studies confirmed that apoptosis induction and cellular uptake on CT26 cells had completely increased in Cur micelles compared with free Cur. Besides, Cur micelles were more effective in suppressing the tumor growth of subcutaneous CT26 colon in vivo, and the mechanisms included the inhibition of tumor proliferation and angiogenesis and increased apoptosis of tumor cells. Furthermore, few side effects were found in Cur micelles. Overall, our findings suggested that Cur micelles could be a stabilized aqueous formulation for intravenous application with improved antitumor activity, which may be a potential treatment strategy for colon cancer in the future.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Colonic Neoplasms; Curcumin; Disease Models, Animal; Drug Liberation; Female; Humans; Inhibitory Concentration 50; Micelles; Particle Size; Platelet Endothelial Cell Adhesion Molecule-1; Polymers; Xenograft Model Antitumor Assays

Tobacco smoke (TS) has been shown to cause bladder cancer. Epithelial-mesenchymal transition (EMT) is a crucial pathophysiological process in cancer development. MAPK pathways play central roles in tumorigenesis including EMT process. Curcumin is a promising chemopreventive agent for several types of cancers. In the present study we investigated the effects of TS on MAPK pathway activation and EMT alterations in the bladder of mice, and the preventive effect of curcumin was further examined. Results showed that exposure of mice to TS for 12 weeks resulted in activation of ERK1/2, JNK, p38 and ERK5 MAPK pathways as well as AP-1 proteins in bladder. TS reduced mRNA and protein expression levels of epithelial markers E-cadherin and ZO-1, while mRNA and protein expression levels of the mesenchymal markers vimentin and N-cadherin were increased. Curcumin treatment effectively attenuated TS-triggered activation of ERK1/2, JNK and p38 MAPK pathways, AP-1 proteins and EMT alterations in bladder tissue. These results suggest the protective effects of curcumin in TS-induced MAPK activation and EMT, thus providing new insights into the chemoprevention of TS-associated bladder cancer.

Topics: Animals; Anticarcinogenic Agents; Biomarkers, Tumor; Cell Transformation, Neoplastic; Curcumin; Enzyme Activation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Male; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Phosphorylation; RNA, Messenger; Signal Transduction; Tobacco Smoke Pollution; Urinary Bladder; Urinary Bladder Neoplasms

Combination therapy using two or more small molecule inhibitors of aberrant signaling cascade in aggressive breast cancers is a promising therapeutic strategy over traditional monotherapeutic approaches. Here, we have studied the synergistic mechanism of resveratrol and curcumin induced apoptosis using in vitro (cigarette smoke condensate mediated transformed breast epithelial cell, MCF-10A-Tr) and in vivo (tumor xenograft mice) model system. Resveratrol exposure increased the intracellular uptake of curcumin in a dose dependent manner and caused apoptosis in MCF-10A-Tr cells. Approximately, ten fold lower IC50 value was noted in cells treated with the combination of resveratrol (3μM) and curcumin (3μM) in comparison to 30μM of resveratrol or curcumin alone. Resveratrol+curcumin combination caused apoptosis by increasing Bax/Bcl-xL ratio, Cytochrome C release, cleaved product of PARP and caspase 3 in cells. Interestingly, this combination unaltered the protein expressions of WNT-TCF and Notch signaling components, β-catenin and cleaved notch-1 val1744, respectively. Furthermore, the combination also significantly decreased the intermediates of Hedgehog-Gli cascade including SMO, SHH, Gli-1, c-MYC, Cyclin-D1, etc. and increased the level of p21(Waf/Cip1) in vitro and in vivo. A significant reduction of Gli- promoter activity was noted in combinational drug treated cells in comparison to individual drug treatment. Un-alteration of the expressions of the above proteins and Gli1 promoter activity in p21(Waf/Cip1) knockout cells suggests this combination caused apoptosis through p21(Waf/Cip1). Thus, our findings revealed resveratrol and curcumin synergistically caused apoptosis in cigarette smoke induced breast cancer cells through p2(Waf/Cip1) mediated inhibition of Hedgehog-Gli cascade.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Breast Neoplasms; Cell Line; Cell Transformation, Neoplastic; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; Drug Synergism; Epithelial Cells; Female; Hedgehog Proteins; Humans; Immunoblotting; Mice, Inbred BALB C; Microscopy, Fluorescence; Nicotiana; Resveratrol; RNA Interference; Signal Transduction; Smoke; Stilbenes; Transcription Factors; Xenograft Model Antitumor Assays; Zinc Finger Protein GLI1

Intestinal microbiota influences the progression of colitis-associated colorectal cancer. With diet being a key determinant of the gut microbial ecology, dietary interventions are an attractive avenue for the prevention of colitis-associated colorectal cancer. Curcumin is the most active constituent of the ground rhizome of the Curcuma longa plant, which has been demonstrated to have anti-inflammatory, antioxidative, and antiproliferative properties.. Il10 mice on 129/SvEv background were used as a model of colitis-associated colorectal cancer. Starting at 10 weeks of age, wild-type or Il10 mice received 6 weekly intraperitoneal injections of azoxymethane (AOM) or phosphate-buffered saline (PBS) and were started on either a control or a curcumin-supplemented diet. Stools were collected every 4 weeks for microbial community analysis. Mice were killed at 30 weeks of age.. Curcumin-supplemented diet increased survival, decreased colon weight/length ratio, and, at 0.5%, entirely eliminated tumor burden. Although colonic histology indicated improvement with curcumin, no effects of mucosal immune responses have been observed in PBS/Il10 mice and limited effects were seen in AOM/Il10 mice. In wild-type and in Il10 mice, curcumin increased bacterial richness, prevented age-related decrease in alpha diversity, increased the relative abundance of Lactobacillales, and decreased Coriobacterales order. Taxonomic profile of AOM/Il10 mice receiving curcumin was more similar to those of wild-type mice than those fed control diet.. In AOM/Il10 model, curcumin reduced or eliminated colonic tumor burden with limited effects on mucosal immune responses. The beneficial effect of curcumin on tumorigenesis was associated with the maintenance of a more diverse colonic microbial ecology.

Topics: Animals; Azoxymethane; Carcinogens; Cell Transformation, Neoplastic; Colitis; Colon; Colorectal Neoplasms; Curcumin; Dietary Supplements; Disease Models, Animal; Immunity, Mucosal; Intestinal Mucosa; Mice; Mice, 129 Strain; Mice, Knockout; Microbiota

Drastic increment of skin cancer incidence has driven natural product-based chemoprevention as a promising approach in anticancer drug development. Apart from its traditional usages against various ailments, Ardisia crispa (Family: Myrsinaceae) specifically its triterpene-quinone fraction (TQF) which was isolated from the root hexane extract (ACRH) was recently reported to exert antitumor promoting activity in vitro. This study aimed at determining chemopreventive effect of TQF against chemically-induced mouse skin tumorigenesis as well as elucidating its possible pathway(s).. Mice (n = 10) were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 μl) followed by, a week later, repeated promotion (twice weekly; 20 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 μl). TQF (10, 30 and 100 mg/kg) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application. Upon termination, histopathological and biochemical analysis, as well as Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and transcription factor enzyme-linked immunosorbent assay (ELISA) assays were performed to elucidate the potential mechanism of TQF.. With comparison to the carcinogen control, results revealed that lower dose of TQF (10 mg/kg) conferred antitumor promoting effect via significant (P < 0.05) suppression against lipid peroxidation (LPO), apoptotic index (cell death) and nuclear factor-kappa B (NF-κB), along with reduction of keratinocyte proliferation; whilst its higher dose (100 mg/kg) was found to promote tumorigenesis by significantly (P < 0.05) increasing LPO and apoptotic index, in addition to aggravating keratinocyte proliferation.. This study evidenced that TQF, particularly at its lower dosage (10 mg/kg), ameliorated DMBA/TPA-induced mouse skin tumorigenesis. Though, future investigations are warranted to determine the lowest possible therapeutic dose of TQF in subsequent in vivo chemopreventive studies.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Anticarcinogenic Agents; Ardisia; Cell Transformation, Neoplastic; Chemical Fractionation; Chemoprevention; Curcumin; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Male; Mice; Mice, Inbred ICR; Plant Extracts; Plant Roots; Quinones; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Triterpenes

Curcumin is widely known for its antioxidant, anti-inflammatory, and antiproliferative activities in cell-culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvent oral bioavailability issues, and tested their potential against 17β-estradiol (E2)-mediated mammary tumorigenesis. Female Augustus Copenhagen Irish (ACI) rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2 cm; 200 mg each; 20% drug load) 4 days before grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Curcumin implants were changed after 4.5 months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months, and after the tumor incidence reached >80% (~6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2 ± 1 vs. 5 ± 3; P = 0.001) and tumor volume (184 ± 198 mm(3) vs. 280 ± 141 mm(3); P = 0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity, whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in the presence of E2. Because CYP1A and CYP3A4 metabolize most of the E2 to its noncarcinogenic 2-OH metabolite, and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by high-performance liquid chromatography showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered.

Topics: Absorbable Implants; Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Curcumin; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Cytochrome P-450 CYP3A; Diet; Estrogens; Female; Liver; Mammary Neoplasms, Experimental; Rats; Rats, Inbred ACI; Tissue Distribution

Drug resistance remains an on-going challenge in breast cancer chemotherapy. Combination of two or more drugs is an effective strategy to access context-specific multiple targets and overcome undesirable toxicity that is almost inevitable in single-drug chemotherapy. Many plant food-derived polyphenolic compounds have been proven to modulate many key factors responsible for cancer drug resistance, which makes them a promising group of low toxicity candidates for reversing cancer resistance. In this study, we analyzed the combination effect of two chemopreventive polyphenols, curcumin (Cur) and epigallocatechin-3-gallate (EGCG), in combating resistant breast cancer. Our present results showed that EGCG significantly enhanced the growth inhibition and apoptosis in both doxorubicin (DOX)-sensitive and resistant MCF-7 cells induced by Cur. The mechanism may be related to the further activation of caspase-dependent apoptotic signaling pathways and the enhanced cellular incorporation of Cur by inhibiting P-glycoprotein (P-gp) pump function. Moreover, Cur and EGCG in combination could enhance the toxicity of DOX and increase the intracellular level of DOX in resistant MCF-7 cells. Our findings with this practical combination of Cur and EGCG encourage us to move on to a promising strategy for successful treatment of human breast cancer resistance by combining two low-toxic chemotherapeutic agents from diet.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Caspases; Catechin; Cell Transformation, Neoplastic; Curcumin; Doxorubicin; Drug Combinations; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; MCF-7 Cells; Phytotherapy; Polyphenols; Signal Transduction

This study aimed to evaluate the antimutagenic and anticarcinogenic activity of turmeric essential oil as well as to establish biochemical mechanisms of action. Antimutagenicity testing was accomplished using strains and known mutagens with and without microsomal activation. Anticarcinogenic activity was assessed by topical application of 7, 12 - dimethylbenz[a]anthracene (DMBA) as initiator and 1% croton oil as promoter for the induction of skin papillomas in mice. Inhibition of p450 enzymes by TEO was studied using various resorufins and aminopyrene as substrate. Turmeric essential oil (TEO) showed significant antimutagenic activity (p<0.001) against direct acting mutagens such as sodium azide (NaN3), 4-nitro-O-phenylenediamine (NPD) and N-methyl- N-nitro N'nitrosoguanine (MNNG). TEO was found to have significant antimutagenic effect (>90%) against mutagen needing metabolic activation such as 2-acetamidoflourene (2-AAF). The study also revealed that TEO significantly inhibited (p<0.001) the mutagenicity induced by tobacco extract to Salmonella TA 102 strain. DMBA and croton oil induced papilloma development in mice was found to be delayed and prevented significantly by TEO application. Moreover TEO significantly (P<0.001) inhibited isoforms of cytochrome p450 (CYP1A1, CYP1A2, CYP2B1/2, CYP2A, CYP2B and CYP3A) enzymes in vitro, which are involved in the activation of carcinogens. Results indicated that TEO is antimutagenic and anticarcinogenic and inhibition of enzymes (p450) involved in the activation of carcinogen is one of its mechanisms of action.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antimutagenic Agents; Carcinogens; Cell Transformation, Neoplastic; Chemoprevention; Croton Oil; Curcuma; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Male; Mice; Mice, Inbred BALB C; Mutagenicity Tests; Mutagens; Oils, Volatile; Papilloma; Plant Extracts; Rats; Rats, Wistar; Skin; Skin Neoplasms

Much fewer mice lacking androgen receptor (AR) in the entire body develop bladder cancer (BCa). However, the role of urothelial AR (Uro-AR) in BCa development remains unclear. In the present study, we generated mice that lacked only Uro-AR (Uro-AR(-/y)) to develop BCa by using the carcinogen BBN [N-butyl-N-(4-hydroxybutyl)-nitrosamine] and found that Uro-AR(-/y) mice had a lower incidence of BCa and a higher survival rate than did their wild-type (WT; Uro-AR(+/y)) littermates. In vitro assay also demonstrated that Uro-AR facilitates the neoplastic transformation of normal urothelial cells to carcinoma. IHC staining exhibited less DNA damage, with much higher expression of p53 and its downstream target protein PNCA in Uro-AR(-/y) than that found in WT urothelium, which suggests that Uro-AR may modulate bladder tumorigenesis through p53-PCNA DNA repair signaling. Indeed, Uro-AR(-/y) mice with the transgene, simian vacuolating virus 40 T (SV40T), in the urothelium (Uro-SV40T-AR(-/y)) had a similar incidence of BCa as did their WT littermates (Uro-SV40T-AR(+/y)), and p53 was inactivated by SV40T in both genotypes. Use of the AR degradation enhancer ASC-J9 led to suppression of bladder tumorigenesis, with few adverse effects in the BBN-induced BCa mouse model. Together, these results provide the first direct in vivo evidence that Uro-AR has an important role in promoting bladder tumorigenesis and BCa progression. Targeting AR with ASC-J9 may provide a novel approach to suppress BCa initiation.

Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogenesis; Cell Transformation, Neoplastic; Curcumin; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; DNA Repair; Humans; Mice; Models, Biological; Proliferating Cell Nuclear Antigen; Proteolysis; Receptors, Androgen; Survival Analysis; Tumor Suppressor Protein p53; Urinary Bladder Neoplasms; Urothelium

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

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

More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk-Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk-Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as curcumin, effective in suppressing TCC-induced cellular pre-malignancy.

Topics: Anti-Infective Agents; Antineoplastic Agents; Breast; Breast Neoplasms; Carbanilides; Carcinogens, Environmental; Cell Line; Cell Transformation, Neoplastic; Curcumin; DNA Damage; Female; Humans; MAP Kinase Signaling System; Reactive Oxygen Species

The major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice.. We used the carcinogen DMBA to induce breast tumors in SENCAR mice on control, CCM, DHA, or DHA + CCM diets. Appearance and tumor progression were monitored daily. The tumors were harvested 15 days following their first appearance for morphological and immunohistological analysis. Western analysis was performed to determine expression of maspin and survivin in the tumor tissues. Characterization of tumor growth was analyzed using appropriate statistical methods. Otherwise all other results are reported as mean ± SD and analyzed with one-way ANOVA and Tukey's post hoc procedure.. Analysis of gene microarray data indicates that combined treatment with DHA + CCM altered the profile of "PAM50" genes in the SK-BR-3 cell line from an ER⁻/Her-2⁺ to that resembling a "normal-like" phenotype. The in vivo studies demonstrated that DHA + CCM treatment reduced the incidence of breast tumors, delayed tumor initiation, and reduced progression of tumor growth. Dietary treatment had no effect on breast size development, but tumors from mice on a control diet (untreated) were less differentiated than tumors from mice fed CCM or DHA + CCM diets. The synergistic effects also led to increased expression of the pro-apoptotic protein, maspin, but reduced expression of the anti-apoptotic protein, survivin.. The SK-BR-3 cells and DMBA-induced tumors, both with an ER⁻ and Her-2⁺ phenotype, were affected by the synergistic interaction of DHA and CCM. This suggests that the specific breast cancer phenotype is an important factor for predicting efficacy of these nutraceuticals. The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon the molecular phenotype of the cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Transformation, Neoplastic; Cluster Analysis; Curcumin; Diet; Docosahexaenoic Acids; Drug Synergism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Inhibitor of Apoptosis Proteins; Mammary Neoplasms, Experimental; Mice; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Serpins; Survivin; Tumor Burden; Tumor Microenvironment

Curcumin (diferuloyl methane) is a well known antioxidant that exerts antiproliferative and apoptotic effects. Curcumin effect was evaluated in a breast cancer model that was developed using the immortalized breast epithelial cell line MCF-10F after exposure to low doses of high LET (linear energy transfer) α particles (150 keV/µm) of radiation, and subsequently cultured in the presence of 17β-estradiol (estrogen). This model consisted of human breast epithelial cells in different stages of transformation: i) MCF-10F; ii) Estrogen cell line; iii) a malignant Alpha3 cell line; iv) a malignant and tumorigenic, Alpha5 cell line; and v) a cell line derived from Alpha5 injected into the nude mice that gave rise to Tumor2 cell line. Curcumin decreased anchorage-independent growh in transformed breast cancer cell lines in comparison to their counterparts and increased the percentage of cells from G₀/G₁ with a concomitant increase in G₂/M phases, as well as a decrease in PCNA and Rho-A protein expression. Among the oncogenes, c-Ha-Ras and Ras homologous A (Rho-A) are important cell signaling factors for malignant transformation and to reach their active GTP bound state, Ras proteins must first release bound GDP mediated by a guanine nucleotide releasing factor (GRF). Then curcumin decrease RasGRF1 protein expression in malignant cell lines. Further, differential expression levels of cleaved (ADP) ribose polymerase 1 (PARP-1) and phosphorylated histone H2AX (γ-H2AX) were observed after curcumin treatment. It seems that PARP-1 similar to H2AX, confers cellular protection against radiation and estrogen-induced DNA damage mediated by curcumin. Therefore, targeting either PARP-1 or H2AX may provide an effective way of maximizing the therapeutic value of antioxidants for cancer prevention.

Topics: Actin Cytoskeleton; Anticarcinogenic Agents; Breast; Cell Cycle; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Curcumin; Epithelial Cells; Estrogens; Female; Humans; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; ras-GRF1

Histone deacetylase inhibitors (HDACi) are actively explored as new-generation epigenetic drugs but have low efficacy in cancer monotherapy. To reveal new mechanism for combination therapy, we show that HDACi induce cell death but simultaneously activate tumor-progressive genes to ruin therapeutic efficacy. Combined treatments to target tumorigenesis and HDACi-activated metastasis with low toxic modalities could develop new strategies for long-term cancer therapy.. Because metastasis is the major cause of cancer mortality, we measured cell migration activity and profiled metastasis-related gene expressions in HDACi-treated cancer cells. We developed low toxic combination modalities targeting tumorigenesis and HDACi-activated metastasis for preclinical therapies in mice.. We showed that cell migration activity was dramatically and dose dependently enhanced by various classes of HDACi treatments in 13 of 30 examined human breast, gastric, liver, and lung cancer cell lines. Tumor metastasis was also enhanced in HDACi-treated mice. HDACi treatments activated multiple PKCs and downstream substrates along with upregulated proapoptotic p21. For targeting tumorigenesis and metastasis with immediate clinical impact, we showed that new modalities of HDACi combined drugs with PKC inhibitory agent, curcumin or tamoxifen, not only suppressed HDACi-activated tumor progressive proteins and cell migration in vitro but also inhibited tumor growth and metastasis in vivo.. Treatments of different structural classes of HDACi simultaneously induced cell death and promoted cell migration and metastasis in multiple cancer cell types. Suppression of HDACi-induced PKCs leads to development of low toxic and long-term therapeutic strategies to potentially treat cancer as a chronic disease.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Movement; Cell Survival; Cell Transformation, Neoplastic; Combined Modality Therapy; Curcumin; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Neoplasm Metastasis; Neoplasms; Protein Kinase C; Tamoxifen

Colorectal cancer is the third most common form of malignancy, behind prostate and lung cancers. Despite recent advances in medicine, mortality from colorectal cancer remains high, highlighting the need for improved therapies. Numerous studies have demonstrated increased activation of EGFR and its family members (EGFRs), IGF-1R as well as c-Src in colorectal cancer. The current study was undertaken to examine the effectiveness of combination therapy of dasatinib (BMS-354825; Bristol-Myers Squibb), a highly specific inhibitor of Src family kinases (SFK) and a nontoxic dietary agent; curcumin (diferuloylmethane), in colorectal cancer in in vitro and in vivo experimental models. For the latter, we utilized C57BL/6 APC(Min+/-) mice. Initial in vitro studies revealed synergistic interactions between the two agents. Additionally, we have observed that combination treatment causes a much greater inhibition of the following metastatic processes than either agent alone: (i) colony formation, (ii) invasion through extracellular matrix and (iii) tubule formation by endothelial cells. Dasatinib affects the cell adhesion phenotype of colon cancer HCT-116 cells whereas the combination therapy enhances this effect to a greater extent. Preclinical investigation revealed that the combination therapy to be highly effective causing an over 95% regression of intestinal adenomas in Apc(Min+/-) mice, which could be attributed to decreased proliferation and increased apoptosis. In conclusion, our data suggest that combination treatment of dasatinib and curcumin could be a potential therapeutic strategy for colorectal cancer.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Antineoplastic Agents; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Colonic Neoplasms; CSK Tyrosine-Protein Kinase; Curcumin; Dasatinib; Drug Synergism; Electrophoretic Mobility Shift Assay; Endothelium, Vascular; ErbB Receptors; Female; Humans; Immunoenzyme Techniques; Intestinal Neoplasms; Mice; Mice, Knockout; Neoplasm Invasiveness; Neovascularization, Pathologic; NF-kappa B; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Receptor, IGF Type 1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; src-Family Kinases; Thiazoles; Umbilical Veins

Cholangiocarcinoma (CCA) is a highly metastatic tumor linked to liver fluke infection and consumption of nitrosamine-contaminated foods and is a major health problem especially in South-Eastern Asia. In search for a suitable chemopreventive agents, we investigated the effect of curcumin, a traditional anti-inflammatory agent derived from turmeric (Curcuma longa), on CCA development in an animal model by infection with the liver fluke Opisthorchis viverrini and administration of N-nitrosodimethylamine and fed with curcumin-supplemented diet. The effect of curcumin-supplemented diet on histopathological changes and survival were assessed in relation to NF-κB activation, and the expression of NF-κB-related gene products involved in inflammation, DNA damage, apoptosis, cell proliferation, angiogenesis and metastasis. Our results showed that dietary administration of this nutraceutical significantly reduced the incidence of CCA and increased the survival of animals. This correlated with the suppression of the activation of transcription factors including NF-κB, AP-1 and STAT-3, and reduction in the expression of proinflammatory proteins such as COX-2 and iNOS. The formation of iNOS-dependent DNA lesions (8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine) was inhibited. Curcumin suppressed the expression of proteins related to cell survival (bcl-2 and bcl-xL), proliferation (cyclin D1 and c-myc), tumor invasion (MMP-9 and ICAM-1) and angiogenesis (VEGF), and microvessel density. Induction of apoptotic events as indicated by caspase activation and PARP cleavage was also noted. Our results suggest that curcumin exhibits an anticarcinogenic potential via suppression of various events involved in multiple steps of carcinogenesis, which is accounted for by its ability to suppress proinflammatory pathways.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Base Sequence; Cell Proliferation; Cell Transformation, Neoplastic; Cholangiocarcinoma; Cricetinae; Curcumin; Deoxyribonucleotides; Diet; Electrophoretic Mobility Shift Assay; Immunohistochemistry; Inflammation; Male; Mesocricetus; NF-kappa B

The efficacy of the diphenol curcumin as a cancer chemopreventive agent is limited by its chemical and metabolic instability. Non-enzymatic degradation has been described to yield vanillin, ferulic acid, and feruloylmethane through cleavage of the heptadienone chain connecting the phenolic rings. Here we provide evidence for an alternative mechanism, resulting in autoxidative cyclization of the heptadienone moiety as a major pathway of degradation. Autoxidative transformation of curcumin was pH-dependent with the highest rate at pH 8 (2.2 μM/min) and associated with stoichiometric uptake of O(2). Oxidation was also catalyzed by recombinant cyclooxygenase-2 (COX-2) (50 nm; 7.5 μM/min), and the rate was increased ≈10-fold by the addition of 300 μM H(2)O(2). The COX-2 catalyzed transformation was inhibited by acetaminophen but not indomethacin, suggesting catalysis occurred by the peroxidase activity. We propose a mechanism of enzymatic or autoxidative hydrogen abstraction from a phenolic hydroxyl to give a quinone methide and a delocalized radical in the heptadienone chain that undergoes 5-exo cyclization and oxygenation. Hydration of the quinone methide (measured by the incorporation of O-18 from H(2)(18)O) and rearrangement under loss of water gives the final dioxygenated bicyclopentadione product. When curcumin was added to RAW264.7 cells, the bicyclopentadione was increased 1.8-fold in cells activated by LPS; vanillin and other putative cleavage products were negligible. Oxidation to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs. It is possible, therefore, that oxidative transformation of curcumin, a prominent but previously unrecognized reaction, contributes to its cancer chemopreventive activity.

Topics: Animals; Antineoplastic Agents; Buffers; Cell Transformation, Neoplastic; Cells, Cultured; Curcumin; Cyclooxygenase 2; Humans; Macrophages; Mice; Neoplasms; Oxidation-Reduction; Oxygen; Placental Lactogen; Signal Transduction; Spodoptera

Cigarette smoking is the main risk factor for bladder cancer development. Among the mediators of this effect of smoking is nuclear factor-kappa B. Curcumin suppresses cellular transformation by downregulating the activity of nuclear factor-kappa B. Prima-1 is a compound that induces apoptosis in human tumor cells, restoring the function of mutant p53. Our study aimed to evaluate the effects of curcumin and prima-1 in an animal model of bladder cancer.. Tumor implantation was achieved in six- to eight-week-old female C57BL/6 mice by introducing MB49 bladder cancer cells into the bladder. Intravesical treatment with curcumin and Prima-1 was performed on days 2, 6, 10, and 14. On day 15, the animals were sacrificed. Immunohistochemistry was used to determine the expression of cyclin D1, Cox-2, and p21. Cell proliferation was examined using PCNA.. Animals treated with curcumin exhibited a higher degree of necrosis than animals in other groups. Immunohistochemistry showed reduced expression of cyclin D1 in the curcumin-treated group. All of the cells in mice treated with curcumin were p21 positive, suggesting that the p53 pathway is induced by this compound. Prima-1 did not induce any change in tumor size, necrosis, cell proliferation, or the expression of proteins related to the p53 pathway in this animal model.. Curcumin showed activity in this animal bladder cancer model and probably acted via the regulation of nuclear factor-kappa B and p53. Therefore, curcumin is a good choice for the use in clinical trials to treat superficial bladder cancer as an alternative to bacillus Calmette-Guerin. In contrast, Prima-1 does not seem to have an effect on bladder cancer.

Topics: Animals; Antineoplastic Agents; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Curcumin; Cyclin D1; Cyclooxygenase 2; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Female; Immunohistochemistry; Mice; Mice, Inbred C57BL; Tumor Suppressor Protein p53; Urinary Bladder Neoplasms

Curcumin, a plant polyphenol, is a widely studied chemopreventive agent with demonstrated antitumor activities in preclinical studies and low toxicity profiles in multiple clinical trials against human malignancies. We previously showed that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts. Here we report that an inhibitory activity of curcumin on the antioxidant enzyme thioredoxin reductase-1 (TxnRd1) is required for curcumin-mediated radiosensitization of squamous carcinoma cells. Stable knockdown of TxnRd1 in both HeLa and FaDu cells nearly abolished curcumin-mediated radiosensitization. TxnRd1 knockdown cells showed decreased radiation-induced reactive oxygen species and sustained extracellular signal-regulated kinase 1/2 activation, which we previously showed was required for curcumin-mediated radiosensitization. Conversely, overexpressing catalytically active TxnRd1 in HEK293 cells, with low basal levels of TxnRd1, increased their sensitivity to curcumin alone and to the combination of curcumin and ionizing radiation. These results show the critical role of TxnRd1 in curcumin-mediated radiosensitization and suggest that TxnRd1 levels in tumors could have clinical value as a predictor of response to curcumin and radiotherapy.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Curcumin; Enzyme Activation; Gene Knockdown Techniques; HeLa Cells; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Radiation-Sensitizing Agents; Reactive Oxygen Species; Thioredoxin Reductase 1

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

Curcumin (diferuloylmethane) has chemopreventive and chemotherapeutic potentials against various types of cancers. We have developed a series of curcumin analogs to improve its low bioavailability by enhancing its potentials. The newly synthesized analog GO-Y030 [(1E, 4E)-1,5-bis-(3,5(-bismethoxymethoxyphenyl) penta-1,4-dien-3-one] showed a 30-fold greater growth suppression in vitro via similar molecular mechanisms to curcumin. The availability of this analog was examined by using a mouse model harboring the germ-line mutation of Apc, Apc(580D/+), in vivo. Apc(580D/+) mice had a very limited survival time with an intestinal obstruction due to polyposis. The average tumor number in mice fed GO-Y030 was reduced to 61.2% of those that were fed the basal diet (P < 0.05). Compared with Apc(580D/+) mice fed the basal diet (median survival time = 166.5 days), a significantly prolonged lifespan (213 days) was observed in Apc(580D/+) mice fed GO-Y030. The chemopreventive effect with GO-Y030 was improved, compared with curcumin (191 days). The survival benefit corresponded to the diminished intestinal tumor incidence in Apc(580D/+) mice fed GO-Y030. No adverse reactions were observed, judging from body weight or biochemical data concerning liver and renal damage. Degradation of accumulated beta-catenin with curcumin is one of the major mechanisms of chemoprevention in colorectal carcinogenesis. It was demonstrated that the number of beta-catenin-positive adenoma cells in Apc(580D/+) mice fed GO-Y030 was reduced.

Topics: Adenoma; Animals; Benzene Derivatives; beta Catenin; Cell Transformation, Neoplastic; Colorectal Neoplasms; Curcumin; Disease Models, Animal; Genetic Predisposition to Disease; Ketones; Mice; Molecular Structure; Survival Rate

Inhibition of defined molecular steps of tumorigenesis by natural nontoxic compounds may be an efficient means to tackle the population cancer burden. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively nontoxic plant-derived polyphenol. This review considers the following properties of curcumin: anticancer effects in animal model systems; metabolism; biological structure and pharmacokinetics; biological properties implicated in chemoprevention; antioxidant properties; influences upon Phase I and II carcinogen-metabolizing enzymes; signal transduction properties and the neoplastic phenotype; apoptosis evasion, cell proliferation, de-differentiation, migration and invasion and clinical studies. This review will summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention.

Topics: Antineoplastic Agents; Apoptosis; Cell Transformation, Neoplastic; Curcumin; Humans; Neoplasms

Mouse transformed keratinocytes cultured in the presence of transforming growth factor-beta1 (TGF-beta1) acquire a set of morphological and functional properties giving rise to a more motile phenotype that expresses mesenchymal markers. In this work, we present evidence showing that TGF-beta1 stimulates cellular production of MMP-9 (Gelatinase B), a metalloproteinase that plays an important role in tumoral invasion. Our results demonstrate that TGF-beta1stimulates MMP-9 production and MMP-9 promoter activity in a process that depends of the activation of the Ras-ERK1,2 MAP kinase pathway. The latter was demonstrated by cellular transfection of TGF-beta1-sensitive cells with a RasN17 mutant gene, using PD 098059, a MEK 1,2 inhibitor, and treating cells with anti-sense oligodeoxinucleotides. The enhanced MMP-9 production proved to be an important factor in the acquisition of migratory and invasive properties as shown by the use of a specific inhibitor of MMP-9 (GM6001) that inhibits the TGF-beta1-stimulated invasive and migratory properties of these transformed keratinocytes.

Topics: Animals; Cell Line, Transformed; Cell Transformation, Neoplastic; Curcumin; Dipeptides; Enzyme Inhibitors; Flavonoids; Genes, Reporter; Humans; Imidazoles; Keratinocytes; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Oligodeoxyribonucleotides, Antisense; Promoter Regions, Genetic; Pyridines; ras Proteins; Recombinant Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured

Many environmental chemicals and pesticides have been found to be estrogenic and have been shown to stimulate the growth of estrogen receptor-positive (ER-positive) human breast cancer cells. Since it is difficult to avoid human exposure to environmental estrogens, a potentially important area of research is the development of dietary strategies to prevent the stimulated growth of breast tumors by environmental estrogens. In this context, the inhibitory action of curcumin and a combination of curcumin and isoflavonoids were studied in ER-positive human breast cancer cells (MCF-7 and T47D) and ER-negative MDA-MB-231 cells induced by the pesticide o,p'-DDT and the environmental pollutants 4-nonylphenol and 4-octylphenol. The median inhibitory concentration (IC50) for curcumin in T47D cells was 10 microM when measured at either a 48-hr or a 6-day incubation time. The IC50 value for curcumin was within the 8-10 microM range for inhibiting the growth of T47D cells induced by a 10- microM concentration each of 4-nonylphenol, 4-octylphenol, and o, p'-DDT. The IC50 for curcumin in MCF-7 cells induced by 10 microM of either o,p'-DDT, 4-octylphenol, or 4-nonylphenol were 9, 39, and >50 microM, respectively. A combination of curcumin and isoflavonoids was able to inhibit the induced growth of ER-positive cells up to 95%. For MDA-MB-231 cells, the IC50 for curcumin was 17 microM, which was reduced to 11 microM in the presence of 25 microM genistein. Curcumin and genistein induce drastic changes in the morphological shape of both ER-positive and ER-negative cells. Data presented here indicate that a mixture of curcumin and isoflavonoids is the most potent inhibitor against the growth of human breast tumor cells. These data suggest that combinations of natural plant compounds may have preventive and therapeutic applications against the growth of breast tumors induced by environmental estrogens.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Cell Transformation, Neoplastic; Curcumin; Dose-Response Relationship, Drug; Estrogens; Female; Humans; Isoflavones; Pesticides; Receptors, Estrogen; Tumor Cells, Cultured

The effects of 12 phytopolyphenols, including 3 catechin derivatives, 8 flavanols, and curcumin, on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced transformation in mouse fibroblast cells are described. The location of hydroxyl functional groups at 2', 3', or 4' site(s), especially at the 4' site, as in apigenin, fisetin, morin, myricetin, and quercetin, seems essential for anti-TPA-induced transformation, anti-protein kinase C (PKC) activation, and anti-TPA-induced c-jun expression activities. Among the catechin derivatives, those with a cis form structure and with an additional hydroxyl group at the R1 site and galloyl groups at the R2 site, such as epigallocatechin gallate, have stronger inhibitory effects on the above-mentioned biochemical activities. Considering their polarities and chemical structures, these compounds have different oxygen radical absorbance capacity in the in vitro assay. In addition, curcumin also has these inhibitory effects on the above-mentioned biochemical activities and antioxidant activities for peroxyl radical but not hydroxyl radical. In addition to PKC activation, active oxygen species production, and c-jun induction, our data suggest that TPA treatment induces cellular transformation by other unknown routes, because some tested compounds have an inhibitory effect on TPA-induced transformation but have no or a slight inhibitory effect on PKC activation, active oxygen species production, and c-jun induction.

Topics: 3T3 Cells; Animals; Carcinogens; Catechin; Cell Line; Cell Transformation, Neoplastic; Curcumin; Down-Regulation; Fibroblasts; Flavonoids; Flavonols; Gene Expression Regulation, Neoplastic; Genes, jun; Mice; Phenols; Polymers; Protein Kinase C; Tetradecanoylphorbol Acetate

Commercial grade curcumin (approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemethoxycurcumin) is widely used as a yellow coloring agent and spice in foods. In the present study topical application of commercial grade curcumin, pure curcumin or demethoxycurcumin had an equally potent inhibitory effect on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases in ornithine decarboxylase activity and TPA-induced tumor promotion in 7,12-dimethylbenz[a]anthracene-initiated mouse skin. Bisdemethoxycurcumin and tetrahydrocurcumin were less active. In additional studies we found that commercial grade curcumin, pure curcumin, demethoxycurcumin and bisdemethoxycurcumin had about the same potent inhibitory effect on TPA-induced inflammation of mouse ears, as well as TPA-induced transformation of cultured JB6 (P+) cells. Tetrahydrocurcumin was less active. The results indicate that pure curcumin and demethoxycurcumin (the major constituents of commercial grade curcumin) have the same potent inhibitory effects as commercial grade curcumin for inhibition of TPA-induced tumor promotion, but bisdemethoxycurcumin and tetrahydrocurcumin are less active.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Cell Line; Cell Transformation, Neoplastic; Coumaric Acids; Curcumin; Diarylheptanoids; Dose-Response Relationship, Drug; Enzyme Induction; Female; Mice; Mice, Inbred Strains; Ornithine Decarboxylase; Skin; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Time Factors

Expression of c-jun protein (c-Jun) was observed in normally proliferating JB6 cells but not in confluent cells. Reduction of the serum concentration from 5% to 2% in the cell culture medium caused JB6 cells to enter a quiescent non-proliferating state and down-regulated the expression of c-Jun. Treatment of quiescent JB6 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) (10 ng/ml) for 24 h markedly stimulated the formation of c-Jun and caused morphological changes. Treatment of JB6 cells with TPA for 48 h resulted in transformed foci with mixed cell populations. Although some cells in these foci expressed high levels of c-Jun, many other cells did not. The increased expression of c-Jun and morphological changes observed at 24 h after treatment of JB6 cells with TPA (10 ng/ml) was inhibited by curcumin (10 nmol/ml). Treatment of JB6 cells with 2.5, 5 or 10 nmol curcumin/ml inhibited the formation of TPA-induced anchorage-independent colonies that grow in soft agar by 31%, 43% and 77%, respectively. Although inhibition of cell proliferation was not observed with 2.5 nmol curcumin/ml, higher concentrations did inhibit cell proliferation. Topical application of 5 nmol TPA to the backs of CD-1 mice once a day for 5 days caused epidermal hyperplasia and the levels of c-Jun were increased in the suprabasal layer of the epidermis and in the muscle layer of the dermis. This treatment also increased c-fos protein (c-Fos) expression in the muscle layer, but there was little or no increase in the expression of c-Fos in the basal or suprabasal layer of the epidermis. Topical application of 10 mumol curcumin together with 5 nmol TPA once a day for 5 days strongly inhibited TPA-induced epidermal hyperplasia and c-Jun and c-Fos expression. A single application of 180 mJ/cm2 of ultraviolet B light (UVB) to the backs of SKH-1 mice caused epidermal hyperplasia and expression of c-Fos and c-Jun in the muscle layer of the dermis and of c-Fos in the suprabasal layer of the epidermis. Maximum effects were observed at 6 days after UVB exposure. Application of 10 mumol curcumin to mouse skin twice a day for 5 days immediately after UVB exposure had only a small/variable inhibitory effect on UVB-induced increases in the expression of c-Fos and c-Jun and on epidermal hyperplasia.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Cocarcinogenesis; Curcumin; Drug Interactions; Female; Gene Expression Regulation; Hyperplasia; Mice; Mice, Hairless; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Ultraviolet Rays