stilbenes and Cell-Transformation--Neoplastic

Preclinical and clinical studies have offered evidence for protective effects of various polyphenol-rich foods against cardiovascular diseases, neurodegenerative diseases, and cancers. Resveratrol is among the most widely studied polyphenols. However, the preventive and treatment effectiveness of resveratrol in cancer remain controversial because of certain limitations in existing studies. For example, studies of the activity of resveratrol against cancer cell lines in vitro have often been conducted at concentrations in the low μM to mM range, whereas dietary resveratrol or resveratrol-containing wine rarely achieve nM concentrations in the clinic. While the mechanisms underlying the failure of resveratrol to inhibit cancer growth in the intact organism are not fully understood, the interference by thyroid hormones with the anticancer activity of resveratrol have been well documented in both in vitro and xenograft studies. Thus, endogenous thyroid hormones may explain the failure of anticancer actions of resveratrol in intact animals, or in the clinic. In this review, mechanisms involved in resveratrol-induced antiproliferation and effects of thyroid hormones on these mechanisms are discussed.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Cell Transformation, Neoplastic; Humans; Neoplasms; Resveratrol; Signal Transduction; Stilbenes; Thyroid Hormones; Treatment Failure

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

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

This review summarizes our current understanding of the role of MTA family members, particularly MTA1, with a special emphasis on prostate cancer. The interest for the role of MTA1 in prostate cancer was boosted from our initial findings of MTA1 as a component of "vicious cycle" and a member of bone metastatic signature. Analysis of human prostate tissues, xenograft and transgenic mouse models of prostate cancer, and prostate cancer cell lines has provided support for the role of MTA1 in advanced disease and its potential role in initial stages of prostate tumor progression. Recent discoveries have highlighted a critical role for MTA1 in inflammation-triggered prostate tumorigenesis, epithelial-to-mesenchymal transition, prostate cancer survival pathways, and site metastasis. Evidence for MTA1 as an upstream negative regulator of tumor suppressor genes such as p53 and PTEN has also emerged. MTA1 is involved in prostate tumor angiogenesis by regulating several pro-angiogenic factors. Evidence for MTA1 as a prognostic marker for aggressive prostate cancer and disease recurrence has been described. Importantly, pharmacological dietary agents, namely resveratrol and its analogs, are potentially applicable to prostate cancer prevention, treatment, and control of cancer progression due to their potent inhibitory effects on MTA proteins.

Topics: Animals; Cell Transformation, Neoplastic; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Histone Deacetylases; Humans; Male; Mice; Molecular Targeted Therapy; Neovascularization, Pathologic; Prostatic Neoplasms; Repressor Proteins; Resveratrol; Stilbenes; Trans-Activators

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

During the last decade, studies aimed at investigating genes and molecular pathways involved in aging have been very fruitful and led to the identification of several mechanisms responsible for aging. Overall, those results put forward the capacity of cells and organisms to sense and respond to stress, as a critical factor for a healthy and long life. Those molecular pathways are tightly linked with the overall metabolism of an organism. Indeed, environmental stresses trigger a plethora of defense mechanisms which are energy demanding while still the organism has to allocate energy for the maintenance of basic functions. So all along our life, we have to adapt to different stresses while optimizing energy use. This review aims at highlighting data from the literature that support the crucial role of metabolism as a modulator of aging and age-associated disease, as illustrated by the beneficial effect of dietary restriction on longevity and cancer development.

Topics: Aging; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Caloric Restriction; Cell Transformation, Neoplastic; Drosophila melanogaster; Energy Metabolism; Homeostasis; Humans; Insulin; Insulin-Like Growth Factor I; Longevity; Membrane Transport Proteins; Mice; Models, Biological; Neoplasms; Protein Kinases; Resveratrol; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases

Resveratrol (3,4',5-trihydroxystilbene) is found in various plants, including grapes, berries and peanuts. It is also present in wines, especially red wines. During the last years, it has been the focus of numerous in vitro and in vivo studies investigating its biological attributes, which include mainly antioxidant and anti-inflammatory activities, anti-platelet aggregation effect, anti-atherogenic property, oestrogen-like growth-promoting effect, growth-inhibiting activity, immunomodulation and chemoprevention. In fact, recently, it has been demonstrated that the stilbene blocks the multistep process of carcinogenesis at various stages: tumour initiation, promotion and progression. More recent results provide interesting insights into the effect of this compound on the life span of yeasts and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. Nevertheless, depending on the concentration of the phytoalexin and the cell type, it has also been shown that resveratrol can exhibit pro-oxidant properties, leading to oxidative breakage of cellular DNA in the presence of transition metal ions such as copper. Recently, it has been proposed that such a pro-oxidant action could be a common mechanism for anticancer and chemopreventive properties of plant polyphenols. The present paper is intended to provide the reader up-to-date information on the antioxidant and pro-oxidant properties of resveratrol and its clinical implications.

Topics: Antioxidants; Cell Transformation, Neoplastic; Humans; Nitrogen; Oxidation-Reduction; Reactive Oxygen Species; Resveratrol; Stilbenes

Resveratrol is a phytoalexin produced by many plants, and the skin of red grapes is particularly rich in resveratrol which accounts for the "French Paradox". Besides its protection of the cardiovascular system, it can affect the processes underlying all three stages of carcinogenesis, involving tumor initiation, promotion and progression. It has also been shown to suppress angiogenesis and metastasis. The anti-carcinogenic effects of resveratrol appear to be closely associated with its capacity to interact with multiple molecular targets involved in cancer development, while minimizing toxicity in normal tissues as tested. By reviewing many in vitro and in vivo studies, also considering both the supporting and challenging evidences, we are provided with a theory in support of the use of resveratrol in human cancer chemoprevention, in combination with either chemotherapeutic drugs or cytotoxic factors for the highly efficient treatment of drug refractory tumor cells. Anti-carcinogenic potential for cancer chemoprevention and anticancer therapy, which is one of the pleiotropic effects of resveratrol, is so called a new enlightenment of French Paradox.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Cardiovascular Diseases; Cell Line, Tumor; Cell Transformation, Neoplastic; Clinical Trials as Topic; Diet; Europe; France; Gene Expression Regulation, Neoplastic; Humans; Incidence; Mice; Mice, Inbred A; Neoplasms; Resveratrol; Stilbenes; Wine

Thyroid tumorigenesis and carcinogenesis accompany progressive loss of thyroid-specific differentiated functions. Some thyroid cancers are or become dedifferentiated, and they become refractory to efficacy-proven conventional therapies such as radioiodine ablation therapy and thyrotropin (TSH)-suppressive therapy. Redifferentiation therapy by either redifferentiating agents or gene transfer of differentiation-related genes may retard tumor growth and make tumors respond to conventional therapies.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Cell Transformation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Phenylacetates; Phenylbutyrates; Receptors, Cytoplasmic and Nuclear; Resveratrol; Retinoids; Stilbenes; Thyroid Neoplasms; Transcription Factors

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

Resveratrol, a phytoalexin found in grapes and wines, has been reported to exhibit a wide range of pharmacological properties and is believed to play a role in the prevention of human cardiovascular disease (the so-called 'French paradox'). This molecule may also play a major role in both cancer prevention and therapy. In this review article we summarize the recent advances that have provided new insights into the molecular mechanisms underlying the promising properties of resveratrol. These include cyclooxygenase, nitric oxide synthase and cytochrome P450 inhibition, as well as cell cycle effects, apoptosis modulation and hormonal activity.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Cell Transformation, Neoplastic; Humans; Neoplasms; Resveratrol; Stilbenes

Chemoprevention can be defined as the use of substances to interfere with the process of cancer development. Although substantial progress has been made in elucidating the basis of carcinogenesis, further advances are needed to identify molecular and cellular targets for effective use of chemopreventive agents. Hundreds of compounds have been identified as potential chemopreventive agents. However, the safety and efficacy of each substance must be thoroughly investigated. Carcinogenesis is a multistage process in which numerous genes are affected. Many of these genes regulate important cellular functions, so they are prime targets for chemopreventive agents. A major focus of our work has been the elucidation of mechanism(s) explaining the anticancer actions attributed to several chemopreventive compounds, especially 'natural compounds' that are considered safe because they are present in commonly consumed foods and beverages. Of particular interest are selected drugs (eg aspirin) and certain dietary factors (eg green and black tea, resveratrol) and their influence on cell-signalling events coinciding with skin cancer promotion. This overview describes recent work from our laboratory and others focusing on molecular mechanisms of selected chemopreventive compounds in growth-related signal transduction pathways and skin cancer.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Cell Transformation, Neoplastic; Disease Models, Animal; Humans; Isothiocyanates; NF-kappa B; Phytic Acid; Resveratrol; Signal Transduction; Skin Neoplasms; Stilbenes; Tea; Transcription Factor AP-1

The use of an optical resolution photoacoustic microscopy (OR-PAM) system to evaluate the vascular disruptive effect of combretastatin A4 Phosphate (CA4P) on a murine orthotopic glioma with intact skull is described here. Second generation optical-resolution photoacoustic microscopy scanner with a 532 nm pulsed diode-pumped solid-state laser that specifically matches the absorption maximum of hemoglobin in tissues was used to image orthotopic glioma inoculated in mouse brain. Two-dimensional maps of brain vasculature with a lateral resolution of 5 μm and a depth of 700 μm at a field of view 5 × 4 mm were acquired on normal brain and glioma brain. Longitudinal imaging of the brain pre- and post-administration of CA4P, a FDA approved drug for solid tumors, enabled the monitoring of hemodynamic changes in tumor vasculature revealing the well documented vascular shutdown and recovery associated with this drug. Our study marks the beginning of potential prospects of this technology as an imaging tool for preclinical and clinical study of pathologies characterized by changes in the vasculature.

Topics: Animals; Blood Vessels; Brain Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Female; Glioma; Humans; Mice; Microscopy; Neovascularization, Pathologic; Photoacoustic Techniques; Stilbenes

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) presents adverse effects on breast development/carcinogenesis. This study aimed to identify the ability of resveratrol (Res) to modify the adverse effects of TCDD in a female offspring. Pregnant female Wistar rats were allocated into four groups: TCDD, TCDD + Res, Res, and control. TCDD (1 μg/kg) was orally administered as a single dose on gestational day (GD) 15, and Res was orally administered during GD10-21 and lactation at a dose of 20 mg/kg/day. Female offsprings were euthanized on a specific postnatal day (PND) for hormonal analysis (PND 22, 48-51), vaginal opening (PND 30-48), and mammary gland morphology (PND 22). Other females received two doses of N-nitroso-N-methylurea (MNU, 50 mg/kg) on PNDs 22 and 51 and were euthanized on PND 24 (Ki-67, ER-α and apoptosis indexes or molecular analysis) or PND 180 (tumor assay). TCDD exposure altered the development of the mammary structure while these alterations were partially improved by maternal Res. Two days after first MNU administration, some genes associated with apoptosis were altered in the mammary tissue from the TCDD group (Bax and Caspase 3 down- and Bcl-2 upregulated) but were also partially reestablished by maternal Res. Mammary gland bcl-2 and bcl-xl proteins expression was increased while the apoptosis index was reduced by TCDD exposure but restored by maternal Res. An increase in number of mammary tumors was observed in female offspring from the TCDD group compared to the other groups. The results indicate that most mammary changes induced in female offspring through TCDD exposure or after MNU administrations were reduced by maternal resveratrol treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Models, Animal; Female; Hormones; Male; Maternal Exposure; Polychlorinated Dibenzodioxins; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Resveratrol; Stilbenes; Teratogens; Tumor Burden

The present study is aimed to evaluate the inhibitory effect of the combination of two phytochemicals; pterostilbeneand lupeol (generally obtained from blue berries, grapes, white cabbage, green pepper, olive and mangoes) on mouse skin tumorigenesis. We hypothesized that the concomitant topical treatment of selected phytochemicals would lead to improved impediment of skin cancer. Swiss albino mice (n = 25) received a topical dose of Benzo[a]pyrene (B[a]P, 5 μg/animal) with pre/post application of pterostilbene (16 μM/0.2 ml acetone/animal) and/or lupeol (500 μM/0.2 ml acetone/animal) for 32 weeks. Results showed that pterostilbene and/or lupeol treatment resulted in a significant delay in onset of tumorigenesis. However, a more promising effect on tumor suppression was noted with the combination of both the phytochemicals. A significant reduction in average tumor volume, cumulative number of tumors and tumor multiplicity was recorded in combination treated group. The histopathological analysis illustrated the marked suppression in epidermal hyperplasia and necrotic cells in combination treated groups. Our study suggests that the combination of pterostilbene and lupeol was more effective in prevention of skin cancer as compared to either of the phytochemical alone. Therefore, the combined treatment of phytochemicals has better potential to prevent skin carcinogenesis.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Benzo(a)pyrene; Cell Cycle; Cell Transformation, Neoplastic; DNA Damage; Flow Cytometry; Immunoenzyme Techniques; Male; Mice; Pentacyclic Triterpenes; Pterocarpus; Skin Neoplasms; Stilbenes

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

Glioblastoma is a malignant human cancer that confers a dismal prognosis. Ionizing radiation (IR) is applied as the standard treatment for malignant gliomas. However, radiotherapy remains merely palliative because of the existence of glioma stem cells (GSCs), which are regarded as highly radioresistant "seed" cells. In this study, the effect and possible mechanisms of radiotherapy in combination with resveratrol (Res) were investigated in a radioresistant GSC line, SU-2. Our results showed that Res inhibited SU-2 proliferation and enhanced radiosensitivity as indicated by clonogenic survival assay. We also observed a decrease in the expression of neural stem cell marker CD133, which indicated that treatment with Res and IR induced SU-2 cell differentiation. In addition, the combination of Res with IR significantly increased autophagy and apoptosis levels in both in vitro cells and nude mouse model. Finally, Res significantly attenuated the repair of radiation-induced DNA damage. Taken together, the present study demonstrated that the significant radiosensitization ability of Res both in vitro and in vivo was attributed to its synergistic antitumor effects, including inhibition of self-renewal and stemness, induction of autophagy, promotion of apoptosis, and prevention of DNA repair. Therefore, Res may function as a radiation sensitizer for malignant glioma treatment.

Topics: AC133 Antigen; Animals; Antigens, CD; Apoptosis; Autophagy; Biomarkers, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Disease Models, Animal; DNA Damage; Glioblastoma; Glycoproteins; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Peptides; Radiation Tolerance; Radiation-Sensitizing Agents; Resveratrol; Stilbenes; Tumor Cells, Cultured

Cigarette smoking is a key factor for the development and progression of different cancers including mammary tumor in women. Resveratrol (Res) is a promising natural chemotherapeutic agent that regulates many cellular targets including p21, a cip/kip family of cyclin kinase inhibitors involved in DNA damage-induced cell cycle arrest and blocking of DNA replication and repair. We have recently shown that cigarette smoke condensate (CSC) prepared from commercially available Indian cigarette can cause neoplastic transformation of normal breast epithelial MCF-10A cell. Here we studied the mechanism of Res mediated apoptosis in CSC transformed (MCF-10A-Tr) cells in vitro and in vivo. Res mediated apoptosis in MCF-10A-Tr cells was a p21 dependent event. It increased the p21 protein expression in MCF-10A-Tr cells and MCF-10A-Tr cells-mediated tumors in xenograft mice. Res treatment reduced the tumor size(s) and expression of anti-apoptotic proteins (e.g. PI3K, AKT, NFκB) in solid tumor. The expressions of cell cycle regulatory (Cyclins, CDC-2, CDC-6, etc.), BER associated (Pol-β, Pol-δ, Pol-ε, Pol-η, RPA, Fen-1, DNA-Ligase-I, etc.) proteins and LP-BER activity decreased in MCF-10A-Tr cells but remain significantly unaltered in isogenic p21 null MCF-10A-Tr cells after Res treatment. Interestingly, no significant changes were noted in SP-BER activity in both the cell lines after Res exposure. Finally, it was observed that increased p21 blocks the LP-BER in MCF-10A-Tr cells by increasing its interaction with PCNA via competing with Fen-1 after Res treatment. Thus, Res caused apoptosis in CSC-induced cancer cells by reduction of LP-BER activity and this phenomenon largely depends on p21.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Death; Cell Line, Transformed; Cell Transformation, Neoplastic; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Epithelial Cells; Female; Flap Endonucleases; Humans; Mammary Glands, Human; Mice; Mice, Inbred BALB C; Proliferating Cell Nuclear Antigen; Resveratrol; RNA Interference; Signal Transduction; Smoke; Smoking; Stilbenes; Time Factors; Transfection; Up-Regulation; Xenograft Model Antitumor Assays

The cancer chemopreventive property of Chinese herb new isolate isorhapontigenin (ISO) and mechanisms underlying its activity have never been explored. Here we demonstrated that ISO treatment with various concentrations for 3 weeks could dramatically inhibit TPA/EGF-induced cell transformation of Cl41 cells in Soft Agar assay, whereas co-incubation of cells with ISO at the same concentrations could elicit G0/G1 cell-cycle arrest without redundant cytotoxic effects on non-transformed cells. Further studies showed that ISO treatment resulted in cyclin D1 downregulation in dose- and time-dependent manner. Our results indicated that ISO regulated cyclin D1 at transcription level via targeting JNK/C-Jun/AP-1 activation. Moreover, we found that ISO-inhibited JNK/C-Jun/AP-1 activation was mediated by both upregulation of MKP-1 expression through increasing its mRNA stability and deactivating MKK7. Most importantly, MKP-1 knockdown could attenuate ISO-mediated suppression of JNK/C-Jun activation and cyclin D1 expression, as well as G0/G1 cell cycle arrest and cell transformation inhibition, while ectopic expression of FLAG-cyclin D1 T286A mutant also reversed ISO-induced G0/G1 cell-cycle arrest and inhibition of cell transformation. Our results demonstrated that ISO is a promising chemopreventive agent via upregulating mkp-1 mRNA stability, which is distinct from its cancer therapeutic effect with downregulation of XIAP and cyclin D1 expression.

Topics: Animals; Blotting, Western; Cell Adhesion; Cell Cycle Checkpoints; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Cyclin D1; Dual Specificity Phosphatase 1; Epidermis; Flow Cytometry; G1 Phase; Luciferases; Mice; Phosphorylation; Real-Time Polymerase Chain Reaction; Resting Phase, Cell Cycle; Reverse Transcriptase Polymerase Chain Reaction; RNA Stability; RNA, Messenger; Stilbenes

The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol (Res), a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism(s) of Res-mediated protection against estrogen-induced breast carcinogenesis. Female August Copenhagen Irish rats were treated with 17β-estradiol (E2), Res and Res + E2 for 8 months. Cotreatment of rats with Res and E2 inhibited E2-mediated proliferative changes in mammary tissues and significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment alone or in combination with E2 significantly upregulated expression of nuclear factor erythroid 2-related factor 2 (NRF2) in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3 and OGG1 that are involved in protection against oxidative DNA damage was increased in Res- and Res + E2-treated mammary tissues. Resveratrol also prevented E2-mediated inhibition of detoxification genes AOX1 and FMO1. Inhibition of E2-mediated alterations in NRF2 promoter methylation and expression of NRF2 targeting miR-93 after Res treatment indicated Res-mediated epigenetic regulation of NRF2 during E2-induced breast carcinogenesis. Resveratrol treatment also induced apoptosis and inhibited E2-mediated increase in DNA damage in mammary tissues. Increased apoptosis and decreased DNA damage, cell migration, colony and mammosphere formation in Res- and Res + E2-treated MCF-10A cells suggested a protective role of Res against E2-induced mammary carcinogenesis. Small-interfering RNA-mediated silencing of NRF2 inhibited Res-mediated preventive effects on the colony and mammosphere formation. Taken together, these results suggest that Res inhibits E2-induced breast carcinogenesis via induction of NRF2-mediated protective pathways.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Apoptosis; Blotting, Western; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; DNA Methylation; Epigenesis, Genetic; Estrogens; Female; Humans; Mammary Neoplasms, Experimental; NF-E2-Related Factor 2; Rats, Inbred ACI; Rats, Inbred Strains; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Stilbenes; Tumor Cells, Cultured

Resveratrol has been widely reported to reduce cancer progression in model systems and to selectively induce cell death in transformed cell lines. Many enzymes have been reported to respond to resveratrol in mammalian cells, including the Ataxia-Telangiectasia Mutated (ATM) protein kinase that acts in DNA damage recognition, signaling, and repair. Here we investigate the responses of ATM to resveratrol exposure in normal and transformed human cell lines and find that ATM autophosphorylation and substrate phosphorylation is stimulated by resveratrol in a manner that is promoted by reactive oxygen species (ROS). We observe direct stimulatory effects of resveratrol on purified ATM in vitro and find that the catalytic efficiency of the kinase on a model substrate is increased by resveratrol. In the purified system we also observe a requirement for oxidation, as the effect of resveratrol on ATM signaling is substantially reduced by agents that prevent disulfide bond formation in ATM. These results demonstrate that resveratrol effects on ATM are direct, and suggest a mechanism by which the oxidizing environment of transformed cells promotes ATM activity and blocks cell proliferation.

Topics: Antioxidants; Ataxia Telangiectasia Mutated Proteins; Bleomycin; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; HCT116 Cells; HEK293 Cells; Humans; Hydrogen Peroxide; Oxidants; Phosphorylation; Reactive Oxygen Species; Resveratrol; Signal Transduction; Stilbenes

Sporadic and non-hereditary mutations account for the majority of colorectal cancers (CRC). After the loss of adenomatous polyposis coli (APC) function and activation of the β-catenin/LEF signaling pathway, activating mutations in Kras are major drivers of sporadic CRC. Preventing the outgrowth of cells that develop sporadic mutations will decrease CRC. Resveratrol, a naturally occurring polyphenolic compound has anti-inflammatory, anti-oxidant and anti-cancer activities. We used a genetically engineered mouse model for sporadic CRC where the APC locus is knocked out and Kras is activated specifically in the distal colon to determine the effects of resveratrol on preventing and treating CRC. Feeding mice a diet supplemented with 150 or 300 ppm resveratrol (105 and 210mg daily human equivalent dose, respectively) before tumors were visible by colonoscopy resulted in a 60% inhibition of tumor production. In the 40% of mice that did develop tumors Kras expression was lost in the tumors. In a therapeutic assay where tumors were allowed to develop prior to treatment, feeding tumor bearing mice with resveratrol resulted in a complete remission in 33% of the mice and a 97% decrease in tumor size in the remaining mice. Analysis of miRNA expression in non-tumoral and tumoral colonic tissue of resveratrol treated mice showed an increased expression of miR-96, a miRNA previously shown to regulate Kras translation. These data indicate that resveratrol can prevent the formation and growth of colorectal tumors by downregulating Kras expression.

Topics: Adenomatous Polyposis Coli Protein; Animals; Anticarcinogenic Agents; Blotting, Western; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; Disease Models, Animal; Female; Humans; Immunoenzyme Techniques; Male; Mice; Mice, Knockout; Mutation; Proto-Oncogene Proteins p21(ras); Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Tumor Cells, Cultured

The protein deacetylase SIRT1 is involved in the regulation of a large number of cellular processes that are thought to be required for cancer initiation and progression. Both SIRT1 activity and tumorigenesis can be influenced by dietary fat and polyphenolics. We set out to determine whether dietary modulations of tumorigenesis are mediated by SIRT1 catalytic functions. We introduced a mammary gland tumor-inducing transgene, MMTV-PyMT, into stocks of mice bearing a H355Y point mutation in the Sirt1 gene that abolishes SIRT1 catalytic activity. Tumor latency was reduced in animals fed a high fat diet but this effect was not dependent on SIRT1 activity. Resveratrol had little effect on tumor formation except in animals heterozygous for the mutant Sirt1 gene. We conclude that the effects of these dietary interventions on tumorigenesis are not mediated by modulation of SIRT1 catalytic activity.

Topics: Analysis of Variance; Animals; Antigens, Polyomavirus Transforming; Antineoplastic Agents, Phytogenic; Biocatalysis; Cell Transformation, Neoplastic; Diet, High-Fat; Heterozygote; Male; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; Mice, Transgenic; Point Mutation; Resveratrol; Sirtuin 1; Stilbenes; Tumor Burden

Quantitative characterization of the in vivo effects of vascular-targeted therapies on tumor vessels is hampered by the absence of useful 3D vascular network descriptors aside from microvessel density. In this study, we extended the quantification of planar vessel distribution to the analysis of vascular volumes by studying the effects of antiangiogenic (sorafenib and sunitinib) or antivascular (combretastatin A4 phosphate) treatments on the quantity and spatial distributions of thin microvessels. These observations were restricted to perinecrotic areas of treated human multiple myeloma tumors xenografted in immunodeficient mice and to microvessels with an approximate cross-sectional area lower than 75 µm(2). Finally, vessel skeletonization minimized artifacts due to possible differential wall staining and allowed a comparison of the various treatment effects. Antiangiogenic drug treatment reduced the number of vessels of every caliber (at least 2-fold fewer vessels vs. controls; p<0.001, n = 8) and caused a heterogeneous distribution of the remaining vessels. In contrast, the effects of combretastatin A4 phosphate mainly appeared to be restricted to a homogeneous reduction in the number of thin microvessels (not more than 2-fold less vs. controls; p<0.001, n = 8) with marginal effects on spatial distribution. Unexpectedly, these results also highlighted a strict relationship between microvessel quantity, distribution and cross-sectional area. Treatment-specific changes in the curves describing this relationship were consistent with the effects ascribed to the different drugs. This finding suggests that our results can highlight differences among vascular-targeted therapies, providing hints on the processes underlying sample vascularization together with the detailed characterization of a pathological vascular tree.

Topics: Animals; Antineoplastic Agents; Artifacts; Cell Line, Tumor; Cell Transformation, Neoplastic; Female; Humans; Imaging, Three-Dimensional; Lymphoma; Mice; Mice, Inbred NOD; Mice, SCID; Microvessels; Molecular Targeted Therapy; Neovascularization, Pathologic; Stilbenes

Excess estrogen stimulates the proliferation of mammary epithelial cells and hence represents a major risk factor for breast cancer. Estrogen is subjected to cytochrome P450-catalysed oxidative metabolism to produce an oncogenic catechol estrogen, 4-hydroxyestradiol (4-OHE₂). 4-OHE₂ undergoes redox cycling during which reactive oxygen species (ROS) as well as the chemically reactive estrogen semiquinone and quinone intermediates are produced, thereby contributing to hormonal carcinogenesis. Resveratrol (3,4',5-trihydroxy stilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the inhibitory effects of resveratrol on 4-OHE₂-induced transformation of human breast epithelial MCF-10A cells. Resveratrol inhibited migration and anchorage-independent growth of MCF-10A cells treated with 4-OHE₂. Resveratrol treatment suppressed the 4-OHE₂-induced activation of IκB kinaseβ (IKKβ) and phosphorylation of IκBα, and consequently NF-κB DNA binding activity and cyclooxygenase-2 (COX-2) expression. Resveratrol suppressed ROS production and phosphorylation of Akt and ERK induced by 4-OHE₂ treatment. In conclusion, resveratrol blocks activation of IKKβ-NF-κB signalling and induction of COX-2 expression in 4-OHE₂-treated MCF-10A cells, thereby suppressing migration and transformation of these cells.

Topics: Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cyclooxygenase 2; Epithelial Cells; Estrogens, Catechol; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression; Humans; I-kappa B Kinase; Mammary Glands, Human; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Resveratrol; Signal Transduction; Stilbenes

4,4'-dihydroxy-trans-stilbene (DHS) is a synthetic analog of resveratrol, a phytoalexin known for its biological activities. We previously demonstrated that DHS exerts an antiproliferative effect on normal human fibroblasts that is higher than that of the natural parent molecule. No evidence regarding its role in human cancer cell lines has been found thus far. In this study, we investigated the effects of DHS both on chemical-induced transformation of BALB/c 3T3 mouse fibroblasts and on the proliferation and invasion of human breast cancer MCF-7 cells. The results showed that DHS markedly suppresses the two-stage (3-methylcholanthrene plus 12-O-tetradecanoylphorbol-13-acetate) cell transformation. Compared with resveratrol, DHS inhibited both anchorage-dependent and -independent MCF-7 growth more efficiently. In addition, a reduction in the number of cells in S-phase, characterized by a concomitant increase in the levels of p21 and p53 proteins, together with a strong inhibition of pRb protein phosphorylation, was observed in DHS-treated cells. Furthermore, DHS effected a strong reduction in matrix metalloproteinase-2 and -9 activities, concomitantly with a marked inhibition of cell adhesion to the extracellular matrix components as well as inhibition of cell migration and invasion. Importantly, modulation of the adhesion molecule E-cadherin was also found in DHS-treated cells. Taken together, these results demonstrate that the two 4,4'-hydroxyl groups on the stilbenic backbone make DHS a more active molecule than resveratrol in inhibiting neoplastic transformation, cancer cell proliferation and invasion. In conclusion, this study suggests that DHS could be a promising anticancer agent.

Topics: Adenocarcinoma; Animals; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Adhesion; Cell Cycle; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Collagen Type I; Female; Fibroblasts; Humans; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Stilbenes; Tumor Stem Cell Assay; Wound Healing

Substantial evidence suggests that catechol estrogen-3,4-quinones react with DNA to form predominantly the depurinating adducts 4-hydroxyestrone (estradiol)-1-N3Ade [4-OHE(1)(E(2))-1-N3Ade] and 4-OHE(1)(E(2))-1-N7Gua. Apurinic sites resulting from these adducts generate critical mutations that can initiate cancer. The paradigm of cancer initiation is based on an imbalance in estrogen metabolism between activating pathways that lead to estrogen-DNA adducts and deactivating pathways that lead to estrogen metabolites and conjugates. This imbalance can be improved to minimize formation of adducts by using antioxidants, such as resveratrol (Resv) and N-acetylcysteine (NAcCys). To compare the ability of Resv and NAcCys to block formation of estrogen-DNA adducts, we used the human breast epithelial cell line MCF-10F treated with 4-OHE(2). Resv and NAcCys directed the metabolism of 4-OHE(2) toward protective pathways. NAcCys reacted with the quinones and reduced the semiquinones to catechols. This pathway was also carried out by Resv. In addition, Resv induced the protective enzyme quinone reductase, which reduces E(1)(E(2))-3,4-quinones to 4-OHE(1)(E(2)). Resv was more effective at increasing the amount of 4-OCH(3)E(1)(E(2)) than NAcCys. Inhibition of estrogen-DNA adduct formation was similar at lower doses, but at higher doses Resv was about 50% more effective than NAcCys. Their combined effects were additive. Therefore, these two antioxidants provide an excellent combination to protect catechol estrogens from oxidation to catechol quinones.

Topics: Acetylcysteine; Anticarcinogenic Agents; Breast Neoplasms; Carcinoma; Cell Line; Cell Transformation, Neoplastic; Drug Combinations; Drug Evaluation, Preclinical; Drug Synergism; Female; Humans; Mammary Glands, Human; Models, Biological; Resveratrol; Stilbenes

Cancer chemoprevention by natural dietary agents has received considerable importance because of their cost-effectiveness and wide safety margin. However, single agent intervention has failed to bring the expected outcome in clinical trials; therefore, combinations of chemopreventive agents are gaining increasing popularity. The present study aims to evaluate the combinatorial chemopreventive effects of resveratrol and black tea polyphenol (BTP) in suppressing two-stage mouse skin carcinogenesis induced by DMBA and TPA. Resveratrol/BTP alone treatment decreased tumor incidence by ∼67% and ∼75%, while combination of both at low doses synergistically decreased tumor incidence even more significantly by ∼89% (p<0.01). This combination also significantly regressed tumor volume and number (p<0.01). Mechanistic studies revealed that this combinatorial inhibition was associated with decreased expression of phosphorylated mitogen-activated protein kinase family proteins: extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase 1/2, p38 and increased in total p53 and phospho p53 (Ser 15) in skin tissue/tumor. Treatment with combinations of resveratrol and BTP also decreased expression of proliferating cell nuclear antigen in mouse skin tissues/tumors than their solitary treatments as determined by immunohistochemistry. In addition, histological and cell death analysis also confirmed that resveratrol and BTP treatment together inhibits cellular proliferation and markedly induces apoptosis. Taken together, our results for the first time lucidly illustrate that resveratrol and BTP in combination impart better suppressive activity than either of these agents alone and accentuate that development of novel combination therapies/chemoprevention using dietary agents will be more beneficial against cancer. This promising combination should be examined in therapeutic trials of skin and possibly other cancers.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Chemoprevention; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Activation; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Phosphorylation; Polyphenols; Proliferating Cell Nuclear Antigen; Protein Stability; Remission Induction; Resveratrol; Skin Neoplasms; Stilbenes; Tea; Tetradecanoylphorbol Acetate; Tumor Suppressor Protein p53

Obesity is associated with a decrease in the antiinflammatory hormone, adiponectin, and increases in the circulating concentrations of multiple proinflammatory cytokines. These changes contribute to colon tumorigenesis. Resveratrol increases adiponectin production in adipocytes and attenuates the development of colon cancer. Thus, we hypothesized that adiponectin is an integral component of the mechanism by which resveratrol antagonizes colorectal tumorigenesis. To investigate this, we induced tumorigenesis in adiponectin knockout (KO) and wild-type (Wt) C57BL/6 mice through combined azoxymethane and dextran sodium sulfate treatment during which mice were fed a high-fat, lard-based diet, or the same diet containing 20 mg/kg resveratrol. After 14 wk on diet, Wt mice gained more weight and, on a percentage basis, had higher fat mass and lower lean mass than KO mice. Resveratrol tended to attenuate this response in male Wt mice. Resveratrol also tended to reduce aberrant crypt foci development and decrease circulating interleukin 6 and insulin concentrations in male but not female Wt mice. Taken together, resveratrol improved overall health of obese Wt but not KO mice as hypothesized with a differential sex response.

Topics: Adipocytes; Adiponectin; Animals; Azoxymethane; Caco-2 Cells; Cell Transformation, Neoplastic; Colorectal Neoplasms; Dextran Sulfate; Dietary Fats; Dose-Response Relationship, Drug; Female; Humans; Insulin; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Resveratrol; Sex Factors; Stilbenes; Weight Gain

We recently developed a Janus kinase 2 (Jak2) small-molecule inhibitor called G6 and found that it inhibits Jak2-V617F-mediated pathologic cell growth in vitro, ex vivo, and in vivo. However, its ability to inhibit Jak2-V617F-mediated myeloproliferative neoplasia, with particular emphasis in the bone marrow, has not previously been examined. Here, we investigated the efficacy of G6 in a transgenic mouse model of Jak2-V617F-mediated myeloproliferative neoplasia. We found that G6 provided therapeutic benefit to the peripheral blood as determined by elimination of leukocytosis, thrombocytosis, and erythrocytosis. G6 normalized the pathologically high plasma concentrations of interleukin 6 (IL-6). In the liver, G6 eliminated Jak2-V617F-driven extramedullary hematopoiesis. With respect to the spleen, G6 significantly reduced both the splenomegaly and megakaryocytic hyperplasia. In the critically important bone marrow, G6 normalized the pathologically high levels of phospho-Jak2 and phospho-signal transducer and activator of transcription 5 (STAT5). It significantly reduced the megakaryocytic hyperplasia in the marrow and completely normalized the M/E ratio. Most importantly, G6 selectively reduced the mutant Jak2 burden by 67%on average, with virtual elimination of mutant Jak2 cells in one third of all treated mice. Lastly, clonogenic assays using marrow stem cells from the myeloproliferative neoplasm mice revealed a time-dependent elimination of the clonogenic growth potential of these cells by G6. Collectively, these data indicate that G6 exhibits exceptional efficacy in the peripheral blood, liver, spleen, and, most importantly, in the bone marrow, thereby raising the possibility that this compound may alter the natural history of Jak2-V617F-mediated myeloproliferative neoplasia.

Topics: Amino Acid Substitution; Animals; Antineoplastic Agents; Bone Marrow Cells; Bone Marrow Neoplasms; Cell Transformation, Neoplastic; Cells, Cultured; Drug Evaluation, Preclinical; Janus Kinase 2; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloproliferative Disorders; Phenylalanine; Protein Kinase Inhibitors; Stilbenes; Valine

The aim of the present study was to assess the effect of dietary supplementation (copper or copper and resveratrol) on the intensity of carcinogenesis and the frequency of microsatellite instability in a widely used model of mammary carcinogenesis induced in the rat by treatment with 7,12-dimethylbenz[a]anthracene (DMBA).. DNA was extracted from rat mammary cancers and normal tisues, amplified by PCR, using different polymorphic DNA markers and the reaction products were analyzed for microsatellite instability.. It was found that irrespectively of the applied diet there was no inhibition of mammary carcinogenesis in the rats due to DMBA. Besides, in the groups supplemented with Cu (II) or Cu (II) and resveratrol the tumor formation was clearly accelerated. Unlike the animals that were fed with standard diet, the supplemented rats were characterized by the loss of heterozygosity of microsatellite D3Mgh9 in cancer tumors (by respectively 50 and 40%). When the animals received Cu (II) and resveratrol supplemented diet the occurrence of genomic instability was additionally found in their livers in the case of microsatellite D1Mgh6 (which was stable in the animals without dietary supplementation).. Identification of the underlying mechanisms by which dietary factors affect genomic stability might prove useful in the treatment of mammary cancer as well as in the incorporation of dietary factors into mammary cancer prevention strategies.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Cell Transformation, Neoplastic; Copper; Dietary Supplements; Female; Genomic Instability; Mammary Neoplasms, Experimental; Microsatellite Repeats; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Oral squamous cell carcinoma (OSCC) develops slowly and it is usually preceded by identifiable oral preneoplastic lesions (OPLs): chemoprevention could be a promising approach. Resveratrol (RV) is a plant-based agent characterized by a strong in vitro antineoplastic action, but this effect has not been clinically confirmed owing to its metabolic inactivation. In order to circumvent this limitation and to improve RV efficacy, it was locally applied and complexed with a protective and solubilising vehicle (2-hydroxypropyl-beta-cyclodextrin, HPbetaCD). The experimentation was performed in vitro on 7,12-dimethylbenz[a]anthracene-induced hamster OSCC cell line (HCPC I) and in vivo in the related animal model, by comparison of two RV-HPbetaCD formulations (cream and mouthwash) and RV alone. Vehicles and RV-formulations were free from toxicity. Antiproliferative action of RV on HCPC I was concentration- and time-dependent, and was improved in HPbetaCD-formulations. In vivo, RV prevented OPL and OSCC appearance and growth. Here, too, HPbetaCD-formulations (mainly mouthwash) demonstrated the best chemopreventive effects in terms of lesions prevalence, multiplicity, dimension, and histological signs of malignancy. HPLC detection of RV corroborated that its action is concentration-correlated and is improved by its inclusion in HPbetaCDs. In summary, our study demonstrates that RV is effective in the chemoprevention of DMBA-induced oral carcinogenesis and when it is complexed with HPbetaCDs its efficacy is significantly improved.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Anticarcinogenic Agents; beta-Cyclodextrins; Carcinogens; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Transformation, Neoplastic; Cheek; Cricetinae; Drug Combinations; Mesocricetus; Mouth Neoplasms; Pharmaceutical Vehicles; Resveratrol; Stilbenes

The purpose of our study was to investigate in vitro the potential cancer preventive properties of several phytochemicals, i.e. grape seed extract (GSE), resveratrol (RES), ursolic acid (URA), ellagic acid (ELA), lycopene and N-acetyl-L-cysteine (NAC) to define the mechanisms by which these compounds may inhibit murine skin carcinogenesis. We measured quenching of peroxyl, superoxide and hydroxyl radicals by these phytochemicals. We also used adenosine triphosphate (ATP) bioluminescence, Caspase-Glo 3/7 and P450-Glo (CYP1A1 and CYP1B1) assays to study antiproliferative, proapoptotic and CYP-inhibiting effects of the phytochemicals. We next determined their effects on a 4 week inflammatory hyperplasia assay using 7,12-dimethylbenz[a]anthracene-induced murine skin carcinogenesis model to further understand their mechanism of action. Three murine keratinocyte cell lines, i.e. non-tumorigenic (3PC), papilloma-derived (MT1/2) and squamous cell carcinoma-derived (Ca3/7) cell lines, were used in in vitro assays. We have found that GSE, ELA and RES are potent scavengers of peroxyl and superoxide radicals. Statistically significant effects on activities of caspase-3 and -7 were observed only after GSE and URA treatments. All tested compounds protected cells from hydrogen peroxide-induced DNA damage. Using a short-term complete carcinogenesis assay, we have found that all selected compounds caused marked decreases of epidermal thickness and (except RES) reduced percentages of mice with mutation in codon 61 of Ha-ras oncogene. In conclusion, differential effects of tested phytochemicals on events and processes critical for the growth inhibition of keratinocytes in vitro and in vivo indicate that combinations of tested compounds may, in the future, better counteract both tumor initiation and tumor promotion/progression.

Topics: Acetylcysteine; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Aryl Hydrocarbon Hydroxylases; Carotenoids; Cell Line; Cell Line, Tumor; Cell Transformation, Neoplastic; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Ellagic Acid; Female; Free Radical Scavengers; Free Radicals; Genes, ras; Keratinocytes; Lycopene; Mice; Mutation; Plant Extracts; Proto-Oncogene Proteins p21(ras); Resveratrol; Skin Neoplasms; Stilbenes; Triterpenes; Ursolic Acid; Vitis

The function of the class III histone deacetylase, Sir2, in promoting lifespan extension is well established in small model organisms. By analogy, SirT1, the mammalian orthologue of Sir2, is a candidate gene to slow down aging and forestall the onset of age-associated diseases. We have used SirT1-null mice to study the function of SirT1 in susceptibility to tumorigenesis. The number of intestinal polyps induced in mice carrying the Apc(min) mutation was unaffected by the SirT1 genotype although the average polyp size was slightly smaller in the SirT1-null animals. Similarly, the presence or absence of SirT1 had no effect on incidence and tumor load of skin papillomas induced by the classical two-stage carcinogenesis protocol. We found that resveratrol topically applied to the skin profoundly reduced tumorigenesis. This chemoprotective effect was significantly reduced but not ablated in SirT1-null mice, suggesting that part of the protection afforded by resveratrol requires the SirT1-encoded protein. Thus, our results suggest that SirT1 does not behave like a classical tumor-suppressor gene but the antitumor activity of resveratrol is mediated at least in part by SirT1.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Angiogenesis Inhibitors; Animals; Blood Vessels; Carcinogens; Cell Transformation, Neoplastic; Female; Genotype; Immunohistochemistry; Intestinal Polyps; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Neoplasms, Experimental; NIH 3T3 Cells; Resveratrol; Sirtuin 1; Sirtuins; Skin Neoplasms; Stilbenes; Tetradecanoylphorbol Acetate; Transfection

There are multiple lines of evidence supporting that inflammation is causally linked to carcinogenesis. Abnormal upregulation of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the prostaglandin biosynthesis, has been implicated in carcinogenesis. Trans-3,4,3',5'-tetrahydroxystilbene (piceatannol), a naturally occurring hydroxylated stilbene with potent anti-inflammatory and antioxidative activities, has been shown to inhibit the proliferation of several cancer cells by inducing apoptosis or blocking cell cycle progression. In this study, we examined the effect of piceatannol on activation of the nuclear transcription factor NF-kappa B, one of the major transcription factors that regulate proinflammatory COX-2 gene transcription, in human mammary epithelial (MCF-10A) cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). When pretreated to MCF-10A cells, piceatannol markedly inhibited TPA-induced NF-kappa B DNA binding to a greater extent than resveratrol and oxyresveratrol, stilbene analogs structurally related to piceatannol. Piceatannol also inhibited TPA-induced phosphorylation and degradation of Ikappa Balpha as well as nuclear translocation of the phosphorylated form of p65, the functionally active subunit of NF-kappa B. Likewise, TPA-induced expression of COX-2 was abrogated by piceatannol pretreatment. The thiol reducing agent dithiothreitol abolished the inhibitory effects of piceatannol on NF-kappa B DNA binding activity, suggesting that piceatannol may directly modify NF-kappa B or its regulator through reaction with the cysteine thiol(s).

Topics: Anti-Inflammatory Agents; Antioxidants; Breast; Breast Neoplasms; Carcinogens; Cell Line; Cell Transformation, Neoplastic; Cyclooxygenase 2; DNA-Binding Proteins; Dose-Response Relationship, Drug; Down-Regulation; Epithelial Cells; Female; Humans; I-kappa B Kinase; NF-kappa B; Phosphorylation; Protein Transport; Stilbenes; Tetradecanoylphorbol Acetate

Resveratrol, present in grapes and red wine, is reported to be a natural chemopreventive agent against cancer. However, the concentrations required to exert these effects may be difficult to achieve by drinking only 1 or 2 glasses of red wine a day. Therefore, developing more potent, nontoxic analogues of resveratrol may provide a feasible means of achieving an effective physiologic concentration. Here we report that the resveratrol analogue, 3,5,3',4',5'-pentahydroxy-trans-stilbene (RSVL2), inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation in JB6 P+ mouse epidermal cells. Further, we identified MEK/ERK signaling as the direct molecular target for the anticancer effects of RSVL2 and demonstrated that RSVL2 inhibited MEK1, but not Raf1 or ERK2 kinase activity. RSVL2 also dose-dependently suppressed MEK1 kinase activity induced by TPA and the inhibition of H-Ras-induced cell transformation was much stronger for RSVL2 than for PD098059 or resveratrol. Both in vitro and ex vivo pull-down assays indicated that RSVL2, but not resveratrol, directly bound with GST-MEK1, but did not compete with ATP for binding. Docking data indicated that the low inhibitory activity of resveratrol might be due to the lack of the hydroxyl group at the meta position of the B ring, thereby preventing resveratrol from forming a hydrogen bond with the backbone amide group of Ser212, which is the key interaction for stabilizing the inactive conformation of the activation loop.

Topics: Adenosine Triphosphate; Animals; Cell Line; Cell Transformation, Neoplastic; Extracellular Signal-Regulated MAP Kinases; Mice; Mitogen-Activated Protein Kinase Kinases; Models, Molecular; Molecular Structure; Phosphorylation; Promoter Regions, Genetic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-raf; Resveratrol; Ribosomal Protein S6 Kinases, 90-kDa; Stilbenes; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Transcriptional Activation

In lower eukaryotes, Sir2 serves as a histone deacetylase and is implicated in chromatin silencing, longevity, and genome stability. Here we mutated the Sirt1 gene, a homolog of yeast Sir2, in mice to study its function. We show that a majority of SIRT1 null embryos die between E9.5 and E14.5, displaying altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage. We demonstrate that Sirt1(+/-);p53(+/-) mice develop tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduces tumorigenesis. Finally, we show that many human cancers exhibit reduced levels of SIRT1 compared to normal controls. Thus, SIRT1 may act as a tumor suppressor through its role in DNA damage response and genome integrity.

Topics: Animals; Anticarcinogenic Agents; Cell Cycle; Cell Transformation, Neoplastic; Cells, Cultured; Chromosomal Instability; DNA Damage; DNA Repair; Down-Regulation; Embryo, Mammalian; Female; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Genomic Instability; Gestational Age; Heterochromatin; Histones; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitosis; Mutation; Neoplasms; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes; Time Factors; Tumor Suppressor Proteins

Exposure to estrogens is a risk factor for breast cancer. Specific estrogen metabolites may initiate breast cancer and other cancers. Genotoxicity may be caused by cytochrome P450 (CYP)-mediated oxidation of catechol estrogens to quinones that react with DNA to form depurinating estrogen-DNA adducts. CYP1B1 favors quinone formation by catalyzing estrogen 4-hydroxylation, whereas NAD(P)H quinone oxidoreductase 1 (NQO1) catalyzes the protective reduction of quinones to catechols. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1B1 expression through the aryl hydrocarbon receptor (AhR). Resveratrol has anticancer effects in diverse in vitro and in vivo systems and is an AhR antagonist that decreases CYP expression but induces NQO1 expression. The chemopreventive effect of resveratrol on breast cancer initiation was investigated in MCF-10F cells. Its effects on estrogen metabolism and formation of estrogen-DNA adducts were analyzed in culture medium by high-performance liquid chromatography, whereas its effects on CYP1B1 and NQO1 were determined by immunoblotting and immunostaining. The antitransformation effects of resveratrol were also examined. TCDD induced expression of CYP1B1 and its redistribution in the nucleus and cytoplasm. Concomitant treatment with resveratrol dose-dependently suppressed TCDD-induced expression of CYP1B1, mainly in the cytoplasm. Resveratrol dose- and time-dependently induced expression of NQO1. NQO1 is mainly in the perinuclear membrane of control cells, but resveratrol induced NQO1 and its intracellular redistribution, which involves nuclear translocation of nuclear factor erythroid 2-related factor 2. Resveratrol decreased estrogen metabolism and blocked formation of DNA adducts in cells treated with TCDD and/or estradiol. Resveratrol also suppressed TCDD and/or estradiol-induced cell transformation. Thus, resveratrol can prevent breast cancer initiation by blocking multiple sites in the estrogen genotoxicity pathway.

Topics: Aryl Hydrocarbon Hydroxylases; Breast Neoplasms; Cell Line; Cell Nucleus; Cell Transformation, Neoplastic; Chemoprevention; Cytochrome P-450 CYP1B1; DNA Adducts; Estradiol; Gene Expression Regulation, Enzymologic; Humans; Models, Biological; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Polychlorinated Dibenzodioxins; Protein Transport; Resveratrol; Stilbenes

Considerable attention has focused on the health-promoting effects of red wine and its nonflavonoid polyphenol compound resveratrol. However, the underlying molecular mechanisms and molecular target(s) of red wine or other potentially active ingredients in red wine remain unknown. Here, we report that red wine extract (RWE) or the red wine flavonoid quercetin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 promotion-sensitive mouse skin epidermal (JB6 P+) cells. The activation of activator protein-1 and nuclear factor-kappaB induced by TPA was dose dependently inhibited by RWE or quercetin treatment. Western blot and kinase assay data revealed that RWE or quercetin inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) 1 and Raf1 kinase activities and subsequently attenuated TPA-induced phosphorylation of ERK/p90 ribosomal S6 kinase. Although either RWE or quercetin suppressed Raf1 kinase activity, they were more effective in inhibiting MEK1 activity. Importantly, quercetin exerted stronger inhibitory effects than PD098059, a well-known pharmacologic inhibitor of MEK. Resveratrol did not affect either MEK1 or Raf1 kinase activity. Pull-down assays revealed that RWE or quercetin (but not resveratrol) bound with either MEK1 or Raf1. RWE or quercetin also dose dependently suppressed JB6 P+ cell transformation induced by epidermal growth factor or H-Ras, both of which are involved in the activation of MEK/ERK signaling. Docking data suggested that quercetin, but not resveratrol, formed a hydrogen bond with the backbone amide group of Ser(212), which is the key interaction for stabilizing the inactive conformation of the activation loop of MEK1.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Cell Transformation, Neoplastic; Cells, Cultured; MAP Kinase Kinase 1; Mice; NF-kappa B; Proto-Oncogene Proteins c-raf; Quercetin; Resveratrol; Skin; Skin Neoplasms; Stilbenes; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Transcriptional Activation; Wine

Targeted molecular cancer therapies can potentially deliver treatment directly to a specific protein or gene to optimize efficacy and reduce adverse side effects often associated with traditional chemotherapy. Key oncoprotein and oncogene targets are rapidly being identified based on their expression, pathogenesis and clinical outcome. One such protein target is cyclooxygenase-2 (COX-2), which is highly expressed in various cancers. Research findings suggest that resveratrol (RSVL; 3,5,4'-trihydroxy-trans-stilbene) demonstrates nonselective COX-2 inhibition. We report herein that RSVL directly binds with COX-2 and this binding is absolutely required for RSVL's inhibition of the ability of human colon adenocarcinoma HT-29 cells to form colonies in soft agar. Binding of COX-2 with RSVL was compared with two RSVL analogues, 3,3',4',5',5-pentahydroxy-trans-stilbene (RSVL-2) or 3,4',5-trimethoxy-trans-stilbene (RSVL-3). The results indicated that COX-2 binds with RSVL-2 more strongly than with RSVL, but does not bind with RSVL-3. RSVL or RSVL-2, but not RSVL-3, inhibited COX-2-mediated PGE(2) production in vitro and ex vivo. HT-29 human colon adenocarcinoma cells express high levels of COX-2 and either RSVL or RSVL-2, but not RSVL-3, suppressed anchorage independent growth of these cells in soft agar. RSVL or RSVL-2 (not RSVL-3) suppressed growth of COX-2(+/+) cells by 60% or 80%, respectively. Notably, cells deficient in COX-2 were unresponsive to RSVL or RSVL-2. These data suggest that the anticancer effects of RSVL or RSLV-2 might be mediated directly through COX-2.

Topics: Cell Line, Tumor; Cell Transformation, Neoplastic; Chromatography, Affinity; Cyclooxygenase 2; Humans; Resveratrol; Spectrometry, Fluorescence; Stilbenes

The tumor suppressor p53-related p73 shares significant amino-acid sequence identity with p53. Like p53, p73 recognizes canonical p53 DNA-binding sites and activates p53-responsive target genes and induces apoptosis. Moreover, SIRT1 binds to p53 while repressing the expression of their target genes. Here, we report that SIRT1 also binds to p73 and suppresses p73-dependent transcriptional activity. SIRT1 in human cells reduces the transcriptional activity of p73, and partly inhibits apoptosis induced by p73. Furthermore, SIRT1 can deacetylate p73 protein acetylation both in vivo and in vitro. Collectively, these data suggest that SIRT1 can modulate p73 activity via deacetylation.

Topics: Acetylation; Apoptosis; bcl-2-Associated X Protein; Cell Transformation, Neoplastic; DNA-Binding Proteins; Down-Regulation; Enzyme Inhibitors; Gamma Rays; Genes, Reporter; HeLa Cells; Humans; Luciferases; Niacinamide; Nuclear Proteins; Oligonucleotides, Antisense; Promoter Regions, Genetic; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-mdm2; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes; Transcription, Genetic; Transfection; Tumor Protein p73; Tumor Suppressor Proteins

The aryl hydrocarbon receptor (AHR) is a cytosolic receptor which upon activation by its agonists, translocates into the nucleus and forms a dimer with ARNT (aryl hydrocarbon nuclear translocator). The AHR/ARNT dimer regulates the expression of its target genes by binding to DNA recognition elements termed dioxin responsive elements (DREs). Many AHR agonists, like the polyaromatic hydrocarbons and polyhalogenated hydrocarbons are known human carcinogens. Human exposure to these compounds is common due to their presence in air pollution and cigarette smoke. Interestingly, many dietary constituents that have chemo preventative properties have been found to also act as antagonists of the AHR pathway. Thus, a chemopreventive approach that may be effective in decreasing the incidences of many human cancers may involve a dietary regimen that includes a number of these naturally occurring AHR antagonists. With this idea in mind, we have assayed the ability of 15 flavonoids to inhibit AHR activated reporter activity and selected kaempferol for further analysis. Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. Using an in vitro paradigm of events that are thought to occur during cigarette-smoke-induced lung cancer, we found that kaempferol also inhibited the ability of cigarette smoke condensate to induce growth of immortalized lung epithelial (BEAS-2B) cells in soft agar. Taken together, these results illustrate the promise associated with the use of flavonoids, that inhibit both AHR signaling and the carcinogenic actions of AHR agonists, for chemopreventive purposes.

Topics: Anticarcinogenic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Transformation, Neoplastic; Dimethyl Sulfoxide; Flavanones; Flavones; Flavonoids; Humans; Kaempferols; Liver Transplantation; Luteolin; Receptors, Aryl Hydrocarbon; Resveratrol; Smoking; Stilbenes

Potential chemopreventive effects of naturally occurring agents were investigated using a new 16-week medium-term pancreatic carcinogenesis models in hamsters. Male 6-week-old Syrian hamsters were subcutaneously injected with 10mg/kg body weight N-nitrosobis(2-oxopropyl)amine (BOP) four times within a week, and fed a diet supplemented with 80ppm benzyl isothiocyanate (BITC), 80ppm sulforaphane (SFN) or 10ppm resveratrol (RES) during the initiation or post-initiation stages. For the initiation stage, each chemical was given for 3 weeks including 1 week before and after the BOP injections. With post-initiation exposure, the groups were changed from basal diet 1 week after the last BOP injection, and then fed each chemical for 14 weeks. All the animals were sacrificed after 16 weeks. The multiplicities of combined pancreatic lesions including atypical hyperplasias and adenocarcinomas were significantly decreased by BITC and SFN given in the initiation but not the post-initiation stage. On the other hand, RES, a naturally occurring inhibitor of cyclooxygenase-2 (COX-2) reported chemopreventive effects, failed to show significant effects on pancreatic carcinogenesis in either the initiation or post-initiation stages. Our data suggest that the naturally occurring isothiocyanates BITC and SFN can block BOP-initiation of hamster pancreatic carcinogenesis.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Carcinogenicity Tests; Carcinogens; Cell Transformation, Neoplastic; Cricetinae; Cyclooxygenase 2; Diet; Injections, Subcutaneous; Isothiocyanates; Male; Membrane Proteins; Mesocricetus; Neoplasms, Experimental; Nitrosamines; Pancreatic Neoplasms; Resveratrol; Stilbenes; Sulfoxides; Thiocyanates

Recent evidence suggests that inflammatory cytokines and growth factors contribute to arsenite (As)-induced human carcinogenesis. We investigated the expression of inflammatory cytokine mRNAs during the transformation process induced by chronic As exposure in non-tumorigenic human osteogenic sarcoma (N-HOS) cells using gene arrays, and results were confirmed by RT-PCR and protein arrays. Caffeic acid phenethyl ester (CAPE), a naturally occurring immunomodulating agent, was used to evaluate the role of inflammatory factors in the process of As-mediated N-HOS cell transformation and in As-transformed HOS (AsT-HOS) cells. We found that an 8-week continuous exposure of N-HOS to 0.3 microM arsenite resulted in HOS cell transformation. That exposure also caused substantial decreases in inflammatory cytokine mRNAs, such as interleukin (IL) IL-1alpha, IL-2, IL-8, IL-18, MCP-1, TGF-beta2, and TNF-alpha, while it increased c-jun mRNA in a time-dependent manner. Co-incubation of N-HOS with As and CAPE (0.5-2.5 microM) prevented As-mediated declines in cytokine mRNAs in the co-treated cells, as well as their transformation to anchorage independence, while it caused decreases in c-jun mRNA. CAPE (up to 10 microM) had no effect on growth of N-HOS cells. However, CAPE (1-10 microM) treatment of AsT-HOS cells inhibited cell growth, induced cell cycle G2/M arrest, and triggered apoptosis, accompanied by changes in cytokine gene expression, as well as decreases in cyclin B1 and cdc2 abundance. Resveratrol (RV) and (-)(.) epigallocatechin gallate (EGCG), preventive agents present in grapes and green tea, respectively, induced similar changes in AsT-HOS cell growth but required much higher doses than CAPE to cause 50% growth arrest (<2.5 microM CAPE versus 25 microM RV or 50 microM EGCG). Overall, our findings suggest that inflammatory cytokines play an important role in the suppressive effects of CAPE on As-induced cell transformation and in the selective cytotoxicity of CAPE to As-transformed HOS cells.

Topics: Antioxidants; Apoptosis; Arsenites; Caffeic Acids; Catechin; Cell Growth Processes; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Cytokines; Drug Interactions; Flow Cytometry; Humans; Oligonucleotide Array Sequence Analysis; Osteosarcoma; Phenylethyl Alcohol; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes

Resveratrol, a constituent found in grapes and various other plants, has been shown to have chemo-preventive activity against cancer, and specifically demonstrated to induce apoptosis by p53-dependent pathways in murine cells. The goal of this research was to identify the role of p53-dependent or p53-independent pathways in the induction of apoptosis in human breast cancer cells by this natural product.. A number of human breast cancer cell lines, as well as a control of a wild-type line (astrocytoma N 1321N1), were investigated for induction of apoptosis by resveratrol using both microscopic evaluation and DNA fragmentation assays. Concurrently, we established the p53 gene status (wild-type or mutant) of each cell line by Western blot using p53-specific antibody.. Apoptosis induced by resveratrol was found to occur only in breast cancer cells expressing wild-type p53 but not in mutant p53-expressing cells.. We therefore conclude that the natural product, resveratrol, induces apoptosis in breast cancer cells via p53-dependent pathways.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Astrocytoma; Blotting, Western; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cell Transformation, Neoplastic; DNA Fragmentation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Resveratrol; Signal Transduction; Stilbenes; Time Factors; Transcriptional Activation; Tumor Suppressor Protein p53

Resveratrol, a constituent of grapes and other foods, has been reported to be a potential cancer chemopreventive agent. Our previous study showed that the antitumor activity of resveratrol occurs through mitogen-activated protein kinases-mediated p53 activation and induction of apoptosis. To develop more effective agents with fewer side effects for the chemoprevention of cancer, we investigated the effect of resveratrol and its structurally related derivatives on epidermal growth factor (EGF)-induced cell transformation. Our results provided the first evidence that one of the resveratrol derivatives exerted a more potent inhibitory effect than resveratrol on EGF-induced cell transformation, but had less cytotoxic effects on normal nontransformed cells. Compared to resveratrol, this compound also caused cell cycle arrest in the G1 phase, but did not induce p53 activation and apoptosis. Furthermore, this compound, but not resveratrol, markedly inhibited EGF-induced phosphatidylinositol-3 kinase (PI-3K) and Akt activation. Collectively, these data suggested that the higher antitumor effect of the compound compared to resveratrol, may act through a different mechanism by mainly targeting PI-3K/Akt signaling pathways.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Line; Cell Transformation, Neoplastic; Epidermal Growth Factor; G1 Phase; Gene Expression Regulation; Genes, p53; Mice; Resveratrol; Stilbenes

Fractionation of an ethyl acetate-soluble extract of the bark of Artocarpus dadah has led to the isolation of three new prenylated stilbenoid derivatives, 3-(gamma,gamma-dimethylallyl)resveratrol (1), 5-(gamma,gamma-dimethylallyl)oxyresveratrol (2), 3-(2,3-dihydroxy-3-methylbutyl)resveratrol (3), and a new benzofuran derivative, 3-(gamma,gamma-dimethylpropenyl)moracin M (4), along with six known compounds, oxyresveratrol, (+)-catechin, afzelechin-3-O-alpha-L-rhamnopyranoside, (-)-epiafzelechin, dihydromorin, and epiafzelechin-(4beta-->8)-epicatechin. From an ethyl acetate-soluble extract of the twigs of the same plant were isolated compound 4 and two new neolignan derivatives, dadahols A (5) and B (6), as well as 10 known compounds, oxyresveratrol, (+)-catechin, afzelechin-3-O-alpha-L-rhamnopyranoside, resveratrol, steppogenin, moracin M, isogemichalcone B, gemichalcone B, norartocarpetin, and engeletin. The structures of compounds 1-6 were determined using spectroscopic and chemical methods. Isolates were evaluated for their inhibitory effects against both cyclooxygenase-1 (COX-1) and -2 (COX-2) and in a mouse mammary organ culture assay.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetylation; Animals; Benzofurans; Breast; Catechin; Cell Transformation, Neoplastic; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Indonesia; Isoenzymes; Membrane Proteins; Methylation; Mice; Mice, Inbred BALB C; Molecular Structure; Moraceae; Nuclear Magnetic Resonance, Biomolecular; Organ Culture Techniques; Plant Bark; Plant Extracts; Plant Shoots; Plants, Medicinal; Prostaglandin-Endoperoxide Synthases; Spectroscopy, Fourier Transform Infrared; Stereoisomerism; Stilbenes

Resveratrol, a plant constituent enriched in the skin of grapes, is one of the most promising agents for the prevention of cancer. However, the mechanism of the anti-carcinogenic activity of resveratrol is not well understood. Here we offer a possible explanation of its anti-cancer effect. Resveratrol suppresses tumor promoter-induced cell transformation and markedly induces apoptosis, transactivation of p53 activity and expression of p53 protein in the same cell line and at the same dosage. Also, resveratrol-induced apoptosis occurs only in cells expressing wild-type p53 (p53+/+), but not in p53-deficient (p53-/-) cells, while there is no difference in apoptosis induction between normal lymphoblasts and sphingomyelinase-deficient cell lines. These results demonstrate for the first time that resveratrol induces apoptosis through activation of p53 activity, suggesting that its anti-tumor activity may occur through the induction of apoptosis.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Line; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epidermal Cells; Mice; Resveratrol; Stilbenes; Transcriptional Activation; Tumor Suppressor Protein p53

The mechanisms of estrogen-induced cancer are still a matter of debate. Previous studies with stilbene estrogens and steroidal estrogens have shown that the in vitro transformation of primary Syrian hamster embryo (SHE) fibroblasts is a good experimental system for discriminating hormonal from nonhormonal events. We have now extended these studies to the triphenylethylene-type antiestrogens tamoxifen (TAM), 3-hydroxy-TAM, 4-hydroxy-TAM and 3,4-dihydroxy-TAM. Furthermore, a structural isomer of diethylstilbestrol (DES) with the hydroxy groups shifted into the meta-positions (3,3'-DES) was included. Our data clearly show that TAM and 4-hydroxy-TAM give rise to morphologic and neoplastic transformation of SHE cells in culture. In contrast, neither 3-hydroxy-TAM nor 3,3'-DES led to a significant transformation, in spite of the fact that both compounds are hormonally active. These results support the notion that nonhormonal events are essential for SHE cell transformation and suggest certain structural features to be necessary for the transforming capability. The putative carcinogenicity of TAM and 4-hydroxy-TAM but not of 3-hydroxy-TAM, as implied by these in vitro transformation studies, is corroborated by recent reports on ovarian and Leydig cell tumors in mice and hepatocellular carcinomas in rats.

Topics: Animals; Cell Transformation, Neoplastic; Cells, Cultured; Cricetinae; Estrogen Antagonists; Estrogens, Non-Steroidal; Fibrosarcoma; Mesocricetus; Mice; Mice, Nude; Stilbenes; Structure-Activity Relationship