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 Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IkappaB kinase.
(08/01/2001) ©
La Journée Vinicole
Holmes-McNary M, Baldwin AS Jr
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599-7295, USA.
Trans-Resveratrol (Res), a phytoalexin found at high levels in grapes and in grape products such as red wine, has been shown to have anti-inflammatory and antioncogenic properties. Because the transcription factor nuclear factor kappaB (NF-kappaB) is involved in inflammatory diseases and oncogenesis, we tested whether Res could modulate NF-kappaB activity. Res was shown to be a potent inhibitor of both NF-kappaB activation and NF-kappaB-dependent gene expression through its ability to inhibit IkappaB kinase activity, the key regulator in NF-kappaB activation, likely by inhibiting an upstream signaling component. In addition, Res blocked the expression of mRNA-encoding monocyte chemoattractant protein-1, a NF-kappaB-regulated gene. Relative to cancer chemopreventive properties, Res induced apoptosis in fibroblasts after the induced expression of oncogenic H-Ras. Thus, Res is likely to function by inhibiting inflammatory and oncogenic diseases, at least in part, through the inhibition of NF-kappaB activation by blocking IkappaB kinase activity. These data may also explain aspects of the so-called "French paradox" that is associated with reduced mortality from coronary heart disease and certain cancers and provide a molecular rationale for the role of a potent chemopreventive compound in blocking the initiation of inflammation and oncogenesis.
Cancer Res 2000 Jul 1;60(13):3477-83
Potent inhibitory action of red wine polyphenols on human breast cancer cells.
(08/01/2001) ©
La Journée Vinicole
Damianaki A, Bakogeorgou E, Kampa M, Notas G, Hatzoglou A, Panagiotou S, Gemetzi C, Kouroumalis E, Martin PM, Castanas E
Laboratory of Experimental Endocrinology, University of Crete, School of Medicine and University Hospital, Heraklion, Greece.
Breast cancer (one of the most common malignancy in Western societies), as well as esophagus, stomach, lung, bladder, and prostate cancer, depend on environmental factors and diet for growth and evolution. Dietary micronutriments have been proposed as effective inhibitory agents for cancer initiation, progression, and incidence. Among them, polyphenols, present in different foods and beverages, have retained attention in recent years. Red wine is a rich source of polyphenols, and their antioxidant and tumor arresting effects have been demonstrated in different in vitro and in vivo systems. In the present study, we have measured the antiproliferative effect of red wine concentrate, its total polyphenolic pool, and purified catechin, epicatechin, quercetin, and resveratrol, which account for more than 70% of the total polyphenols in red wine, on the proliferation of hormone sensitive (MCF7, T47D) and resistant (MDA-MB-231) breast cancer cell lines. Our results indicate that polyphenols, at the picomolar or the nanomolar range, decrease cell proliferation in a dose- and a time-dependant manner. In hormone sensitive cell lines, a specific interaction of each polyphenol with steroid receptors was observed, with IC(50)s lower than previously described. Interaction of polyphenols with steroid receptors cannot fully explain their inhibitory effect on cell proliferation. In addition, discrete antioxidant action on each cell line was detected under the same concentrations, both by modifying the toxic effect of H(2)O(2), and the production of reactive oxygen species (ROS), after phorbol ester stimulation. Our results suggest that low concentrations of polyphenols, and consecutively, consumption of wine, or other polyphenol-rich foods and beverages, could have a beneficial antiproliferative effect on breast cancer cell growth.
J Cell Biochem 2000 Jun 6;78(3):429-41
Inhibitory effect of resveratrol on the proliferation of human and rat hepatic derived cell lines.
(08/01/2001) ©
La Journée Vinicole
Delmas D, Jannin B, Malki MC, Latruffe N
LBMC, Molecular and Cellular Laboratory, University of Burgundy, 21000 Dijon, France.
Resveratrol is a polyphenolic compound especially produced by grapevine and consequently found in wine. Based on epidemiological studies resveratrol may act as a cancer chemopreventive compound. The ability of resveratrol to inhibit cell proliferation was studied in rat hepatoma Fao cell line and human hepatoblastoma HepG2 cell line. The results show that resveratrol strongly inhibits cell proliferation at the micromolar range in a time- and dose-dependent manner. Concentrations higher than 50 &mgr;M become toxic. Fao cells are more sensitive than HepG2 cells. Interestingly, the presence of ethanol lowers the threshold of resveratrol effect. Resveratrol appears to prevent or to delay the entry to mitosis since no inhibition of [3H]thymidine incorporation is observed, while there is an increase of cell number in S and G2/M phases. In conclusion, resveratrol shows a strong inhibition of hepatic cell proliferation where alcohol may act as an enhancing agent.
Oncol Rep 2000 Jul-Aug;7(4):847-52
Anti-tumor effect of methanol extracts from red and white wines.
(08/01/2001) ©
La Journée Vinicole
Kamei H, Hashimoto Y, Koide T, Kojima T, Hasegawa M
Department of Surgery, Aichi-Gakuin University Hospital, Nagoya, Japan. kamei@dpc.aichi-gakuin.ac.jp
Crude methanol extracts of red and white wines were added to diethyl ether in order to divide them into the anthocyanin fraction (insoluble in diethyl ether) and fractions containing other flavonoids and their derivatives (soluble in diethyl ether). However, the white wine did not contain anthocyanins (all of the methanol extract was soluble in diethyl ether). When HCT-15 cells, derived from human colon cancer or AGS cells, derived from human gastric cancer, were cultured with these fractions, the anthocyanin fraction from the red wine and the non-anthocyanic substances extracted from red and white wines suppressed the growth of the cells, and the suppression rate by the anthocyanin fraction was significantly higher than that of the other fractions. Thin-layer chromatographic analysis revealed mostly delphinidin in the anthocyanin fraction. The other fractions contained mostly flavonoids and their derivatives. The sugars in all fractions were mainly glucose, fucose, and fructose. Flow cytometric study suggested that the anthocyanin fraction blocked mostly S, G2, and M phase, and the non-anthocyanic flavonoids also blocked these phases, although the histographic pattern varied depending on the fractions. Methanol insoluble but water soluble fractions (mostly free sugars) of red and white wines did not show such suppressive effects.
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Cancer Biother Radiopharm 1998 Dec;13(6):447-52
Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells.
(08/01/2001) ©
La Journée Vinicole
Schneider Y, Vincent F, Duranton B, Badolo L, Gosse F, Bergmann C, Seiler N, Raul F
ULP/CJF INSERM 95-09, Laboratory of Metabolic and Nutritional Control in Digestive Oncology, IRCAD, 1 Place de l’Hopital, 67091, Strasbourg, France
Resveratrol, a natural polyphenolic phytoalexine present in grapes and wines, has been reported to exert a variety of important pharmacological effects. We investigated the effects of resveratrol on the growth and polyamine metabolism of CaCo-2 human colon cancer cells. Treatment of the CaCo-2 cells with 25 muM resveratrol caused a 70% growth inhibition. The cells accumulated at the S/G2 phase transition of the cell cycle. No signs of cytotoxicity or apoptosis were detected. Resveratrol caused a significant decrease of ornithine decarboxylase (ODC) activity, a key enzyme of polyamine biosynthesis, which is enhanced in cancer growth. ODC inhibition resulted in the reduction of the intracellular putrescine content, indicating that polyamines might represent one of several targets involved in the anti-proliferative effects of resveratrol.
Cancer Lett 2000 Sep 29;158(1):85-91
Resveratrol, a natural stilbene in grapes and wine, enhances intraphagocytosis in human promonocytes: a co-factor in antiinflammatory and anticancer chemopreventive activity.
(08/01/2001) ©
La Journée Vinicole
Bertelli AA, Ferrara F, Diana G, Fulgenzi A, Corsi M, Ponti W, Ferrero ME, Bertelli A
Institute of Human Anatomy, Faculty of Medicine, University of Milan, Italy. MariaElena.Ferrero@unimi.it
Trans-resveratrol, a natural stilbene present in wine and grapes, has been studied mainly for its antiinflammatory and anticancer activities. In this study the activity of resveratrol on proliferative immunological parameters (differentiation, apoptosis, phagocytosis and intracellular killing) was studied using a U937 human promonocytic cell line in comparison with another polyphenol, quercetin. After incubation of the pathogen, Candida albicans, intracellular killing by macrophage-like cells was decreased by quercetin and resveratrol 10 microM but was enhanced by resveratrol 1 microM after 20 h of treatment. Phagocytosis rate, expressed as phagocytosis frequency, (i.e., percentage number of phagocytosing cells/total cells) at 20 h was highest with resveratrol 10 microM and was higher with quercetin 10 microM than with resveratrol 1 microM. The phagocytosis index exhibited the same trend. While both polyphenols demonstrated cytostatic activity on U937 growth, a prointraphagocytic effect for resveratrol 10 microM-treated cells at 10 min, resveratrol 1 microM-treated cells at 20 h and resveratrol 10 microM-treated cells at 48 h was observed. Morphological examination with optic microscopy demonstrated both apoptotic and differentiating cells, even after 10 min treatment. Resveratrol-induced apoptosis (following 4 h treatment) was confirmed by flow cytometry at concentrations as low as 1 microM and 100 nM in the assay for detection of membrane phosphatidylserine. Resveratrol- or quercetin-treated, but unstimulated cells, did not produce tumor necrosis factor-alpha protein. As phosphatidylserine externalization triggers specific recognition by monocytes and macrophages, removal of intact apoptotic cells is important a) in cell population selection and differentiation for antiblastic therapy, and b) in preventing the release of toxic inflammatory substances such as reactive oxygen substances and proteolytic enzymes by dying cells. This observation suggests that wine polyphenols, at the same concentrations as those found in plasma after moderate wine consumption, are important cofactors in antiinfective, antiinflammatory and anticancer nonspecific immune reactions.
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Int J Tissue React 1999;21(4):93-104
Smoking, type of alcoholic beverage and squamous-cell oesophageal cancer in northern Italy.
(08/01/2001) ©
La Journée Vinicole
Zambon P, Talamini R, La Vecchia C, Dal Maso L, Negri E, Tognazzo S, Simonato L, Franceschi S
Servizio di Epidemiologia dei Tumori, Registro Tumori del Veneto, Padua, Italy.
Between 1992 and 1997, we conducted a case-control study of oesophageal cancer in 3 areas of northern Italy. Cases were 275 men, ages 39-77 years (median age 60), with a first incident squamous-cell carcinoma of the oesophagus. Controls were 593 men, ages 36-77 years (median age 60) admitted for acute illnesses, unrelated to tobacco and alcohol, to major hospitals of the areas under surveillance. Number of daily cigarettes was strongly associated with risk [odds ratio (OR) for > or =25 cigarettes/day = 7.0)]. Long-duration smoking showed particularly elevated ORs (OR = 6.4 for > or =35 years), and excess risk declined after smoking cessation (OR = 1.5 after > or = 10 years). Oesophageal cancer risk steeply rose with increasing level of alcohol consumption. ORs were 6.2 for 35-55 drinks and 24.5 for 84 drinks or more per week. No trend in risk emerged for duration of alcohol drinking or age at start of drinking. The risk in the highest joint level of alcohol drinking and current smoking was increased 130 folds (i.e., compatible with a multiplicative model). Excess risk in drinkers chiefly derived from wine. In conclusion, alcohol drinking and cigarette smoking were both important, but the roles of dose and duration of exposure differed. The association with alcohol was stronger than the one with smoking by exposure intensity, but apparently unaffected by duration or other temporal variables.
Int J Cancer 2000 Apr 1;86(1):144-9
Resveratrol induces Fas signalling-independent apoptosis in THP-1 human
(08/01/2001) ©
La Journée Vinicole
Tsan MF, White JE, Maheshwari JG, Bremner TA, Sacco J
Research and Medical Services, Stratton VA Medical Center, Albany, NY 12208, USA.
Resveratrol, a natural product present in wine, has recently been shown to inhibit the growth of a number of cancer cell lines in vitro. In the current study, we have demonstrated that resveratrol inhibits the growth of THP-1 human monocytic leukaemia cells in a dose-dependent manner with a median effective dose of 12 microM. It did not induce differentiation of THP-1 cells and had no toxic effect on THP-1 cells that had been induced to differentiate into monocytes/macrophages by phorbol myristate acetate. A significant fraction of resveratrol-treated cells underwent apoptosis as judged by flow cytometric analysis of DNA content, DNA fragmentation and caspase-specific cleavage of poly(ADP-ribosyl) polymerase. Resveratrol treatment had no effect on the expression of Fas receptor or Fas ligand (FasL) in THP-1 cells, nor did it induce clustering of Fas receptors. In addition, THP-1 cells were resistant to activating anti-Fas antibody, and neutralizing anti-Fas and/or anti-FasL antibodies had no protective effect against resveratrol-induced inhibition of THP-1 cell growth. The effect of resveratrol on THP-1 cells was reversible after its removal from the culture medium. These results suggest that (1) resveratrol inhibits the growth of THP-1 cells, at least in part, by inducing apoptosis, (2) resveratrol-induced apoptosis of THP-1 cells is independent of the Fas/FasL signalling pathway and (3) resveratrol does not induce differentation of THP-1 cells and has no toxic effect on differentiated THP-1 cells. Thus, resveratrol may be a potential chemotherapeutic agent for the control of acute monocytic leukaemia.
Br J Haematol 2000 May;109(2):405-12
A prospective cohort study on consumption of alcoholic beverages in relation to prostate cancer incidence (The Netherlands).
(08/01/2001) ©
La Journée Vinicole
Schuurman AG, Goldbohm RA, van den Brandt PA
Department of Epidemiology, Maastricht University, The Netherlands. Agnes.Schuurman@hag.unimaas.nl
OBJECTIVES: To examine alcohol consumption in relation to prostate cancer incidence in the Netherlands Cohort Study. METHODS: At baseline in 1986, 58,279 men aged 55-69 years completed a self-administered questionnaire on diet, consumption of alcoholic beverages and other risk factors for cancer. For data processing and analyses the case-cohort approach was used. After 6.3 years of follow-up, 680 incident primary prostate cancer cases were available for analysis. RESULTS: In multivariate analyses adjusted for age, socioeconomic status and family history of prostate cancer, no association between total alcohol consumption, alcohol intake from beer and liquor and prostate cancer risk was found. Increased associations were found for alcohol from white wine and fortified wines compared to nondrinkers, but not for red wine. The RRs (95% CI) in the intake category of > or = 15 g/day were 3.3 (1.2-9.2) and 2.3 (1.2-4.7), respectively, after additional adjustment for total alcohol intake. There was, however, no significant trend in risk. Alcohol intake was more strongly related with localized than with advanced prostate tumors. CONCLUSION: Our results do not support an important role for alcohol in prostate cancer etiology. Nevertheless, for specific types of alcoholic beverages, particularly wines, a positive association was suggested which needs examination in further studies.
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Cancer Causes Control 1999 Dec;10(6):597-605
Chemoprevention of cancer and cardiovascular disease by resveratrol.
(08/01/2001) ©
La Journée Vinicole
Lin JK, Tsai SH
Institute of Biochemistry, College of Medicine, National Taiwan University, Taipei, R.O.C.
Resveratrol (trans-3,4’,5-trihydroxystibene) is a phytopolyphenol isolated from the seeds and skins of grapes. Recent studies indicate that resveratrol can block the process of multistep carcinogenesis, namely, tumor initiation, promotion and progression. Resveratrol can also reduce the risk of cardiovascular disease in man. The molecular mechanisms of resveratrol in chemoprevention of cancer and cardiovascular disease are interesting and under intensive investigation. Resveratrol was found to strongly inhibit nitric oxide (NO) generation in activated macrophages, as measured by the amount of nitrite released into the culture medium, and resveratrol strongly reduced the amount of cytosolic inducible nitric oxide synthase (iNOS) protein. The activation of nuclear factor kappa B (NF kappa B) induced by lipopolysaccharide (LPS) was inhibited by resveratrol. The phosphorylation and degradation of nuclear factor inhibitor kappa B alpha (I kappa B alpha) were inhibited by resveratrol simultaneously. Reactive oxygen species (ROS) are regarded as having carcinogenic potential and have been associated with tumor promotion. Resveratrol may act as a reactive oxygen species scavenger to suppress tumor development. In addition, resveratrol may block multistep carcinogenesis through mitotic signal transduction blockade. Reactive oxygen species are pivotal factors in the genesis of heart disease. Meanwhile, efficient endogenous antioxidants, including superoxide dismutase (SOD), glutathione peroxidase (GSHPx), and catalase, are present in tissues. A fine balance between reactive oxygen species and endogenous antioxidants is believed to exist. Any disturbance of this balance in favor of reactive oxygen species causes an increase in oxidative stress and initiates subcellular changes, leading to cardiomyopathy and heart failure. The experimental results indicate that exogenous antioxidant resveratrol is of value in chemopreventing the development of heart disease. It is urgent that more efforts be made to investigate newer therapies employing antioxidants for the chemoprevention of cardiovascular disease and cancer.
Proc Natl Sci Counc Repub China B 1999 Jul;23(3):99-106
Resveratrol, an antioxidant present in red wine, induces apoptosis in human promyelocytic leukemia (HL-60) cells.
(08/01/2001) ©
La Journée Vinicole
Surh YJ, Hurh YJ, Kang JY, Lee E, Kong G, Lee SJ
Laboratory of Biochemistry and Molecular Toxicology, College of Pharmacy, Seoul National University, South Korea. surh@plaza.snu.ac.kr
Resveratrol, a triphenolic stilbene present in grapes and other plants, has striking antioxidant and anti-inflammatory activities which have been considered to be responsible for the beneficial effects of red wine consumption on coronary heart disease. Recent studies reveal that resveratrol can inhibit each step of multistage carcinogenesis. However, the molecular mechanisms underlying anti-tumorigenic or chemopreventive activities of this phytochemical remain largely unknown. In the present work, we have found that resveratrol reduces viability and DNA synthesis capability of cultured human promyelocytic leukemia (HL-60) cells. The growth inhibitory and antiproliferative properties of resveratrol appear to be attributable to its induction of apoptotic cell death as determined by morphological and ultrastructural changes, internucleosomal DNA fragmentation, and increased proportion of the subdiploid cell population. Resveratrol treatment resulted in a gradual decrease in the expression of anti-apoptotic Bcl-2. These results, together with previous findings, suggest the cancer therapeutic as well as chemopreventive potential of resveratrol.
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Cancer Lett 1999 Jun 1;140(1-2):1-10
Alcohol intake and the risk of lung cancer: influence of type of alcoholic beverage.
(08/01/2001) ©
La Journée Vinicole
Prescott E, Gronbaek M, Becker U, Sorensen TI
Copenhagen Centre for Prospective Population Studies, Danish Epidemiology Science Centre at the Institute of Preventive Medicine, H:S Kommunehospitalet, Copenhagen University Hospital.
Alcohol consumption has been associated with an increased risk of lung cancer, but the antioxidants in wine may, in theory, provide protection. This association was studied in 28,160 men and women subjects from three prospective studies conducted in 1964-1992 in Copenhagen, Denmark. After adjustment for age, smoking, and education, a low to moderate alcohol intake (1-20 drinks per week) was not associated with an increased risk of lung cancer. Men who consumed 21-41 and more than 41 drinks per week had relative risks of 1.23 (95% confidence interval (CI) 0.88-1.74) and 1.57 (95% CI 1.06-2.33), respectively. The risk of lung cancer differed according to the type of alcohol consumed: After abstainers were excluded, drinkers of 1-13 and more than 13 glasses of wine per week had relative risks of 0.78 (95% CI 0.63-0.97) and 0.44 (95% CI 0.22-0.86), respectively, as compared with nondrinkers of wine (p for trend = 0.002). Corresponding relative risks for beer intake were 1.09 (95% CI 0.83-1.43) and 1.36 (95% CI 1.02-1.82), respectively (p for trend = 0.01); for spirits, they were 1.21 (95% CI 0.97-1.50) and 1.46 (95% CI 0.99-2.14), respectively (p for trend = 0.02). In women, the ability to detect associations with high alcohol intake and type of beverage was limited because of a limited range of alcohol intake. The authors concluded that in men, a high consumption of beer and spirits is associated with an increased risk of lung cancer, whereas wine intake may protect against the development of lung cancer.
Am J Epidemiol 1999 Mar 1;149(5):463-70
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