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292 A. SCALBERT ET AL. Both green tea polyphenols and curcumin were found to inhibit cyclooxygenase-2 activity and arachidonic metabolism in the colonic mucosa of rats.127 Phenolic phytoestrogens could influ- ence the growth of hormone responsive tumors through their estrogenic properties or their capacity to affect the response to endogenous estrogens.128,129 This may explain the protective effects of isoflavones against mammary and prostate cancers observed in different animal models.130 Polyphenols can induce apoptosis of tumor cells and, there- fore, reduce the growth of tumors. Evidence has been given both in vitro121 and in vivo.131,132 However, the significance of this mechanism in cancer prevention is not clear, as polyphenols may also have opposite effects. They were shown to inhibit apopto- sis of some non-tumorigenic cells when induced by hydrogen peroxide.133,134 Lastly, polyphenols, such as those of green tea, can also inhibit angiogenesis and, therefore, limit the growth of the tumors,135,136 or prevent tumor invasion through inhibition of the matrix metalloproteinases.137,138 However, in an experi- ment with nude-mice inoculated sub-cutaneously with a human colon carcinoma cell line, the growth of the tumors was inhibited by EGCG added in the drinking water from d 45, after inocula- tion and thereafter.139 The authors concluded that an effect on angiogenesis starting earlier in the development of the tumor was unlikely; they showed that an inhibition of telomerase was involved. The anticarcinogenic properties of polyphenols could, thus, be explained by many different mechanisms. To explain their protective effect by their antioxidant properties and inhibition of DNA oxidative damage is certainly an oversimplification. How- ever, various antioxidants, including polyphenols, inhibit NF-kB activation, probably through triggering a redox-sensitive signal in the cells.140,141 The inhibition of such transcription factors by polyphenols may play an essential role in the prevention of cancers.142,143 Beyond these, many hypotheses on mechanisms of action, the most difficult task, remain to demonstrate their anticarcinogenic effects in humans. Often, the doses used in animal or cell experiments largely exceed those that can be expected in humans on a regular diet. All the corresponding literature should clearly be re-examined to take into account the doses applied, as well as the mode of administration. More credit should be given to the effects ob- served at low doses. Intravenous administration of very high doses of quercetin (up to 2000 mg/m2) at a 3-wk interval to 51 patients having a cancer resistant to standard therapies in- duced a decrease of some tumor markers.144 These doses are clearly far beyond what could be expected from dietary expo- sure, and such results are of low value to elucidate the role of dietary polyphenols in cancer prevention. A clear distinction between cancer treatment at pharmacological doses and cancer prevention at dietary levels of exposure should be made when discussing experimental results obtained on animal models or on cell lines grown in vitro. The confusion is often maintained on purpose, to communicate on the beneficial health effects of polyphenol-containing food products. For example, resveratrol has interesting anticarcinogenic properties that may lead to the development of new drugs.145 Its presence in wine and absence in any food sources has stimulated the interest of the industry to promote the health properties of wine. However, its very low concentration in wine (0.3–2 mg/L in red wines)146 makes the attribution of the wine health benefits to this molecule unlikely. The question of doses is essential, as opposite effects have been observed at different exposure levels. Caffeic acid induces hyperplasia and tumors in the forestomach and kidney when ad- ministered in the diet of rats or mice at a dose of 0.5–2% of the diet, whereas it shows anticarcinogenic effects at doses of 0.05– 0.15 %.147 On the contrary, genistein at high doses (50–100 μM) inhibits the growth of human breast cancer cells in vitro, whereas it induces proliferation at lower doses (0.01–10 μM), effects that were explained by their estrogenic properties at low doses and cytotoxicity at higher doses.148 A similar influence of the dose of genistein was observed on the expression of prostate-specific antigen by prostate cancer cells.149 Neurodegeneration induced in mice by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was prevented by low doses of green tea (0.5–1 mg/kg i.p.), whereas higher doses (5 mg/kg) increased the toxicity of the drug.150 In the future, more attention should be paid to those studies showing effects at doses compatible with exposure experienced by humans with their diet, or to in vitro studies using polyphe- nol concentrations close to documented plasmatic or tissular concentrations. When calculating the dose to be administered to animals, extrapolation from human dietary intake should be made, preferentially at a constant content in the diet rather than at a constant intake per body weight unit, as has been recently discussed.151 For example, an intake of 40 mg/d isoflavone, an average value for Japanese populations,152 would correspond to a dose of about 0.01% in the diet, well below most of the doses tested in animal experiments. More credit should also be given to the studies where polyph- enols were administered per os, or to in vitro studies using polyphenol metabolites (largely conjugated metabolites), and not polyphenols in their ingested form. Indeed, as stressed above, polyphenols are essentially present in blood and tissues as con- jugated metabolites, and there is still limited evidence that they can be deconjugated in vivo.3,153 Thus, studies where dietary polyphenols are administered by injection are of limited value to understand their health effects, and in vitro studies with non- conjugated polyphenols should be re-evaluated using their con- jugated metabolites.14,133,154−156 The final evidence on the prevention of cancers by polyphe- nols will come from clinical and epidemiological studies. Tumor biomarkers are useful tools for prognosis, for the monitoring of therapy in various cancers, and for the evaluation of the influence of diet on the disease.157 Some polyphenols have been shown to reduce the levels of tumor biomarkers in different cancer cell lines. Genistein decreased the expression of protein-specific antigen (PSA) in prostate cancer cells149 and EGCG, epicate- chin gallate, or genistein significantly reduced in a human lung cancer cell line, the levels of heterogeneous nuclear ribonucleo- protein B1, a new biomarker for early clinical diagnosis of lung cancer.158 However, clinical evidence of an effect of polyphenolsPDF Image | Dietary Polyphenols and the Prevention of Diseases
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