Prevention of breast cancer progression by red wine polyphenols Free

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Grape polyphenols in red wine are thought to function as cancer chemopreventives. The most abundant grape polyphenols resveratrol, quercetin, and catechins are structurally similar to estrogen and thus may be especially relevant for hormonal cancers such as breast cancer. While, dietary resveratrol has been shown to prevent mammary carcinogenesis in animal models, the combinatory role of grape polyphenols on established mammary cancers is not known. The hypothesis that grape polyphenols may inhibit breast cancer progression was tested by investigating the effect of resveratrol, quercetin, and catechin on low metastatic MDA-MB-231 human breast cancer cell line in vitro and in vivo. Since cell migration is necessary for invasion during metastasis, we investigated the effect of red wine polyphenols on MDA-MB-231 cell migration. In vitro, high concentrations of resveratrol (50 μM) inhibit migration and invasion of MDA-MB-231 cells, while low concentrations of resveratrol (5 μM) act similar to estrogen and increase breast cancer cell migration and invasion. Individual polyphenols (resveratrol, quercetin, or catechins) at 20 μM did not affect cell migration; however, combined resveratrol, quercetin, and catechins at 20 μM significantly decreased cell migration by 70%. Similarly, 0.5 μM resveratrol, quercetin, or catechins had no effect on cell proliferation of MDA-MB-231 cells but a combination of resveratrol, quercetin, and catechin at 0.5, 5, or 20 μM each reduced cell number significantly from controls by 65%, 83%, and 98% respectively. We then tested the effect of combined dietary resveratrol, quercetin, and catechin on GFP-tagged MDA-MB-231 mammary tumors in nude mice. Eight week old female athymic nude mice were given vehicle or 0.5, 5, or 25 mg/kg body weight of resveratrol, quercetin, and catechin 3X a week starting at the week of xenograft implantation. Mice were implanted with ~2 mm² xenografts of GFP-MDA-MB-231 in the mammary fat pad and imaged starting directly after implantation and 2X a week thereafter. Digital images acquired by a fluorescence macroscopic imaging system were used to calculate the pixel intensity of GFP fluorescence as a measure of tumor growth. At 115 days post implantation, average mammary tumor area increased 5-fold compared to day 0 in mice treated with vehicle alone. Average mammary tumor growth in mice treated with grape polyphenols at 0.5 mg/kg was 3-fold, 5.0 mg/kg was 1.5-fold, and 25.0 mg/kg was 1.6-fold compared to tumor size at day 0. This statistically-significant reduction of primary mammary tumor growth by dietary (5 mg/kg) and pharmacological (25 mg/kg) concentrations of grape polyphenols demonstrates that resveratrol, quercetin, and catechins may exert a synergistic inhibitory effect on mammary tumor progression. This study implicates grape polyphenols as effective therapeutics and preventives of progressive breast cancer. (Supported by AICR IIG 03-31-06 and NCCR/NIH 2G12RR003035)