The
cancer preventive properties of grape products such as red wine have been attributed to
polyphenols enriched in red wine. However, much of the studies on
cancer preventive mechanisms of grape
polyphenols have been conducted with individual compounds at concentrations too high to be achieved via dietary consumption. We recently reported that combined grape
polyphenols at physiologically relevant concentrations are more effective than individual compounds at inhibition of
ERalpha(-),
ERbeta(+) MDA-MB-231
breast cancer cell proliferation, cell cycle progression, and primary mammary
tumor growth (Schlachterman et al., Transl Oncol 1:19-27, 2008). Herein, we show that combined grape
polyphenols induce apoptosis and are more effective than individual
resveratrol,
quercetin, or
catechin at inhibition of cell proliferation, cell cycle progression, and cell migration in the highly metastatic ER (-) MDA-MB-435 cell line. The combined effect of dietary grape
polyphenols (5 mg/kg each
resveratrol,
quercetin, and
catechin) was tested on progression of mammary
tumors in nude mice created from
green fluorescent protein-tagged MDA-MB-435 bone metastatic variant. Fluorescence image analysis of primary
tumor growth demonstrated a statistically significant decrease in
tumor area by dietary grape
polyphenols. Molecular analysis of excised
tumors demonstrated that reduced mammary
tumor growth may be due to upregulation of FOXO1 (forkhead box O1) and NFKBIA (
IkappaBalpha), thus activating apoptosis and potentially inhibiting NfkappaB (
nuclear factor kappaB) activity. Image analysis of distant organs for
metastases demonstrated that grape
polyphenols reduced
metastasis especially to liver and bone. Overall, these results indicate that combined dietary grape
polyphenols are effective at inhibition of mammary
tumor growth and site-specific
metastasis.