Inhibition of mammary tumor growth and metastases to bone and liver by dietary grape polyphenols
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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 ERα(−), ERβ(+) 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 (IκBα), thus activating apoptosis and potentially inhibiting NfκB (nuclear factor κB) 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.
KeywordsBreast cancer Catechin Metastasis Quercetin Resveratrol
We acknowledge the excellent technical assistance of Alexander Schlachterman, Felix Valle, and Alina De La Mota-Peynado with the animal protocols. This research was supported by grant numbers AICR IIG 03-31-06 and DoD/BCRP W81XWH-07-1-0330 to SD; DoD/BCRP W81XWH-08-01-0258 to LCP; NCCR/NIH 2G12RR003035, S06GM050695, and G11HD052352 to UCC; and NIH/RCMI G12-RR03051 and MBRS-RISE 5R25GM061838-08 to UPR-MSC. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCRR, NICHD, NIGMS or the National Institutes of Health.
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