Chemopreventive effects of oral gallic acid feeding on tumor growth and progression in TRAMP mice

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Prostate cancer (PCa) is the most common malignancy in elderly men in the United States, and is the second leading cause of cancer related-deaths in men. Chemoprevention of PCa by dietary agents is expectedto delay the neoplastic progression to more advanced state of the disease, which potentially would improve the survival time in PCa patients. One such dietary agent is grape seed extract (GSE), marketed as a dietary supplement, which is a complex mixture of procyanidins and their gallate derivatives. Studies by us and others have shown that GSE inhibits growth of many cancers of epithelial origin including PCa in cell culture. More recently we have shown that GSE inhibits DU145 xenograft growth in nude mice and that it blocks PCa growth and progression of neoplastic stage in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We have identified gallic acid (GA) as one of the constituents of GSE showing in vitro anticancer efficacy against human PCa cells. This was an important observation as GA, in both free and ester forms, is abundantly found in fruits, vegetables and green tea, and has been reported to inhibit growth and induce apoptosis in various cancer cell lines. Based on the anticancer efficacy of GA against PCa cells and the fact that the parent agent GSE exhibits anticancer efficacy against prostate cancer in xenograft and TRAMP model, here, for the first time, we evaluated the chemopreventive efficacy of GA feeding against PCa growth and progression and associated molecular alterations in TRAMP model. At 4 weeks of age, mice were fed with drinking water supplemented with 0.3% and 1% (w/v) GA till 24 weeks of age. The positive control group was fed with regular drinking water for the same period. Our results showed that GA-fed groups had a higher incidence of differentiated lower grade prostatic tumors and a strong decrease (~60 %, P<0.01) in poorly differentiated tumors. Immunohistochemical analysis of prostate tissue showed a decrease in proliferative index by 36%- 41% (P<0.05) in 0.3-1% GA-fed groups; with an increase in the apoptotic cells by 3 fold (P<0.05). Further, GA feeding completely diminished the expression of Cdc2, together with 69-100% (P<0.001-P<0.05) decrease in the expression of Cdk2, Cdk4 and Cdk6 in the prostatic tissue. The protein levels of cyclin B1 and cyclin E were also decreased by more than 50% (P<0.05) by GA-feeding. Together, for the first time we identified that oral GA feeding inhibits PCa growth and progression to advanced stage adenocarcinoma in TRAMP mice via a strong suppression of cell cycle progression and cell proliferation, and an increase in apoptosis. Our findings suggest that GA could be a useful agent for PCa prevention and intervention. However, more studies are warranted to assess whether the anti-PCa efficacy of GA also involves other molecular mechanisms.