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Research Articles: Therapeutics, Targets, and Development

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

¹ Department of Pharmaceutical Sciences, School of Pharmacy, ² Department of Pathology, and ³ University of Colorado Cancer Center, University of Colorado-Denver, Denver, Colorado

Requests for reprints: Chapla Agarwal, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado-Denver, 4200 East Ninth Street, Box C238, Denver, CO 80262. Phone: 303-315-1382; Fax: 303-315-6281. E-mail: Chapla.Agarwal{at}uchsc.edu

Abstract

Our recent studies have identified gallic acid as one of the major constituents of grape seed extract showing strong in vitro anticancer efficacy against human prostate cancer cells. Herein, for the first time, we established the in vivo chemopreventive efficacy of gallic acid against prostate cancer by evaluating its activity against prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. At 4 weeks of age, male TRAMP mice were fed with drinking water supplemented with 0.3% and 1% (w/v) gallic acid until 24 weeks of age. Positive control group was fed with regular drinking water for the same period. Our results showed that gallic acid–fed groups had a higher incidence of differentiated lower-grade prostatic tumors at the expense of strong decrease (60%; P < 0.01) in poorly differentiated tumors. Immunohistochemical analysis of prostate tissue showed a decrease in proliferative index by 36% to 41% (P < 0.05) in 0.3% to 1% gallic acid–fed groups, with an increase in the apoptotic cells by 3-fold (P < 0.05). Further, both doses of gallic acid completely diminished the expression of Cdc2 in the prostatic tissue together with strong decrease in the expression of Cdk2, Cdk4, and Cdk6. The protein levels of cyclin B1 and E were also decreased by gallic acid feeding. Together, for the first time, we identified that oral gallic acid feeding inhibits prostate cancer 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. [Mol Cancer Ther 2008;7(5):1258–67]

Grant support: National Cancer Institute grant RO1 CA91883.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Rajesh Agarwal, unpublished data.

Received 10/22/07; revised 1/31/08; accepted 2/ 2/08.