Raina Komal, Rajamanickam Subapriya, Deep Gagan, Singh Meenakshi, Agarwal Rajesh, Agarwal Chapla
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado-Denver, 4200 East Ninth Street, Box C238, Denver, CO 80262, USA.
Mol Cancer Ther. 2008 May;7(5):1258-67. doi: 10.1158/1535-7163.MCT-07-2220. Epub 2008 Apr 29.
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 ( approximately 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.
我们最近的研究已确定没食子酸是葡萄籽提取物的主要成分之一，其在体外对人前列腺癌细胞显示出强大的抗癌功效。在此，我们首次通过评估没食子酸对小鼠前列腺转基因腺癌（TRAMP）模型中前列腺肿瘤生长和进展的活性，确立了其对前列腺癌的体内化学预防功效。4周龄时，给雄性TRAMP小鼠饮用补充有0.3%和1%（w/v）没食子酸的水，直至24周龄。阳性对照组在同一时期饮用常规饮用水。我们的结果表明，食用没食子酸的组中分化程度较低的前列腺肿瘤发生率较高，代价是低分化肿瘤大幅减少（约60%；P<0.01）。前列腺组织的免疫组织化学分析显示，在食用0.3%至1%没食子酸的组中，增殖指数降低了36%至41%（P<0.05），凋亡细胞增加了3倍（P<0.05）。此外，两种剂量的没食子酸都完全消除了前列腺组织中Cdc2的表达，并使Cdk2、Cdk4和Cdk6的表达大幅下降。食用没食子酸还降低了细胞周期蛋白B1和E的蛋白质水平。总之，我们首次发现，口服没食子酸可通过强烈抑制细胞周期进程和细胞增殖以及增加细胞凋亡，来抑制TRAMP小鼠前列腺癌的生长和向晚期腺癌的进展。
