Abstract
3348
Prostate cancer is the most common malignancy in elderly American men and second only to lung cancer in deaths. According to the American Cancer Society in the United States alone, there are an estimated 234,460 new prostate cancer cases, which will take the lives of an estimated 27,350 men in 2006. In the past few years there has been a lot of activity directed towards the identification of dietary products for both prevention and intervention of prostate cancer. One such agent is Grape seed extract (GSE) which has shown promising chemopreventive and anticancer effects in various cancer cell lines and animal tumor models. In the present study we have evaluated the chemopreventive efficacy of GSE against prostate cancer in TRAMP mice by oral gavage of GSE (200 mg/kg body weight) for 4-28 weeks of age. At the time of necropsy, the lower genitourinary tract (GUT) was removed en bloc. The dorsolateral prostate/ tumor was microdissected and divided into two portions, one part was snap frozen for the preparation of tissue lysates and the other fixed for histopathological studies. Our results showed a significant reduction (46.1%, P<0.01) in the weight of genitourinary tract (GUT) organs in the GSE-fed mice compared to those of the control group. The GSE-fed mice had a higher incidence of PIN but showed a reduction in the incidence of adenocarcinoma than the control mice. This suggests that GSE causes an arrest of the tumor progression in neoplastic stage thereby reducing the incidence of adenocarcinoma in TRAMP mice after 4-28 weeks of treatment. The quantification of PCNA immunohistochemical staining showed a decrease in proliferation index in GSE-fed groups (31.8%, P<0.001) as compared with the control group. Immunoblot analysis of the tissue lysates showed a 64 ± 6.3% (P<0.01) decrease in PCNA protein expression in the GSE-fed mice compared with the control group. The number of TUNEL-positive apoptotic cells in the GSE-fed group was 22.3 ± 1.2% as compared to 2.8 ± 0.21% in the control group. Immunoblot analysis of the tissue lysates showed that the expression of cyclin B1 and cyclin A was strongly decreased by 84% and 95.7% (P<0.05, for both) respectively; levels of cyclin E protein was also found to decrease by 89% (P<0.001) in the GSE-fed group. The expression of Cdc2, Cdk2 and Cdk6 was decreased by more than 90% in the GSE-fed mice, P<0.05. These results indicate that by inhibiting the expression of cyclins and cyclin dependant kinases, GSE feeding led to an arrest of the tumor grade at an earlier stage and hence was able to inhibit the progression of the tumor in the TRAMP mice. Thus the present investigation shows that the oral gavage of GSE decreases cell proliferation and increases apoptosis in TRAMP mice leading to inhibition of prostate cancer growth. These observations strongly support the fact that GSE may prove to be a promising chemopreventive agent that can prevent or slow the progress of prostate cancer in humans.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA