Abstract #960: Finasteride in combination with NSAIDs modulates the genetic risk of prostate cancer: In vivo evidence

Background: The Prostate Cancer Prevention Trial (PCPT) in a total of 1,626 men demonstrated that finasteride, a 5\#945; reductase inhibitor reduces prostate cancer risk by 24.8%, and however, it was associated with a risk of small increase in high-Gleason grade tumors. To enhance the efficacy of finasteride, earlier studies have successfully used finasteride with other agents such as flutamide. Based on our earlier experience in enhancing the chemopreventive effects of NSAIDs, in this study, we tested the efficacy of finasteride with celecoxib and aspirin in preclinical models to synergistically decrease prostate cancer incidence. Methods: We examined the effects of finasteride individually and in combination with celecoxib or aspirin using in vitro and in vivo models. We used murine prostate cancer cells (CaP8) deleted for Pten-/- and human benign prostate hyperplastic epithelial cells (BPH1) to understand the mechanisms. The cells were pretreated for 24h with testosterone before incubating with different doses of finasteride (15\#956;M) or aspirin (40\#956;M) or celecoxib (40\#956;M) individually and in combination (half of each of the single dose) for 48 h. Effect on cell growth, cell cycle, apoptosis, molecular targets AR, 5aR, AKT, Cyclin D1, COX-2 and serum PGE2 levels were analyzed with MTT, flow cytometry, Western blot and ELISA assays. To determine in vivo efficacy, four week old PTEN/KO mice (n=20/group) were administered orally with finasteride (72mg/kg/bw) or celecoxib (500 mg/kg/bw) individually and in combinations. The agents were administered three times in a week for a period of eight weeks and terminated at the age of 12 weeks. Histopathological analysis was performed to determine the incidence of mPIN or adenocarcinomas. Specific immunohistochemical staining was performed to detect the molecular targets. Results: In vitro studies using Cap8 and human BPH1cells showed a significant inhibitory effect on cell survival and induced cell cycle arrest at the G1-S phase transition after treatment with celecoxib and aspirin in combination with finasteride for 48h. In vivo evidence on the histological determination of mPIN showed a significant decrease in the group of mice that received finasteride in combination with celecoxib or aspirin after six 8 weeks of treatment in contrast to the mice that received finasteride alone (P Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 960.