Abstract #953: Prostate cancer chemopreventive efficacy and mechanisms of a novel sulindac derivative

Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac have promising potential for cancer chemoprevention. However, low efficacy and dose-limiting toxicities related to cyclooxygenase (COX-1,2) inhibition pose major problems for their clinical development. In this study, we tested the merit of SRI21009, a prototypic sulindac derivative synthesized and developed at Southern Research Institute as a safer and effective chemopreventive agent for prostate cancer. SRI21009 is totally devoid of COX-1,2-inhibitor activity using purified isozymes. Using human prostate cancer cell lines, SRI 21009 displayed high potency to inhibit growth by causing G₁ cell cycle arrest and caspase-mediated apoptosis. In support of a specificity for prostate cancer prevention, SRI21009 potently decreased androgen receptor expression. These data led us to test the hypothesis that SRI21009 might prevent prostate carcinogenesis through COX-independent mechanisms using the transgenic adenocarcinoma of mouse prostate (TRAMP) mouse model. In a short-term experiment, eighteen 6-week old male C57BL6 TRAMP mice were randomly divided into 2 groups and fed Teklad 2918 diet with 3000 ppm SRI21009 (n= 12) or without (n=6), respectively, as were 12 wild-type male mice. All the mice were monitored and weighed once a week, and euthanized at 12-weeks of age. The genito-urinary (GU) tract and dorsal-lateral prostate (DLP) were dissected, weighed and normalized to body weight. The results showed that dietary SRI21009 decreased the relative weight of the GU tract in TRAMP mice by 18% (t-test, p<0.01), and significantly reduced the relative weight of DLP by 43% (P <0.00001) where most of the epithelial lesions are located in the TRAMP model. No difference was observed for the relative DLP weight with regard to SRI21009 feeding in the wild type mice (t-test, p=0.62). Histo-pathological examination showed that SRI21009 feeding significantly delayed prostate lesion progression. A second experiment (sixteen-week treatment) is ongoing to further investigate the safety and efficacy as well as the potential biological targets of SRI21009 feeding at 2000 ppm. Overall, available data suggest that SRI21009 or a related analog with improved bioavailability may be a potential chemopreventive drug candidate against prostate cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 953.