Nonsteroidal anti-inflammatory drugs including
sulindac are well documented to be highly effective for
cancer chemoprevention. However, their
cyclooxygenase (COX)-inhibitory activities cause severe gastrointestinal, renal, and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of nonsteroidal anti-inflammatory drugs and support the potential for the development of a novel generation of
sulindac derivatives lacking COX inhibition for
cancer chemoprevention. A prototypic
sulindac derivative with a N,N-dimethylammonium substitution called
sulindac sulfide amide (SSA) was recently identified to be devoid of COX-inhibitory activity yet displays much more potent
tumor cell growth-inhibitory activity in vitro compared with
sulindac sulfide. In this study, we investigated the
androgen receptor (AR) signaling pathway as a potential target for its COX-independent
antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate
carcinogenesis using the transgenic
adenocarcinoma of mouse prostate model. The results showed that SSA significantly suppressed the growth of human and mouse
prostate cancer cells expressing AR in strong association with G(1) arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression through repressing cell proliferation in the transgenic
adenocarcinoma of mouse prostate mice, whereas it did not significantly affect
neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial
carcinogenesis.