Chemoprevention of Prostate Cancer by Naturally Occurring and Synthetic Organoselenium Compounds

摘要

The lack of treatment for worried well patients with prostatic intraepithelial neoplasia (a premalignant condition) combined with issues of recurrence and hormone resistance present significant obstacles to prostate cancer survivorship. The long latency of prostate cancer provides opportunity to intervene with mechanistically-based agents at various stages of disease progression. Selenium, an essential nutrient and known antioxidant, has been shown in epidemiologic and preclinical studies to be protective against prostate cancer. However, clinical intervention trials with selenium have thus far had contradictory outcomes and the anti-cancer mechanisms of selenium compounds are not well understood. In the present investigation we have found that, in contrast to naturally occurring SM, the synthetic organoselenium agent p-XSC dose-dependently inhibits viability, induces apoptosis, and modulates critical signaling molecules in both AR and AI cells. p-XSC effectively inhibits androgen receptor expression and transcriptional activity, Akt phosphorylation, and Akt-specific phosphorylation of the androgen receptor. We also show that p-XSC preferentially inhibits mTOR complex 2 (mTORC2) signaling in AI cells, a novel potential target for selenium in prostate cancer. We also show that p-XSC in combination with the mTORC1 inhibitor rapamycin more effectively inhibits aggressive prostate cancer cell growth than either agent alone, highlighting the importance of mechanistic information for the design of combination strategies. Our findings support the notion that selenium compounds may be of value, either individually or in combination with other therapies, for the treatment of prostate cancer because of their potential to inhibit critical prostate signaling pathways.