Prostate cancer (PCa) is one of the most commonly diagnosed malignancies and a leading cause of cancer related deaths among men in the United States. It is usually diagnosed in the sixth and seventh decades of life, which provides a large window of opportunity for intervention to prevent or slow disease progression. Current clinical options available to control growth of advanced (hormone-refractory) human prostate cancer are sub-optimal, which necessitates exploration of novel agents potentially useful for prevention and/or treatment of PCa. Commiphora mukul has been used for millennia in Indian Ayurvedic medicine to treat diseases ranging from heart problems to arthritis. We have previously shown that z-guggulsterone (z-GS), a bioactive component of Commiphora mukul, inhibits growth of human PCa cells in culture. We now demonstrate that the extract of Commiphora mukul standardized to z-GS (CME) is significantly more potent than z-GS against proliferation of cultured human PCa cells, and is capable of sensitizing PCa cells to docetaxel. CME treatment significantly decreased cell viability and concordantly increased apoptosis in a dose-dependent manner in human PCa cells (C-81, LNCaP, and DU145) regardless of their androgen sensitivity or p53 status. In contrast, a normal prostate epithelial cell line (PrEC) was significantly more resistant to CME-mediated apoptosis compared with PCa cells. We additionally found that CME caused G0/G1 phase cell cycle arrest in all 3 PCa cell lines; however cell cycle progression was restored 48 hours after removal of the agent. The CME-induced apoptosis correlated with changes in levels of Bcl-2 family proteins (induction of Bax and Bak and down-regulation of Bcl-xL protein expression) and activation of c-Jun N-terminal kinase (JNK). Pharmacological inhibition of JNK activation conferred partial yet statistically significant protection against CME-induced apoptosis in C-81 and LNCaP cells, which implicated JNK as an important mediator of CME-induced apoptosis. When DU145 cells were simultaneously treated with sub-IC50 doses of CME and docetaxel, CME dramatically enhanced docetaxel-induced apoptosis and helped reduce cell viability in a dose-dependent manner. Overall, our results demonstrate that CME not only inhibits PCa cell growth regardless of their androgen sensitivity or p53 status, but also sensitizes hormone-refractory PCa cells to docetaxel. CME is now being tested in animal models to determine its preventive and therapeutic efficacy in vivo. This study was supported in part by NCI grants CA113363 and CA115498.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA