Prostate cancer (PCa) continues to increase in prevalence worldwide, while persisting as the second leading cause of cancer related deaths among American men. Given that treatment options for advanced PCa remain predominantly palliative, chemopreventive interventions which can prevent and/or delay PCa disease progression are sorely needed. Furthermore, PCa is ideally suited for chemoprevention efforts because of its often long latency and slow progression. Complementary and alternative medicines, such as the Ayurvedic constituent guggulipid (GL), are a source of potential novel chemopreventive agents. In our earlier studies, GL (standardized to z-guggulsterone) inhibited cell viability in androgen-dependent (LNCaP) and androgen-independent (C-81, DU145) cultured human PCa cells, in part by selectively inducing apoptosis in a dose-dependent manner. Pharmacological inhibition of JNK partially protected against GL-induced apoptosis, which implicated JNK as an important mediator of the anti-cancer effect of GL. Since JNK can be activated ROS, we subsequently explored the effect of GL on ROS generation in human PCa cells using oxidative stress indicator dyes H2DCFDA and HE. We now provide evidence that GL-induced apoptosis is indeed mediated in part by ROS generation of mitochondrial origin. In LNCaP and C-81 cells, GL treatment at low concentrations caused a dose-dependent increase in ROS that peaked around 2.5 microM. The GL-induced ROS production in both PCa cell lines was transient and limited to the first 2 hours post-exposure. In mitochondrial complex assays, GL functionally impaired complex I and III (both sources of mitochondrial ROS) in LNCaP cells within the same timeframe (2 hours post-exposure). This implicated the mitochondria as a source of GL-induced ROS production. Finally, pretreatment with antioxidant N-acetylcysteine (NAC) conferred significant protection against GL-induced apoptosis in LNCaP and C-81 cells, confirming that ROS generation is required for a significant proportion of GL-induced apoptosis. The lack of full protection with NAC also indicated the presence of alternative non-ROS mediated mechanisms by which GL induces apoptosis in human PCa cells. In conclusion, GL induces apoptosis in human PCa cells by causing ROS generation independent of androgen-responsiveness. This study was supported in part by NCI grant CA113363.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 954.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO