Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the U.S. and many western countries. Although early diagnosis of PCa has improved significantly in recent years, there is a, need for more effective treatment strategies for patients presenting with advanced or metastatic disease. Earlier, we reported that the chloroform fraction of Rasagenthi Lehyam (cRL), an herbal preparation, is effective for the treatment of PCa (Ranga et al., 2004). In subsequent studies, we identified the most potent compound (cRL-CI: psoralidin) from the cRL fraction, which exhibited more potent anti-cancer effects in PCa cells compared to other isolated components from the cRL fraction. We found that cRL-CI inhibited cell viability and induced apoptosis in PC-3 and DU-145 cells. Additional studies of cRL-CI revealed (i) induction of G2/M arrest of cell cycle, (ii) inhibition of NFkB activation, (iii) alteration of Bcl2/Bax proteins, and (iv) activation of caspase signaling in cell culture models of PCa. In addition, in vivo xenograft assays substantiate these in vitro findings and show that cRL-CI inhibits prostate tumor growth in nude mice. Interestingly, our results demonstrate that cRL-CI, specifically targets cancer cells without causing significant toxicity to normal prostate epithelial cells. Although these results suggest cRL-CI alters molecular signaling, its effect on inhibition of pro-survival mechanisms, activation of pro-apoptotic signaling and cell cycle arrest are not well understood. Our proposed aims will not only delineate these potential mechanisms of action but will also address the pre-clinical evaluation of cRL-CI against PCa cells. Based on our preliminary studies, we hypothesize that cRL-CI will effectively suppress the growth of PCa due to its ability to inactivate NFkB and IAP signaling, induce cell cycle arrest and initiate caspase-mediated apoptosis in PCa. This hypothesis will be tested by the following specific aims using in vitro and in vivo approaches.
Aim 1. Study the mechanism(s) of NFkB inhibition in PCa by cRL-CI.
Aim 2. Elucidate the role of inhibition of apoptosis (lAPs) family proteins in cRL-CI induced apoptosis in PCa cells.
Aim 3. Investigate the molecular mechanism(s) for cRL-CI -induced cell cycle arrest in PCa cells.
Aim 4. Explore the anti-tumor activity of cRL-CI in animal models. The proposed studies will define the mechanism by which cRL-CI inhibits growth of PCa cells and may lead to the identification of mechanism-based biomarkers. Additionally, the results from the proposed studies can be exploited to develop chemotherapeutic and/or chemoprevention strategies for PCa, thus leading to clinical trials to determine the efficacy of the cRL-CI against PCa. ? ? ?
