Prostate Cancer Prevention by Pachymic Acid

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DESCRIPTION (provided by applicant): Prostate cancer is one of the most common malignancies and the second leading cause of cancer-related death in men in the United States. Progression of prostate cancer from its non-metastatic androgen-dependent phenotype to a more malignant metastatic androgen-independent phenotype is a slow and multi-step process that depends on both genetic and epigenetic factors. This slow progressing period provides a window for cancer prevention by intervention with compounds that interfere with specific stages of neoplastic progression. Poria cocos (P. Cocos) is a medicinal herb widely used in Asian countries for its sedative, diuretic, and tonic actions. Alcoholic extracts of P. cocos that are rich in lanostane-type triterpenoids have recently been shown to have anti-cancer and anti-inflammatory activities. However, the mechanism, efficacy, and safety of these triterpenoids in cancer treatment or prevention have not been systemically evaluated. Recently, in our preliminary experiments, we showed that extracts of P. cocos (PCE) (1) inhibit the growth of prostate cancer cells in vitro and in vivo (xenografts in nude mice) and (2) induce caspase-driven apoptosis in both androgen-dependent (LNCaP) and androgen-independent (DU145) human prostate carcinoma cells, indicating that triggering of apoptosis by PCE might occur independently of androgen responsiveness. The goals of this study are (1) to establish pachymic acid (PA), a triterpenoid and a major constituent of PCE, as a safe and effective anti-cancer agent for prostate cancer, and (2) to elucidate the potential molecular anticancer mechanism of PA. In particular, we will test the hypothesis that PA imparts cancer therapeutic and possibly cancer preventive effects by modulating the apoptotic machinery of prostate cancer cells via inhibition of phospholipase A2 (PLA2), removing potential downstream signals for AKT activation. To accomplish these objectives, we will employ LNCaP and DU145 prostate cancer cell lines to (1) determine the most effective and safe dose of PA for inhibition of cancer growth in nude mice with prostate cancer xenografts, and (2) define the molecular pathway through which PA induces prostate cancer cell apoptosis. Through this study, it is anticipated that the potential of PA as a novel and safe agent for treatment or prevention against prostate cancer will be identified.