Prostate Cancer Prevention by Pachymic Acid

描述（由申请人提供）：前列腺癌是美国最常见的恶性肿瘤之一，也是男性癌症相关死亡的第二大原因。前列腺癌从其非转移性雄激素依赖性表型进展为更恶性的转移性雄激素非依赖性表型是一个缓慢的多步骤过程，取决于遗传和表观遗传因素。这一缓慢进展期提供了一个窗口，通过干预与干扰肿瘤进展的特定阶段的化合物的癌症预防。椰子（P. Cocos）是一种在亚洲国家广泛使用的草药，具有镇静、利尿和滋补作用。富含羊毛甾烷型三萜类化合物的椰子醇提取物最近被证明具有抗癌和抗炎活性。然而，这些三萜类化合物在癌症治疗或预防中的机制、有效性和安全性尚未得到系统评价。最近，在我们的初步实验中，我们发现椰子提取物（PCE）（1）在体外和体内（裸鼠异种移植）抑制前列腺癌细胞的生长，（2）在雄激素依赖性（LNCaP）和雄激素非依赖性（DU 145）人前列腺癌细胞中诱导半胱天冬酶驱动的凋亡，表明PCE触发凋亡可能独立于雄激素反应性。本研究的目的是：（1）确定茯苓酸（pachymic acid，PA）作为一种三萜类化合物和PCE的主要成分，作为一种安全有效的前列腺癌抗癌药物;（2）阐明PA潜在的分子抗癌机制。特别是，我们将测试的假设，PA赋予癌症治疗和可能的癌症预防作用，通过调节前列腺癌细胞的凋亡机制，通过抑制磷脂酶A2（PLA 2），消除潜在的下游信号AKT激活。为了实现这些目标，我们将使用LNCaP和DU 145前列腺癌细胞系来（1）确定PA抑制前列腺癌异种移植物裸鼠中癌症生长的最有效和安全剂量，以及（2）确定PA诱导前列腺癌细胞凋亡的分子途径。通过这项研究，预计PA作为治疗或预防前列腺癌的新型安全药物的潜力将得到确定。

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.