Prostate Cancer Prevention by Pachymic Acid

通过茯苓酸预防前列腺癌

• 批准号: 7116669
• 负责人: LAWRENCE K NG
• 金额: $ 11.61万
• 依托单位: NATIONAL UNIVERSITY OF SINGAPORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116669
• 关键词: alternative medicine; antineoplastics; apoptosis; biological signal transduction; cancer prevention; inflammation; laboratory mouse; medicinal plants; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; phospholipase A2; plant extracts; prostate neoplasms; therapy design /development; triterpenes

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.

描述（由申请人提供）：前列腺癌是最常见的恶性肿瘤之一，也是美国男性癌症相关死亡的第二大原因。前列腺癌从非转移性雄激素依赖表型发展到更恶性的转移性雄激素不依赖表型是一个缓慢的多步骤过程，这取决于遗传和表观遗传因素。这种缓慢的进展期为通过干预肿瘤进展的特定阶段的化合物来预防癌症提供了一个窗口。茯苓（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。可可树的酒精提取物富含毛甾烷型三萜，最近被证明具有抗癌和抗炎活性。然而，这些三萜在癌症治疗或预防中的作用机制、疗效和安全性尚未得到系统评价。最近，在我们的初步实验中，我们发现椰子树提取物（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）和雄激素依赖性（DU145）的人前列腺癌细胞中诱导caspase驱动的凋亡，表明PCE触发凋亡可能独立于雄激素反应。本研究的目的是：(1)确定厚皮酸（PA）作为三萜，是PCE的主要成分之一，是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，我们将验证PA通过抑制磷脂酶A2 （PLA2）调节前列腺癌细胞的凋亡机制，去除AKT激活的潜在下游信号，从而具有癌症治疗和可能的癌症预防作用的假设。为了实现这些目标，我们将利用LNCaP和DU145前列腺癌细胞系(1)确定PA抑制前列腺癌异种移植裸鼠肿瘤生长的最有效和安全剂量，(2)确定PA诱导前列腺癌细胞凋亡的分子途径。通过本研究，预期PA作为一种新的、安全的治疗或预防前列腺癌的药物的潜力将被确定。