Prostate Cancer Prevention by Commiphora mukul Extract

描述（由申请人提供）：前列腺癌是美国男性癌症相关死亡的主要原因，通常在60或70岁时被诊断出来，这为预防疾病进展的干预提供了一个大窗口。预防前列腺癌的药物的临床开发可能会对很大一部分人群的发病率和死亡率产生重大影响。本R21申请拟开展临床前研究，以确定麻瓜提取物（comiphora mukul extract， CME）体内预防前列腺癌的疗效，并阐明其抗癌作用的机制。在印度阿育吠陀医学实践中，Commiphora mukul被用于治疗不同的疾病已有数千年的历史。comiphora mukul（由GNC公司生产）的标准化配方已经作为降胆固醇剂用于人体（gugu脂质(R)， 500毫克胶囊，标准化至2.5% z- gugugulsterone）。根据我们的初步研究结果，我们假设CME可能由于其能够引起G2/M期细胞周期阻滞和Bak/Bcl-xL介导的细胞凋亡而预防前列腺癌。本申请的特定目的1和2中提出的研究将阐明CME引起人前列腺癌细胞G2/M期细胞周期阻滞和诱导凋亡的机制，而特定目的3中的研究将确定CME在体内预防前列腺癌的作用。机制研究的结果可能会导致基于cme的化学预防方案的生物标记物的鉴定和优化，以预防前列腺癌。在动物模型中确定CME对前列腺癌的疗效是开展临床试验以确定其对人类前列腺癌活性的先决条件。

DESCRIPTION (provided by applicant): Prostate cancer, a leading cause of cancer related deaths among men in the United States, is usually diagnosed in the sixth or seventh decades of life, which allows a large window for intervention to prevent disease progression. Clinical development of agents that can prevent prostate cancer could have a significant impact on morbidity and mortality for a large segment of population. This R21 application proposes preclinical studies to determine efficacy of Commiphora mukul extract (CME) for prevention of prostate cancer in vivo and to elucidate the mechanism of its anti-carcinogenic effect. Commiphora mukul has been used in the Indian Ayurvedic medicine practice for thousands of years for different ailments. A standardized formulation of Commiphora mukul (manufactured by GNC) is already in human use as a cholesterol-lowering agent (Gugulipid(R), 500 mg capsule standardized to 2.5% z-guggulsterone). Guided by the results of our preliminary studies, we hypothesize that CME may prevent prostate cancer due to its ability to cause G2/M phase cell cycle arrest and Bak/Bcl-xL mediated apoptosis. Studies proposed in specific aims 1 and 2 of this application will elucidate the mechanism by which CME causes G2/M phase cell cycle arrest and apoptosis induction in human prostate cancer cells, whereas studies in specific aim 3 will determine efficacy of CME for prevention of prostate carcinogenesis in vivo in TRAMP model. The results from proposed mechanistic studies may lead to identification of biomarker(s) optimization of CME-based chemopreventive regimens for prevention of prostate cancer. Determining efficacy of CME against prostate cancer in animal models is a prerequisite for initiation of clinical trials to determine its activity against human prostate cancers. PUBLIC HEALTH RELEVANCE: The long term goal of this preclinical research project is to develop a safe and effective strategy for prevention of human prostate cancer, which is a leading cause of cancer related deaths among men in the United States, using an Indian Ayurvedic medicine component [Commiphora mukul extract (CME)]. Studies proposed in this application will define the mechanism by which CME inhibits growth of human prostate cancer cells, which may lead to identification of biomarker(s) of CME response potentially useful in future clinical trials as well as optimization of CME-based regimens for prevention of prostate cancer, and determine efficacy of CME in vivo for prevention of prostate cancer in an animal model (TRAMP), which is a prerequisite for initiation of clinical trials to determine its activity against human prostate cancers.