Prostate Cancer Prevention by Commiphora mukul Extract

通过没药提取物预防前列腺癌

• 批准号: 7656469
• 负责人: Dong Xiao
• 金额: $ 16.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656469
• 关键词: Androgens; Animal Model; Apoptosis; Ayurvedic Medicine; Biological Markers; CDC2 Protein Kinase; Cancer Cell Growth; Cancer Etiology; Caspase; Cell Cycle; Cell Cycle Arrest; Cell Line; Cells; Cessation of life; Chemopreventive Agent; Cholesterol; Clinical; Clinical Trials; Commiphora mukul; Complex; Development; Diagnosis; Disease Progression; Drug Formulations; Epithelial Cells; Future; Goals; Growth; Human; Incidence; Induction of Apoptosis; Intervention; LNCaP; Lead; Life; Malignant neoplasm of prostate; Mediating; Mitosis; Modeling; Morbidity - disease rate; Mus; Nuclear; Phosphoric Monoester Hydrolases; Play; Population; Prevention; Prevention strategy; Prostate; Prostate carcinoma; Proteins; Regulation; Research Project Grants; Resistance; Role; Stimulus; Study Section; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Time; Treatment Protocols; United States; bak protein; base; cancer cell; capsule; cyclin B1; design; gugulipid; in vivo; indexing; insight; men; mortality; nutrition; overexpression; pre-clinical research; preclinical study; prevent; prostate cancer prevention; prostate carcinogenesis; public health relevance; research study; response; tumor

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.

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，通常在生命的第六或第七个十年中被诊断出来，这允许进行干预以防止疾病进展的大窗口。预防前列腺癌的药物的临床开发可能对大部分人群的发病率和死亡率产生重大影响。这项R21申请提出了临床前研究，以确定没药提取物（CME）在体内预防前列腺癌的功效，并阐明其抗癌作用的机制。没药mukul已被用于印度阿育吠陀医学实践数千年的不同疾病。没药的标准化制剂（由GNC制造）已经在人类中用作降胆固醇剂（Gugulipid（R），500 mg胶囊标准化为2.5%z-guggulsterone）。根据我们的初步研究结果，我们推测CME可能预防前列腺癌，因为它能够引起G2/M期细胞周期阻滞和巴克/Bcl-xL介导的凋亡。本申请的具体目的1和2中提出的研究将阐明CME在人前列腺癌细胞中引起G2/M期细胞周期停滞和凋亡诱导的机制，而具体目的3中的研究将确定CME在TRAMP模型中体内预防前列腺癌发生的功效。来自所提出的机制研究的结果可能导致生物标志物的鉴定以及用于预防前列腺癌的基于CME的化学预防方案的优化。在动物模型中确定CME对前列腺癌的疗效是启动临床试验以确定其对人类前列腺癌活性的先决条件。 公共卫生相关性：该临床前研究项目的长期目标是开发一种安全有效的预防人类前列腺癌的策略，这是美国男性癌症相关死亡的主要原因，使用印度阿育吠陀药物成分[Commiphora mukul提取物（CME）]。本申请中提出的研究将定义CME抑制人前列腺癌细胞生长的机制，这可能导致鉴定在未来临床试验中潜在有用的CME应答的生物标志物以及优化用于预防前列腺癌的基于CME的方案，并确定CME在动物模型（TRAMP）中预防前列腺癌的体内功效，这是开始临床试验以确定其抗人前列腺癌活性的先决条件。