Prostate Cancer Prevention by Procyanidins in Grape Seed Extract

葡萄籽提取物中的原花青素预防前列腺癌

基本信息

批准号：
8079119
负责人：
CHAPLA AGARWAL
金额：
$ 32.25万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-14 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079119
关键词：
Address Adenocarcinoma Androgen Receptor Apoptosis Apoptotic Applications Grants Biological Biological Assay Biological Availability Biological Factors Blood Cancer Etiology Carcinoma Caspase Cell Culture Techniques Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Death Cells Cessation of life Chemopreventive Agent Complex Mixtures Consumption DU145 Defect Development Diagnosis Diet Disease Disease Progression Dose Effectiveness Elderly man Epithelial Epithelial Cells Family member Feces Funding Goals Health Human Hydrolysis In Vitro Induction of Apoptosis Ions Lesion Malignant Neoplasms Malignant neoplasm of prostate Measures Methodology Methylation Modeling Molecular Mus Oral Outcome Phase Phytochemical Plasma Preventive Proanthocyanidins Procedures Procyanidins Prostate Prostate carcinoma Prostatic Neoplasms Public Health Publishing Research Risk Sampling Signal Pathway Solutions Source Staging Stromal Cells Techniques Testing Time Tissue Sample Tissues Transgenic Organisms Treatment Efficacy United States Urine Work anticancer activity base cancer cell cell growth cytotoxic cytotoxicity dietary constituent feeding fruits and vegetables grape seed extract hydroxyl group in vivo in vivo Model interest men milligram multiple reaction monitoring neoplastic oxidation polyphenol procyanidin B2 prostate cancer prevention prostate carcinogenesis research study response selected ion monitoring uptake

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer (PCA) is the most frequently diagnosed malignancy in elderly men, and is rated as second leading cause of cancer deaths in men. The malignancy has long latent period of development from pre-neoplastic lesion to full-blown cancer providing ample time to intervene or alter the progression of this disease employing chemopreventive strategies. Additionally, numerous studies have shown that the risk for certain cancers could be lowered by dietary manipulations, especially by increased consumption of fruits and vegetables. Accordingly, there has been serious interest in identifying diets or dietary constituents (both nutritive and non-nutritive phytochemicals) for their potential use as chemopreventive agents. Grape seed extract (GSE), a rich and commercially available source of proanthocyanidins (also known as procyanidins), is usually consumed as a health supplement for its wide range of beneficial effects. Regarding cancer, several studies by us and others have demonstrated the anti-cancer and chemopreventive efficacy of GSE against various epithelial malignancies including PCA cells. Since GSE represents a complex mixture of polyphenols, the central focus of the studies during the last funding period was to isolate and characterize active component(s) in GSE to carry out detailed mechanistic and efficacy studies for anticancer activity employing pure and defined agents. We recently isolated and characterized procyanidin B2- 3,3'-di-O-gallate (B2-G2) as an active compound from GSE with strong anti-cancer activity against human prostate carcinoma DU145 cells. Further studies with this compound revealed that it is taken up by PCA cells and that it causes both cytotoxic as well as cell growth inhibitory effects. Additional studies revealed that B2-G2 causes both cell cycle arrest and apoptosis induction in human PCA cells carrying functional androgen receptor; these cells specifically represent majority of human prostate tumors. Importantly, B2-G2 did not show cytotoxicity in normal human prostate epithelial and stromal cells, showing its selectivity in human PCA cells. Since uncontrolled proliferation due to deregulated cell cycle progression and loss of apoptotic function are the major underlying defects in most of the cancers including PCA and since B2-G2 exerts strong cell cycle arrest and apoptotic responses in PCA cells, our central hypothesis is that procyanidin B2-3,3'-di-O-gallate selectively induces cell cycle arrest and apoptosis in neoplastic prostate epithelial cells which collectively leads to its preventive and therapeutic efficacy against PCA. Our specific aims are to: 1) prepare B2-G2 needed for planned mechanistic, bioavailability and efficacy studies, 2) conduct in vitro studies to address mechanism of action of B2-G2 involved in cell cycle arrest and apoptosis, and 3) determine efficacy and bioavailability of B2-G2 employing an in vivo transgenic carcinoma of the mouse prostate (TRAMP) model, which closely and naturally mimics the progression of prostatic carcinoma in humans. Overall, our long term goal is to develop procyanidin B2-3,3'-di- O-gallate as a mechanism-based potential chemopreventive agent against PCA. PUBLIC HEALTH RELEVANCE Prostate cancer is second leading cause of cancer-related deaths in United States, and thus is an important public health issue. Use of chemopreventive agents seems to be more effective approach for the control of prostate cancer as it has long latent period of development; sometimes over decades from precursor lesions to full blown disease. Current grant proposal focuses on the development of one such agent, which has been isolated from grape seed extract, a widely consumed health supplement. Outcomes of our proposed research will provide a mechanism-based agent for the prevention of prostate cancer in humans.

描述（由申请人提供）：前列腺癌（PCA）是老年男性最常见的恶性肿瘤，被评为男性癌症死亡的第二大原因。恶性肿瘤具有长期的潜在发展，从肿瘤前病变到成熟的癌症，提供了充足的时间来干预或改变采用化学预防策略的这种疾病的进展。此外，许多研究表明，某些癌症的风险可以通过饮食中的操纵来降低，尤其是通过增加水果和蔬菜的消耗。因此，人们对识别饮食或饮食成分（营养和非营养植物化学物质）的潜在用作化学预防剂的兴趣很大。葡萄种子提取物（GSE）是一种丰富且可商购的原蛋白蛋白（也称为procyanidins）的来源，通常被用作其广泛有益作用的健康补充剂。关于癌症，我们和其他人的几项研究表明，GSE对包括PCA细胞在内的各种上皮恶性肿瘤的抗癌和化学预防功效。由于GSE代表了多酚的复杂混合物，因此在最后一个资金期间，研究的核心重点是隔离和表征GSE中的主动成分，以进行详细的机械和功效研究，用于使用纯和定义的药物进行抗癌活性。我们最近分离并表征了procyanidin b2-3,3'-di-o-gallate（B2-g2）作为活性化合物，从具有强抗癌活性的GSE对人类前列腺癌DU145细胞具有很强的抗癌活性。对该化合物的进一步研究表明，它被PCA细胞吸收，并且会引起细胞毒性和细胞生长抑制作用。其他研究表明，携带功能性雄激素受体的人PCA细胞中B2-G2引起细胞周期停滞和凋亡诱导。这些细胞特别代表大多数人前列腺肿瘤。重要的是，B2-G2在正常人前列腺上皮和基质细胞中未显示细胞毒性，显示其在人PCA细胞中的选择性。 Since uncontrolled proliferation due to deregulated cell cycle progression and loss of apoptotic function are the major underlying defects in most of the cancers including PCA and since B2-G2 exerts strong cell cycle arrest and apoptotic responses in PCA cells, our central hypothesis is that procyanidin B2-3,3'-di-O-gallate selectively induces cell cycle arrest and apoptosis in neoplastic prostate共同导致其针对PCA的预防和治疗功效的上皮细胞。我们的具体目的是：1）准备计划的机械，生物利用性和功效研究所需的B2-G2，2）进行体外研究，以解决与细胞周期停滞和凋亡相关的B2-G2作用机制，以及3）确定B2-G2的功效和生物可利用性，该B2-G2的B2-G2具有跨性别的Mim carcinity of Mim of Mimim thymim themim of Mimim thymim themim themim themim offivo carcination themim of Mimim coartility of Mimim coartime of Mimim coartime of Mimim coartime of小鼠collamp offerication themim（人类前列腺癌。总体而言，我们的长期目标是开发procyanidin B2-3,3'-di-o-gallate作为基于机制的针对PCA的潜在化学预防剂。公共卫生相关性前列腺癌是美国与癌症相关死亡的第二大原因，因此是一个重要的公共卫生问题。由于长期存在的发育时期，因此使用化学预防剂似乎是控制前列腺癌的方法。有时从前体病变到全肿瘤的数十年来。当前的赠款提案的重点是一种此类代理的发展，该代理已经与广泛消费的健康补充剂中的葡萄种子提取物隔离。我们提出的研究的结果将为预防人类前列腺癌提供基于机制的药物。