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：
7643461
负责人：
CHAPLA AGARWAL
金额：
$ 33.36万
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/7643461
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 Receptor Cell 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 public health relevance 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）是老年男性中最常诊断出的恶性肿瘤，并且被评为男性癌症死亡的第二大原因。这种恶性肿瘤从肿瘤前期病变到成熟癌症的发展潜伏期很长，为采用化学预防策略干预或改变这种疾病的进展提供了充足的时间。此外，大量研究表明，通过饮食控制，特别是增加水果和蔬菜的摄入量，可以降低患某些癌症的风险。因此，人们对鉴定饮食或饮食成分（营养性和非营养性植物化学物质）作为化学预防剂的潜在用途产生了浓厚的兴趣。葡萄籽提取物 (GSE) 是一种丰富的市售原花青素（也称为原花青素）来源，由于其广泛的有益作用，通常作为保健补充剂食用。关于癌症，我们和其他人的几项研究已经证明了 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 代表多酚的复杂混合物，因此上一个资助期间研究的中心重点是分离和表征 GSE 中的活性成分，以使用纯且确定的药物进行抗癌活性的详细机制和功效研究。我们最近从 GSE 中分离并表征了原花青素 B2-3,3'-二-O-没食子酸酯 (B2-G2)，它是一种活性化合物，对人前列腺癌 DU145 细胞具有很强的抗癌活性。对这种化合物的进一步研究表明，它被 PCA 细胞吸收，并引起细胞毒性和细胞生长抑制作用。其他研究表明，B2-G2 会导致携带功能性雄激素受体的人 PCA 细胞的细胞周期停滞和细胞凋亡诱导；这些细胞具体代表了大多数人类前列腺肿瘤。重要的是，B2-G2 在正常人前列腺上皮细胞和基质细胞中没有表现出细胞毒性，显示出其在人 PCA 细胞中的选择性。由于细胞周期进展失调和细胞凋亡功能丧失导致的不受控制的增殖是包括 PCA 在内的大多数癌症的主要潜在缺陷，并且由于 B2-G2 在 PCA 细胞中发挥强烈的细胞周期停滞和细胞凋亡反应，因此我们的中心假设是原花青素 B2 -3,3'-二-O-没食子酸酯选择性诱导肿瘤性前列腺上皮细胞的细胞周期停滞和细胞凋亡，这共同导致其对 PCA 的预防和治疗功效。我们的具体目标是：1) 制备计划的机制、生物利用度和功效研究所需的 B2-G2，2) 进行体外研究以解决 B2-G2 参与细胞周期停滞和细胞凋亡的作用机制，以及 3) 确定功效B2-G2 的生物利用度采用体内转基因小鼠前列腺癌 (TRAMP) 模型，该模型密切自然地模拟了人类前列腺癌的进展。总体而言，我们的长期目标是开发原花青素 B2-3,3'-二-O-没食子酸酯作为基于机制的潜在 PCA 化学预防剂。公共卫生相关性前列腺癌是美国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。由于前列腺癌具有较长的潜伏期，因此使用化学预防药物似乎是控制前列腺癌的更有效方法；有时从前兆病变到全面发展的疾病需要数十年的时间。目前的拨款提案侧重于开发一种此类药物，该药物是从葡萄籽提取物（一种广泛食用的保健补充剂）中分离出来的。我们提出的研究结果将为预防人类前列腺癌提供基于机制的药物。