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：
8309786
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309786
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

6. PROJECT SUMMARY ABSTRACT 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. 7. PROJECT NARRATIVE 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 decade 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.

6。项目摘要摘要前列腺癌（PCA）是老年男性最常见的恶性肿瘤，被评为第二大领先男性癌症死亡的原因。恶性肿瘤具有长期的潜在发展时期，从神经前病变到成熟的癌症提供了充足的时间进行干预或改变这种疾病的进展化学预防策略。此外，许多研究表明，某些癌症的风险可能是降低了饮食操纵，特别是通过增加水果和蔬菜的消耗。因此，那里人们对识别饮食或饮食成分（营养和非营养植物化学物质）非常感兴趣因为它们的潜在用作化学预防剂。葡萄种子提取物（GSE），富裕且可商用的普罗氏蛋白酶（也称为procyanidins）的来源通常被作为其广泛的健康补充剂食用一系列有益效果。关于癌症，我们和其他研究证明了抗癌者 GSE对包括PCA细胞在内的各种上皮恶性肿瘤的化学预防疗效。自gse以来代表多酚的复杂混合物，在最后一个资金期间研究的中心重点是分离和表征GSE中的活动成分，以进行详细的机械和功效研究抗癌活性采用纯和定义的药物。我们最近分离并表征了procyanidin b2- 3,3'-di-o-gallate（B2-g2）作为GSE的活性化合物，具有强大的抗癌活性对人前列腺 DU145细胞癌。该化合物的进一步研究表明，它被PCA细胞占用，并且引起细胞毒性和细胞生长抑制作用。其他研究表明，B2-G2引起了两者携带功能性雄激素受体的人PCA细胞中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在正常情况下未显示细胞毒性人前列腺上皮细胞和基质细胞，显示其在人PCA细胞中的选择性。自从不受控制由于失调的细胞周期进程和凋亡功能的丧失而引起的增殖是主要的基础包括PCA在内的大多数癌症和B2-G2施加强大的细胞周期停滞和凋亡的缺陷 PCA细胞的反应，我们的中心假设是procyanidin b2-3,3'-di-o-gallate选择性诱导细胞肿瘤前列腺上皮细胞中的循环停滞和凋亡，该细胞共同导致其预防和针对PCA的治疗功效。我们的具体目的是：1）准备计划中所需的B2-G2 机械，生物利用度和功效研究，2）在体外研究中进行B2-G2的作用机理参与细胞周期停滞和凋亡，3）确定B2-G2的功效和生物利用度小鼠前列腺（Tramp）模型的体内转基因癌，它们紧密而自然地模仿人类前列腺癌的进展。总体而言，我们的长期目标是开发procyanidin b2-3,3'-di- O-Gallate是针对PCA的基于机制的潜在化学预防剂。 7。项目叙述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。化学预防剂的使用似乎是控制的更有效方法前列腺癌长期以来一直具有潜在的发展时期；有时从前体病变到十多年完全吹牛的疾病。当前的赠款提案着重于一个这样的代理人的发展从葡萄种子提取物中分离出来，这是一种广泛消费的健康补充剂。我们提议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。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of oxidative stress in cytotoxicity of grape seed extract in human bladder cancer cells.

DOI：
10.1016/j.fct.2013.06.039
发表时间：
2013-11
期刊：
FOOD AND CHEMICAL TOXICOLOGY
影响因子：
4.3
作者：
Raina, Komal;Tyagi, Alpna;Kumar, Dileep;Agarwal, Rajesh;Agarwal, Chapla
通讯作者：
Agarwal, Chapla

A novel anticancer agent, decursin, induces G1 arrest and apoptosis in human prostate carcinoma cells.

DOI：
10.1158/0008-5472.1035.65.3
发表时间：
2005-02
期刊：
Cancer research
影响因子：
11.2
作者：
Dongsool Yim;R. Singh;C. Agarwal;S. Lee;Hyungjoon Chi;R. Agarwal
通讯作者：
Dongsool Yim;R. Singh;C. Agarwal;S. Lee;Hyungjoon Chi;R. Agarwal

Silibinin strongly inhibits growth and survival of human endothelial cells via cell cycle arrest and downregulation of survivin, Akt and NF-kappaB: implications for angioprevention and antiangiogenic therapy.

水飞蓟宾通过细胞周期停滞和下调生存素、Akt 和 NF-κB 强烈抑制人内皮细胞的生长和存活：对血管预防和抗血管生成治疗的影响。

DOI：
10.1038/sj.onc.1208276
发表时间：
2005
期刊：
Oncogene.
影响因子：
0
作者：
Singh,RanaP;Dhanalakshmi,Sivanandhan;Agarwal,Chapla;Agarwal,Rajesh
通讯作者：
Agarwal,Rajesh

Gallic acid, an active constituent of grape seed extract, exhibits anti-proliferative, pro-apoptotic and anti-tumorigenic effects against prostate carcinoma xenograft growth in nude mice.

DOI：
10.1007/s11095-009-9926-y
发表时间：
2009-09
期刊：
PHARMACEUTICAL RESEARCH
影响因子：
3.7
作者：
Kaur, Manjinder;Velmurugan, Balaiya;Rajamanickam, Subapriya;Agarwal, Rajesh;Agarwal, Chapla
通讯作者：
Agarwal, Chapla

Differential effect of grape seed extract against human non-small-cell lung cancer cells: the role of reactive oxygen species and apoptosis induction.