Colon Cancer Chemoprevention by Grape Seed Extract

葡萄籽提取物化学预防结肠癌

• 批准号: 7259998
• 负责人: CHAPLA AGARWAL
• 金额: $ 37.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259998
• 关键词: Colon; Cancer; Chemoprevention; Grape; Seed

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second most common cause of cancer deaths in humans, and about 5% of the US population will develop CRC in their life times. Overall, CRC growth, progression and metastasis involve a gradual accumulation of genetic and epigenetic changes over a period of years. One approach to control CRC growth and metastasis could be its prevention by phytochemicals present in diet and those consumed as dietary supplement, which inhibit one or more events of neoplastic stages and reduce overall cancer risk. Grape seed extract (GSE) is a widely consumed dietary supplement in the United States for its several health benefits, and is a rich source of standardized phytochemicals known as proanthocyanidins. Recently, we observed that GSE significantly inhibits growth, causes cell cycle arrest and induces apoptosis in human colon carcinoma HT29, SW480 and LoVo cells, and that GSE feeding significantly inhibits HT29 tumor xenograft growth in nude mice and prevents polyp formation and its growth in APCmin mice without any apparent signs of toxicity as measured in terms of animal body weight and diet consumption. Mechanistic studies in human CRC cell lines showed that GSE very strongly induces Cip1/p21 levels, together with a decrease in CDKs and cyclins; p21 induction was also observed in GSE-treated HT29 xenografts. Other studies found that GSE causes strong caspase 3 and PARP cleavage in CRC cell lines. We also observed that GSE inhibits ligand-induced AKT activation in CRC cells. Recent studies have also shown that GSE feeding prevents azoxymethane (AOM)-induced colon carcinogenesis in rat model, which was associated with its in vivo anti-proliferative and apoptotic effects. Together, based on these studies, we hypothesize that GSE is a novel colon cancer chemopreventive dietary supplement agent, which targets cell cycle progression and cell survival signaling leading to its anti-proliferative and apoptotic efficacy against CRC. Our specific aims are to: I) further assess and establish GSE efficacy in AOM-induced rat CRC model, II) establish the role of Cip1/p21 induction by GSE in its biological efficacy against CRC, III) assess and define GSE effect on mitogenic and cell survival signaling, and APC/p-catenin/ TCF4 pathway, and IV) further examine and define the effects of GSE on apoptosis regulators. We anticipate that proposed studies will identify GSE as a mechanism-based dietary supplement agent for the prevention of CRC, and will establish its in vivo efficacy in pre-clinical CRC models. As a practical and translational approach, the long- range goal of these studies would be to define and establish the usefulness of GSE for the prevention and intervention of human CRC.

描述（由申请人提供）：结直肠癌（CRC）是人类癌症死亡的第二大常见原因，大约 5% 的美国人口在一生中会患上结直肠癌。总体而言，结直肠癌的生长、进展和转移涉及多年来遗传和表观遗传变化的逐渐积累。控制结直肠癌生长和转移的一种方法可能是通过饮食中存在的植物化学物质和作为膳食补充剂食用的植物化学物质进行预防，这些植物化学物质可抑制肿瘤阶段的一种或多种事件并降低总体癌症风险。葡萄籽提取物 (GSE) 因其多种健康益处而在美国成为一种广泛食用的膳食补充剂，并且是被称为原花青素的标准化植物化学物质的丰富来源。最近，我们观察到GSE显着抑制人结肠癌HT29、SW480和LoVo细胞的生长，导致细胞周期停滞并诱导细胞凋亡，并且GSE喂养显着抑制裸鼠HT29肿瘤异种移植物的生长，并防止息肉形成及其在APCmin中的生长根据动物体重和饮食消耗测量，小鼠没有任何明显的毒性迹象。对人类 CRC 细胞系的机制研究表明，GSE 非常强烈地诱导 Cip1/p21 水平，同时降低 CDK 和细胞周期蛋白；在 GSE 处理的 HT29 异种移植物中也观察到 p21 诱导。其他研究发现，GSE 在 CRC 细胞系中引起强烈的 caspase 3 和 PARP 裂解。我们还观察到 GSE 抑制 CRC 细胞中配体诱导的 AKT 激活。最近的研究还表明，GSE 喂养可预防氧化偶氮甲烷 (AOM) 诱导的大鼠模型结肠癌发生，这与其体内抗增殖和细胞凋亡作用有关。基于这些研究，我们共同假设 GSE 是一种新型结肠癌化学预防膳食补充剂，其目标是细胞周期进程和细胞存活信号传导，从而产生针对 CRC 的抗增殖和凋亡功效。我们的具体目标是：I) 进一步评估和确定 GSE 在 AOM 诱导的大鼠 CRC 模型中的功效，II) 确定 GSE 诱导 Cip1/p21 在其针对 CRC 的生物学功效中的作用，III) 评估和定义 GSE 对有丝分裂的作用和细胞存活信号传导，以及 APC/p-catenin/TCF4 途径，以及 IV) 进一步检查和定义 GSE 对细胞凋亡调节因子的影响。我们预计拟议的研究将确定 GSE 作为预防 CRC 的基于机制的膳食补充剂，并将在临床前 CRC 模型中确定其体内功效。作为一种实用的转化方法，这些研究的长期目标是确定和确立 GSE 在预防和干预人类 CRC 方面的有用性。