Colon Cancer Chemoprevention by Grape Seed Extract

葡萄籽提取物化学预防结肠癌

• 批准号: 8056607
• 负责人: CHAPLA AGARWAL
• 金额: $ 36.74万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056607
• 关键词: Animals; Apoptosis; Apoptosis Regulator; Apoptotic; Azoxymethane; Biological; Body Weight; Cancer Etiology; Cancer Model; Cancer cell line; Cell Cycle Arrest; Cell Cycle Progression; Cell Survival; Cells; Cessation of life; Chemopreventive Agent; Colon Carcinoma; Colorectal Cancer; Consumption; Cyclins; Diet; Epigenetic Process; Event; Goals; Growth; Health Benefit; Human; Intestinal Polyps; Life; Ligands; MAPK3 gene; Manuscripts; Measures; Modeling; Mus; Mutation; Neoplasm Metastasis; Nude Mice; Pathway interactions; Phytochemical; Polyps; Population; Prevention; Preventive Intervention; Proanthocyanidins; Proto-Oncogene Proteins c-akt; Rattus; Role; Signal Transduction; Source; Staging; TCF7L2 gene; Time; Toxic effect; United States; Xenograft procedure; base; cancer cell; cancer chemoprevention; cancer risk; caspase-3; colon carcinogenesis; colorectal cancer prevention; dietary supplements; feeding; grape seed extract; in vivo; neoplastic; novel; pre-clinical; prevent; translational approach; tumor xenograft

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）：大肠癌（CRC）是人类癌症死亡的第二大原因，大约5％的美国人口将在其一生中发展CRC。总体而言，CRC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CRC生长和转移的一种方法可能是饮食中存在的植物化学物质以及作为饮食补充剂食用的植物化学物质的预防方法，抑制了肿瘤阶段的一个或多个事件，并降低了整体癌症的风险。葡萄种子提取物（GSE）是美国多种健康益处的一种广泛消费的饮食补充剂，并且是标准化植物化学物质的丰富来源，称为原腺苷蛋白。最近，我们观察到，GSE显着抑制了生长，引起细胞周期停滞并诱导人结肠癌HT29，SW480和LOVO细胞的凋亡，并且GSE喂养显着抑制了HT29肿瘤肿瘤内移植的生长，并预防腹膜及其在动物症状上的质量均可表达的腹膜及其体重的生长。在人CRC细胞系中的机械研究表明，GSE非常强烈诱导CIP1/P21水平，以及CDK和细胞周期蛋白的降低。在经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会在CRC细胞系中引起强caspase 3和PARP裂解。我们还观察到GSE抑制了配体诱导的CRC细胞中AKT激活。最近的研究还表明，GSE喂养可防止大鼠模型中甲氧烷甲烷（AOM）诱导的结肠致癌作用，这与其体内抗增殖和凋亡作用有关。总之，根据这些研究，我们假设GSE是一种新型的结肠癌化学预防饮食补充剂，它靶向细胞周期的进展和细胞存活信号传导，导致其抗增殖性和凋亡功效对CRC。我们的具体目的是：i）进一步评估和建立AOM诱导的大鼠CRC模型中的GSE功效，ii）确定GSE通过GSE诱导CIP1/P21在其针对CRC的生物学疗效中诱导的作用，III）评估并定义了GSE对有丝源和细胞存活信号的影响，以及APC/PC-catenin/tcf4 Pation和IV的效果，以及IV的APC/P-catenin and IV）。监管机构。我们预计拟议的研究将确定GSE是预防CRC的基于机制的饮食补充剂，并将在临床前CRC模型中确立其体内功效。作为一种实际和转化的方法，这些研究的长距离目标是定义和确定GSE对人类CRC的预防和干预的有用性。

项目成果

Grape seed extract efficacy against azoxymethane-induced colon tumorigenesis in A/J mice: interlinking miRNA with cytokine signaling and inflammation.

葡萄籽提取物对 A/J 小鼠中氧化偶氮甲烷诱导的结肠肿瘤发生的功效：将 miRNA 与细胞因子信号传导和炎症联系起来。

• DOI: 10.1158/1940-6207.capr-13-0053
• 发表时间: 2013-07
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Derry MM;Raina K;Balaiya V;Jain AK;Shrotriya S;Huber KM;Serkova NJ;Agarwal R;Agarwal C
• 通讯作者: Agarwal C