Prevention of Colon Cancer by Epigallocatechin Gallate and Atorvastatin

表没食子儿茶素没食子酸酯和阿托伐他汀预防结肠癌

• 批准号: 8107078
• 负责人: CHUNG S. YANG
• 金额: $ 15.01万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107078
• 关键词: Abbreviations; Aberrant crypt foci; Adenomatous Polyposis Coli; Affect; Anabolism; Analysis of Variance; Animal Experiments; Animal Model; Apoptosis; Arachidonic Acids; Azoxymethane; Bile Acid Biosynthesis Pathway; Biochemical; Biological Markers; Blood; Carcinogenesis Inhibition; Cell Line; Cell Proliferation; Chemopreventive Agent; Cholesterol; Coenzyme A; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Cyclin D1; Diet; Dinoprostone; Dose; E-Cadherin; Epidermal Growth Factor Receptor; Epigallocatechin Gallate; Future; Glycogen Synthase Kinases; Human; Immunohistochemistry; Insulin-Like-Growth Factor I Receptor; Intestinal Neoplasms; Investigation; Malignant Neoplasms; Membrane; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mucins; Names; Non-Steroidal Anti-Inflammatory Agents; Nuclear; Odds Ratio; Oncogenic; PTGS2 gene; Polyphenon E; Prevention; Preventive; RXR; Rattus; Research Personnel; Sampling; Signal Transduction Pathway; Signaling Molecule; T cell factor 4; TCF7L2 gene; Tea; Tissues; Yang; adenoma; atorvastatin; base; cancer prevention; cancer risk; colon cancer cell line; colon carcinogenesis; cyclooxygenase 2; farnesyl pyrophosphate; gallocatechol; geranylgeranyl pyrophosphate; human NOS2A protein; in vivo; mevalonate; novel; programs; response; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The objective of this project is to study the inhibition of colon carcinogenesis by green tea polyphenols and their combination with atorvastatin (ATST, trade name Lipitor). Tea and ATST are commonly consumed or used by humans. Both agents have been shown to inhibit colon tumorigenesis in animal models and have been suggested to reduce colon cancer risk in humans. Based on our preliminary results, we hypothesize that when the two agents are combined, the cancer preventive activity would be higher. In this project, the inhibitory activities and the mechanisms of action of (-)-epigallocatechin-3-gallate (EGCG), alone and in combination with ATST, will be studied in a rat model and related cell lines. The specific aims are as follows: 1. Determine the inhibitory actions of EGCG and its combination with ATST in an AOM-induced rat colon carcinogenesis model. We will use different concentrations of EGCG (0.08, 0.16, 0.32, & 0.48% in the diet) to determine the dose-response relationship in the inhibition of colon carcinogenesis. Then we will study the combination of EGCG and ATST at different doses to determine whether the inhibitory effect is synergistic or additive. The inhibitory action will be correlated with the levels of EGCG and ATST in colonic tissues and blood. 2. Elucidate the mechanisms of inhibition of colon carcinogenesis by EGCG and its combination with ATST in AOM-treated rats. Using samples from Aim 1, we will examine the effects of the different treatments on cell proliferation and apoptosis, on key oncogenic signaling molecules (such as (3-catenin, Akt, Erk1/2, and COX-2), key tumor suppressive signaling molecules (such as E-cadherin and RXRcc), and on membrane association of small G-proteins in the tumorous and non-tumorous colon samples. Short-term animal experiments with adenoma-bearing rats will be used as a direct approach to obtain mechanistic information in vivo. Combined immunohistochemical (IHC) and biochemical analyses will be used for these studies. 3. Delineate detailed mechanisms of colon cancer prevention by EGCG and its combination with ATST in integrated studies with human colon cancer cell lines and the animal model. More detailed mechanistic studies on the actions of EGCG and its combination with ATST will be pursued in human colon cell lines and then in colon tumor samples from animal experiments. We will study possible direct targets of EGCG action and related novel mechanisms for the inhibition of carcinogenesis. From these studies, we hope to develop a better understanding of the chemopreventive activities of EGCG and their combination with ATST against colon carcinogenesis. as well as promising biomarkers for future studies.

描述（由申请人提供）：本项目的目的是研究绿色茶多酚及其与阿托伐他汀（ATST，商品名立普妥）组合对结肠癌发生的抑制作用。茶和ATST通常被人类消费或使用。这两种药物已被证明可以抑制动物模型中的结肠肿瘤发生，并被认为可以降低人类结肠癌的风险。根据我们的初步结果，我们假设当两种药物联合使用时，癌症预防活性会更高。在本项目中，将在大鼠模型和相关细胞系中研究（-）-表没食子儿茶素-3-没食子酸酯（EGCG）单独和与ATST组合的抑制活性和作用机制。具体目标如下：1.在AOM诱导的大鼠结肠癌模型中确定EGCG及其与ATST组合的抑制作用。我们将使用不同浓度的表没食子儿茶素没食子酸酯（在饮食中为0.08%、0.16%、0.32%和0.48%）来确定抑制结肠癌发生的剂量-反应关系。然后我们将研究不同剂量的表没食子儿茶素没食子酸酯（表没食子酸酯）和ATST的组合，以确定抑制作用是协同作用还是相加作用。其抑制作用与结肠组织和血液中EGCG和ATST的水平有关。2.探讨表没食子儿茶素没食子酸酯（EGCG）及其联合ATST抑制AOM诱导的大鼠结肠癌发生的机制。使用目标1的样品，我们将检查不同治疗对细胞增殖和凋亡、对关键致癌信号分子（如（3-连环蛋白、Akt、Erk 1/2和考克斯-2）、关键肿瘤抑制信号分子（如E-钙粘蛋白和RXR α）以及对肿瘤和非肿瘤结肠样品中小G蛋白的膜结合的影响。短期的动物实验与腺瘤轴承大鼠将被用作一种直接的方法，以获得在体内的机制信息。这些研究将使用联合免疫组织化学（IHC）和生化分析。3.在人结肠癌细胞系和动物模型的综合研究中，阐明EGCG及其与ATST联合预防结肠癌的详细机制。将在人类结肠细胞系中以及动物实验的结肠肿瘤样本中对表没食子酸没食子酸酯及其与ATST的组合的作用进行更详细的机制研究。我们将研究EGCG作用的可能的直接靶点和抑制致癌作用的相关新机制。从这些研究中，我们希望开发一个更好地了解的化学预防活动的表没食子儿茶素没食子酸酯及其与ATST对结肠癌的发生。以及未来研究的有希望的生物标志物。