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）：该项目的目的是研究绿茶多酚对结肠癌的抑制及其与Atorvastatin（ATST，商品名称Lipitor）的结合。茶和ATST通常被人类消耗或使用。两种药物均已证明可以抑制动物模型中的结肠肿瘤发生，并被建议降低人类的结肠癌风险。根据我们的初步结果，我们假设两种药物合并后，癌症预防活性将更高。在该项目中，将在大鼠模型和相关的细胞系中研究（ - ） - epigallocatechin-3-gallate（EGCG）（EGCG）（EGCG）（EGCG）的抑制活性和作用机理。具体目的如下：1。确定EGCG的抑制作用及其在AOM诱导的大鼠结肠癌发生模型中与ATST的结合。我们将使用不同浓度的EGCG（饮食中的0.08、0.16、0.32和0.48％）来确定结肠癌发生的剂量反应关系。然后，我们将研究EGCG和ATST以不同剂量的组合，以确定抑制作用是协同作用还是添加剂。抑制作用将与结肠组织和血液中的EGCG和ATST水平相关。 2。阐明了通过EGCG抑制结肠癌的机制及其与ATST在AM处理的大鼠中的结合。使用AIM 1中的样品，我们将检查不同处理对细胞增殖和凋亡的影响，对关键的致癌信号分子（例如（3-catenin，Akt，Erk1/2和Cox-2），关键的抑制性抑制性信号分子（例如E-Cadherin and RxRCC），以及在经膜中均与膜的相关素（例如，均匀的grofore smill grombrane secsission），以及膜片的相关蛋白。含有腺瘤的大鼠的短期动物实验将作为一种直接的方法，以在体内获得机理信息，并将其生化分析用于这些研究。 EGCG及其与ATST的组合将在人类结肠细胞系中，然后在动物实验中的结肠肿瘤样品中追求。从这些研究中，我们希望能够更好地了解EGCG的化学预防活性及其与ATST相结合的反对结肠癌的结合。以及有希望将来研究的生物标志物。