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: 7661674
• 负责人: CHUNG S. YANG
• 金额: $ 29.18万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661674
• 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(申请人提供)：本项目的目标是研究绿茶多酚及其与阿托伐他汀(ATST，商标为立普妥)联合使用对结肠癌的抑制作用。茶和ATST通常是人类消费或使用的。在动物模型中，这两种药物都被证明可以抑制结肠癌的发生，并被建议降低人类患结肠癌的风险。根据我们的初步结果，我们假设当两种药物联合使用时，癌症预防活性将更高。在这个项目中，将研究(-)-表没食子儿茶素没食子酸酯(EGCG)单独和与ATST联合使用对大鼠模型和相关细胞系的抑制活性和作用机制。具体目的如下：1.研究EGCG及其与ATST合用对AOM诱导的大鼠结肠癌模型的抑制作用。我们将使用不同浓度的EGCG(饲料中的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EGCG和ATST的联合作用，以确定抑制作用是协同作用还是相加作用。其抑制作用可能与结肠组织和血液中EGCG和ATST的水平有关。2.阐明EGCG及其与ATST合用抑制AOM大鼠结肠癌发生的机制。利用AIM 1的样本，我们将检测不同处理对细胞增殖和凋亡的影响，对关键致癌信号分子(如3-连环蛋白、Akt、ERK1/2和COX-2)、关键肿瘤抑制信号分子(如E-钙粘素和RXRcc)的影响，以及对肿瘤和非肿瘤结肠样本中小G蛋白膜结合的影响。携带腺瘤的大鼠的短期动物实验将被用作获得体内机制信息的直接途径。免疫组织化学(IHC)和生化分析将用于这些研究。3.通过对人结肠癌细胞株和动物模型的综合研究，阐明了EGCG及其与ATST联用预防结肠癌的具体机制。关于EGCG的作用及其与ATST结合的更详细的机制研究将在人类结肠细胞系中进行，然后在动物实验的结肠癌样本中进行。我们将研究EGCG作用的可能直接靶点和相关的抑制癌变的新机制。通过这些研究，我们希望更好地了解EGCG的化学预防活性以及它们与ATST联合应用对结肠癌发生的影响。以及未来研究的有前景的生物标记物。