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

基本信息

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
项目类别：
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

项目摘要

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）：本项目的目的是研究绿茶多酚及其与阿托伐他汀（ATST，商品名立普妥）的组合对结肠癌的抑制作用。茶和 ATST 是人类普遍消费或使用的。这两种药物已被证明可以在动物模型中抑制结肠肿瘤的发生，并被建议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。在该项目中，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) 单独使用以及与 ATST 联合使用的抑制活性和作用机制。具体目的如下： 1.确定EGCG及其与ATST组合在AOM诱导的大鼠结肠癌模型中的抑制作用。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的组合，以确定抑制作用是协同的还是相加的。抑制作用与结肠组织和血液中EGCG和ATST的水平相关。 2. 阐明EGCG及其与ATST联用对AOM治疗大鼠抑制结肠癌发生的机制。使用目标 1 中的样本，我们将检查不同治疗对细胞增殖和凋亡、关键致癌信号分子（例如（3-连环蛋白、Akt、Erk1/2 和 COX-2）、关键肿瘤抑制信号传导的影响）分子（如 E-钙粘蛋白和 RXRcc），以及肿瘤和非肿瘤结肠样本中小 G 蛋白的膜关联，将使用带有腺瘤的大鼠进行短期动物实验。这些研究将采用联合免疫组织化学 (IHC) 和生化分析的方法来获取体内机制信息。 3. 在对人类结肠癌细胞系和结肠癌的综合研究中，描述 EGCG 及其与 ATST 的组合预防结肠癌的详细机制。我们将在人类结肠细胞系和动物实验的结肠肿瘤样本中对 EGCG 的作用及其与 ATST 的结合进行更详细的机制研究。抑制癌变的作用和相关新机制。通过这些研究，我们希望更好地了解 EGCG 的化学预防活性及其与 ATST 的组合对抗结肠癌的作用。以及用于未来研究的有前景的生物标志物。