Prevention of Colon Cancer by Epigallocatechin Gallate and Atorvastatin

项目描述（由申请人提供）：本项目旨在研究绿茶多酚及其与阿托伐他汀（ATST，商品名立普妥）联合使用对结肠癌发生的抑制作用。茶和ATST通常被人类消费或使用。这两种药物在动物模型中都显示出抑制结肠肿瘤的发生，并被建议降低人类结肠癌的风险。根据我们的初步结果，我们假设当这两种药物结合使用时，预防癌症的活性会更高。本项目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）单独和联合ATST的抑制活性和作用机制。具体目的如下：1。测定EGCG及其联合ATST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0.08,0.16,0.32和0.48%）来确定抑制结肠癌发生的量效关系。然后，我们将研究不同剂量的EGCG和ATST联合使用，以确定其抑制作用是协同作用还是相加作用。抑制作用将与结肠组织和血液中EGCG和ATST的水平相关。2. 探讨EGCG及其联合ATST抑制aom大鼠结肠癌发生的作用机制。利用Aim 1的样本，我们将研究不同处理对肿瘤和非肿瘤结肠样本中细胞增殖和凋亡、关键致癌信号分子（如3-catenin、Akt、Erk1/2和COX-2）、关键肿瘤抑制信号分子（如E-cadherin和RXRcc）以及小g蛋白膜结合的影响。短期的腺瘤大鼠动物实验将作为获得体内机制信息的直接方法。联合免疫组织化学（IHC）和生化分析将用于这些研究。3. 通过人结肠癌细胞系和动物模型的综合研究，详细描述EGCG及其联合ATST预防结肠癌的机制。对EGCG及其与ATST联合作用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肿瘤样本中进行。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及其与ATST联合对结肠癌的化学预防作用。以及未来研究中有前途的生物标志物。

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.