Inhibition of Lung Carcinogenesis by Tea Polyphenols and Atorvastatin

茶多酚和阿托伐他汀抑制肺癌发生

基本信息

批准号：
8018089
负责人：
CHUNG S. YANG
金额：
$ 30.99万
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：
2008-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018089
关键词：
A/J Mouse Abbreviations Acids Adenocarcinoma Anabolism Analysis of Variance Animal Experiments Apoptosis Arachidonic Acids Biochemical Butanones Cancer cell line Carcinogenesis Inhibition Cell Line Cell Proliferation Cholesterol Coenzyme A Cyclin-Dependent Kinases Diet Dinoprostone Dose Epidermal Growth Factor Receptor Epigallocatechin Gallate GRP78 gene Glucose Human Immunohistochemistry In Situ Nick-End Labeling In Vitro Insulin-Like-Growth Factor I Receptor Investigation Label Leukotriene B4 Lung MAPK8 gene Malignant neoplasm of lung Membrane Metabolism Modeling Molecular Monomeric GTP-Binding Proteins Mus Myeloid Cells Names Oxidative Stress Oxidoreductase PTGS2 gene Pharmaceutical Preparations Plasma Polyphenon E Preventive Proliferating Cell Nuclear Antigen Propidium Diiodide Proteins Public Health Reactive Oxygen Species Sampling Signal Transduction Pathway Staging Structure of parenchyma of lung Superoxide Dismutase Tea Testing Vascular Endothelial Growth Factors adenoma angiogenesis atorvastatin base cyclooxygenase 2 farnesyl pyrophosphate gallocatechol geranylgeranyl pyrophosphate human H2AX protein in vivo isoprenoid leukemia lung cancer prevention lung carcinogenesis lung tumorigenesis polyphenol public health relevance response tumor

项目摘要

DESCRIPTION (provided by applicant): The objective of this project is to study the inhibition of lung carcinogenesis by green tea polyphenols and the synergistic action when used in combination with atorvastatin (ATST, trade name Lipitor). Tea is commonly consumed by humans, and Lipitor is a popular cholesterol-lowering drug. Based on our preliminary results, we hypothesize that green tea polyphenols, especially the major polyphenol (-)- epigallocatechin-3-gallate (EGCG), interact synergistically with ATST in the inhibition of lung carcinogenesis. The possible use of the combination of EGCG and ATST for lung cancer prevention is an attractive strategy that needs more investigation. To test our hypothesis, these agents will be studied in a 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis model in A/J mice and related cell lines. The inhibitory action and the mechanisms involved will be thoroughly investigated with specific aims as follows: 1. Determine the inhibitory actions of EGCG and its combination with ATST in an NNK-induced mouse lung carcinogenesis model at the post-initiation and progression stages. We will use different concentrations of EGCG (0.1, 0.2, & 0.4%) and ATST (0.01, 0.02, & 0.04%) administered in the diet to determine the dose-response relationship and the interactions of these two agents in the inhibition of lung carcinogenesis. The inhibitory action will be correlated with the levels of EGCG and ATST in lung tissues and plasma. 2. Elucidate the mechanisms of inhibition of lung carcinogenesis by EGCG and its combination with ATST in NNK-treated mice. Using samples from Aim 1, we will examine the effects of the different treatments on cell proliferation, apoptosis, angiogenesis, and related molecular changes (e.g., Erk1/2, Akt, JNK, VEGF, arachidonic acid metabolism, and oxidative stress parameters) and on membrane association of small G-proteins using immunohistochemical and biochemical analyses. Short-term animal experiments with tumor-bearing mice will be used as a direct approach to obtain mechanistic information in vivo. 3. Delineate detailed mechanisms of lung cancer prevention by EGCG and its combination with ATST in lung cancer cell lines. Mechanisms of interaction between EGCG and ATST will be investigated. The activity of a green tea polyphenol mixture (Polyphenon E) will also be studied as a comparison. We will integrate the results from studies in vitro and in vivo to gain a better understanding of lung cancer preventive activities of EGCG and its combination with ATST. PUBLIC HEALTH RELEVANCE: The objective of this project is to study the inhibition of lung carcinogenesis by green tea polyphenols and the synergistic action when used in combination with atorvastatin (ATST, trade name Lipitor). Tea is commonly consumed by humans and Lipitor is a popular cholesterol-lowering drug. The possible use of the combination of tea polyphenols and Lipitor for lung cancer prevention is an attractive strategy and could have a large impact in public health.

描述（由申请人提供）：该项目的目的是研究绿茶多酚抑制肺癌发生的作用以及与阿托伐他汀（ATST，商品名立普妥）联合使用时的协同作用。茶是人类普遍饮用的饮料，立普妥是一种流行的降胆固醇药物。根据我们的初步结果，我们假设绿茶多酚，尤其是主要的多酚 (-)-表没食子儿茶素-3-没食子酸酯 (EGCG)，与 ATST 协同作用，抑制肺癌发生。联合使用 EGCG 和 ATST 来预防肺癌是一种有吸引力的策略，需要更多的研究。为了检验我们的假设，将在 A/J 小鼠和相关细胞系的 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 诱导的肺癌模型中研究这些药物。我们将深入研究其抑制作用和机制，具体目标如下： 1. 确定 EGCG 及其与 ATST 组合在 NNK 诱导的小鼠肺癌模型中起始后和进展阶段的抑制作用。我们将使用饮食中不同浓度的 EGCG（0.1、0.2 和 0.4%）和 ATST（0.01、0.02 和 0.04%）来确定剂量反应关系以及这两种药物在肺抑制中的相互作用。致癌作用。抑制作用与肺组织和血浆中EGCG和ATST的水平相关。 2. 阐明EGCG及其与ATST联用对NNK治疗小鼠抑制肺癌发生的机制。使用目标 1 中的样本，我们将检查不同治疗对细胞增殖、凋亡、血管生成和相关分子变化（例如 Erk1/2、Akt、JNK、VEGF、花生四烯酸代谢和氧化应激参数）的影响，以及使用免疫组织化学和生化分析研究小 G 蛋白的膜关联。用荷瘤小鼠进行的短期动物实验将被用作获得体内机制信息的直接方法。 3. 描绘EGCG及其与ATST组合在肺癌细胞系中预防肺癌的详细机制。将研究 EGCG 和 ATST 之间的相互作用机制。作为比较，还将研究绿茶多酚混合物（Polyphenon E）的活性。我们将整合体外和体内研究的结果，以更好地了解 EGCG 及其与 ATST 组合的肺癌预防活性。公共健康相关性：该项目的目的是研究绿茶多酚对肺癌发生的抑制作用以及与阿托伐他汀（ATST，商品名立普妥）联合使用时的协同作用。茶是人类普遍饮用的饮料，立普妥是一种流行的降胆固醇药物。茶多酚和立普妥的组合可能用于预防肺癌，这是一种有吸引力的策略，可能对公共健康产生巨大影响。