Inhibition of Lung Carcinogenesis by Tea Polyphenols and Atorvastatin

描述（由申请人提供）： 本项目的目的是研究绿色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Lipitor）联合使用时的协同作用。茶通常被人类消费，立普妥是一种受欢迎的降胆固醇药物。基于我们的初步结果，我们假设绿色茶多酚，特别是主要的多酚（-）-表没食子儿茶素-3-没食子酸酯（EGCG），相互作用协同ATST在抑制肺癌的发生。EGCG和ATST联合用于肺癌预防的可能性是一个有吸引力的策略，需要更多的研究。为了验证我们的假设，这些药物将在A/J小鼠和相关细胞系的4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）诱导的肺癌模型中进行研究。本论文将对该化合物的抑制作用及其机制进行深入的研究，具体目标如下：1。在NNK诱导的小鼠肺癌发生模型中，确定EGCG及其与ATST组合在开始和进展后阶段的抑制作用。我们将使用不同浓度的表没食子儿茶素没食子酸酯（0.1，0.2，和0.4%）和ATST（0.01，0.02，和0.04%）的饮食管理，以确定剂量-反应关系和这两种药物在抑制肺癌发生的相互作用。其抑制作用与肺组织和血浆中EGCG和ATST的水平有关。 2.探讨EGCG及其与ATST联合应用抑制NNK小鼠肺癌发生的机制。使用来自目标1的样品，我们将检查不同处理对细胞增殖、凋亡、血管生成和相关分子变化（例如，Erk 1/2、Akt、JNK、VEGF、花生四烯酸代谢和氧化应激参数）和使用免疫组织化学和生物化学分析的小G蛋白的膜缔合。荷瘤小鼠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.阐明表没食子儿茶素没食子酸酯及其联合ATST对肺癌细胞系的预防作用的详细机制。本研究将探讨EGCG与ATST相互作用的机制。还将研究绿色茶多酚混合物（Polyphenon E）的活性作为比较。我们将整合体内外研究的结果，以更好地了解EGCG及其与ATST组合的肺癌预防活性。公共卫生相关性：本项目的目的是研究绿色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Lipitor）联合使用时的协同作用。茶通常被人类消费，立普妥是一种受欢迎的降胆固醇药物。茶多酚和立普妥联合用于肺癌预防的可能性是一种有吸引力的策略，可能对公共卫生产生重大影响。

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.