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茶多酚对肺癌的抑制作用以及与阿托伐他汀(ATST，商品名立普妥)合用时的协同作用。茶通常是人类消费的，立普妥是一种受欢迎的降胆固醇药物。根据我们的初步结果，我们假设绿茶多酚，特别是主要的多酚(-)-表没食子儿茶素没食子酸酯(EGCG)，与ATST在抑制肺癌发生中具有协同作用。联合使用EGCG和ATST预防肺癌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4-(甲基亚硝基)-1-(3-吡啶)-1-丁酮(NNK)诱导的A/J小鼠和相关细胞系的肺癌模型中进行研究。1.研究EGCG及其与ATST合用对NNK诱导的小鼠肺癌发生发展的抑制作用。我们将在饲料中添加不同浓度的EGCG(0.1%、0.2%和0.4%)和ATST(0.01%、0.02%和0.04%)，以确定这两种药物在抑制肺癌发生中的剂量-反应关系和相互作用。其抑制作用可能与肺组织和血浆中EGCG和ATST的水平有关。2.阐明EGCG及其与ATST合用抑制NNK小鼠肺癌发生的机制。我们将利用AIM 1的样本，通过免疫组织化学和生化分析，检测不同处理对细胞增殖、凋亡、血管生成和相关分子变化(如ERK1/2、Akt、JNK、VEGF、花生四烯酸代谢和氧化应激参数)以及对小G蛋白膜结合的影响。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途径。3.详细阐述了EGCG及其与ATST联合应用对肺癌细胞株的预防作用机制。EGCG和ATST之间的相互作用机制将被研究。作为比较，绿茶多酚混合物(多酚E)的活性也将被研究。我们将结合体外和体内的研究结果，以更好地了解EGCG及其与ATST联合应用对肺癌的预防作用。公共卫生相关性：本项目的目标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，商标为立普妥)联合使用时的协同作用。茶通常是人类消费的，立普妥是一种很受欢迎的降胆固醇药物。茶多酚和立普妥联合使用预防肺癌是一种有吸引力的策略，可能会对公共健康产生重大影响。

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.