Inhibition of Lung Carcinogenesis by Tea Polyphenols and Atorvastatin

摘要： 本课题的目的是研究绿茶多酚对肺癌的抑制作用。 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 利普妥是一种广受欢迎的降胆固醇药物。基于我们的 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。 联合应用EGCG和ATST预防肺癌是一种有吸引力的策略。 这需要更多的调查。为了验证我们的假设，我们将对这些药物进行4- (甲基亚硝氨基)-1-(3-吡啶)-1-丁酮(NNK)诱发A/J小鼠肺癌模型的建立 相关的细胞系。抑制作用和涉及的机制将通过 具体目标如下： 1.测定EGCG及其与ATST合用对NNK诱导的小鼠腹水肿胀的抑制作用 小鼠肺癌发生发展后阶段的动物模型。我们将使用 不同浓度的EGCG(0.1、0.2和0.4%)和ATST(0.01、0.02和0.04%)在 饮食，以确定剂量-反应关系和这两种药物的相互作用 抑制肺癌的发生。这种抑制作用将与EGCG和 肺组织和血浆中的ATST。 2.阐明EGCG及其联合应用抑制肺癌发生的机制 在NNK处理的小鼠中使用ATST。使用来自目标1的样本，我们将检查 不同处理方法对细胞增殖、凋亡、血管生成及相关分子变化的影响 (例如，ERK1/2、Akt、JNK、VEGF、花生四烯酸代谢和氧化应激参数)和 用免疫组织化学和生化分析研究小G蛋白的膜结合。 荷瘤小鼠的短期动物实验将被用作获得 体内的机械性信息。 3.阐明EGCG及其联合应用预防肺癌的具体机制 ATST在肺癌细胞系中的表达。EGCG和ATST之间的相互作用机制将是 调查过了。绿茶多酚混合物(多酚E)的活性也将作为一种 比较一下。我们将整合体外和体内研究的结果，以获得更好的 对EGCG及其与ATST联用预防肺癌作用的认识。公共卫生相关声明(叙述性附件)： 本课题的目的是研究绿茶多酚对肺癌的抑制作用。 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 利普妥是一种受欢迎的降胆固醇药物，通常为人类所食用。可能使用的 茶多酚和立普妥联合用于预防肺癌是一种有吸引力的策略，可以 对公共卫生有很大的影响。

Abstract: 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 Statement (Narrative attachment): 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.