Inhibition of Lung Carcinogenesis by Tea Polyphenols and Atorvastatin

茶多酚和阿托伐他汀抑制肺癌发生

• 批准号: 7850510
• 负责人: CHUNG S. YANG
• 金额: $ 1.92万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7850510
• 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; abstracting; 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

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.

抽象的： 该项目的目的是研究绿茶多酚抑制肺癌发生的作用 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 人类普遍食用，立普妥是一种流行的降胆固醇药物。基于我们的 初步结果，我们推测绿茶多酚，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 这需要更多的调查。为了检验我们的假设，这些药物将在 4- (甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 诱导的 A/J 小鼠肺癌模型和 相关细胞系。将彻底研究抑制作用和所涉及的机制 具体目标如下： 1. 确定 EGCG 及其与 ATST 组合对 NNK 诱导的抑制作用 启动后和进展阶段的小鼠肺癌模型。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%） 饮食以确定剂量反应关系以及这两种药物的相互作用 抑制肺癌的发生。抑制作用与 EGCG 和 肺组织和血浆中的 ATST。 2.阐明EGCG及其组合抑制肺癌发生的机制 在 NNK 处理的小鼠中使用 ATST。使用目标 1 中的样本，我们将检查 对细胞增殖、凋亡、血管生成和相关分子变化的不同治疗 （例如，Erk1/2、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化分析研究小 G 蛋白的膜关联。 荷瘤小鼠的短期动物实验将作为直接方法来获得 体内机械信息。 3. 阐明EGCG及其联合预防肺癌的详细机制 肺癌细胞系中的 ATST。 EGCG 和 ATST 之间的相互作用机制将是 调查了。绿茶多酚混合物（Polyphenon E）的活性也将作为一种 比较。我们将整合体外和体内研究的结果以获得更好的结果 了解 EGCG 及其与 ATST 组合的肺癌预防活性。公共卫生相关性声明（叙述性附件）： 该项目的目的是研究绿茶多酚抑制肺癌发生的作用 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 人类普遍食用，立普妥是一种流行的降胆固醇药物。可能的用途 茶多酚和立普妥的组合预防肺癌是一种有吸引力的策略，可以 对公众健康有很大影响。