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.
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