The objective of this project is to study the inhibition of colon carcinogenesis by green tea polyphenols and their combination with atorvastatin (ATST, trade name Lipitor). Tea and ATST are commonly consumed or used by humans. Both agents have been shown to inhibit colon tumorigenesis in animal models and have been suggested to reduce colon cancer risk in humans. Based on our preliminary results, we hypothesize that when the two agents are combined, the cancer preventive activity would be higher. In this project, the inhibitory activities and the mechanisms of action of (-)-epigallocatechin-3-gallate (EGCG), alone and in combination with ATST, will be studied in a rat model and related cell lines.
The specific aims are as follows: 1. Determine the inhibitory actions of EGCG and its combination with ATST in an AOM-induced rat colon carcinogenesis model. We will use different concentrations of EGCG (0.08, 0.16, 0.32, &0.48% in the diet) to determine the dose-response relationship in the inhibition of colon carcinogenesis. Then we will study the combination of EGCG and ATST at different doses to determine whether the inhibitory effect is synergistic or additive. The inhibitory action will be correlated with the levels of EGCG and ATST in colonic tissues and blood. 2. Elucidate the mechanisms of inhibition of colon carcinogenesis by EGCG and its combination with ATST in AOM-treated rats. Using samples from Aim 1, we will examine the effects of the different treatments on cell proliferation and apoptosis, on key oncogenic signaling molecules (such as (3-catenin, Akt, Erk1/2, and COX-2), key tumor suppressive signaling molecules (such as E-cadherin and RXRcc), and on membrane association of small G-proteins in the tumorous and non-tumorous colon samples. Short-term animal experiments with adenoma-bearing rats will be used as a direct approach to obtain mechanistic information in vivo. Combined immunohistochemical (IHC) and biochemical analyses will be used for these studies. 3. Delineate detailed mechanisms of colon cancer prevention by EGCG and its combination with ATST in integrated studies with human colon cancer cell lines and the animal model. More detailed mechanistic studies on the actions of EGCG and its combination with ATST will be pursued in human colon cell lines and then in colon tumor samples from animal experiments. We will study possible direct targets of EGCG action and related novel mechanisms for the inhibition of carcinogenesis. From these studies, we hope to develop a better understanding of the chemopreventive activities of EGCG and their combination with ATST against colon carcinogenesis. as well as promising biomarkers for future studies.
|Hao, Xingpei; Xiao, Hang; Ju, Jihyeung et al. (2017) Green Tea Polyphenols Inhibit Colorectal Tumorigenesis in Azoxymethane-Treated F344 Rats. Nutr Cancer 69:623-631|
|Wang, Hong; Liu, Anna; Kuo, Yingyi et al. (2016) Obesity promotes PhIP-induced small intestinal carcinogenesis in hCYP1A-db/db mice: involvement of mutations and DNA hypermethylation of Apc. Carcinogenesis 37:723-730|
|Jin, Huanyu; Chen, Jayson X; Wang, Hong et al. (2015) NNK-induced DNA methyltransferase 1 in lung tumorigenesis in A/J mice and inhibitory effects of (-)-epigallocatechin-3-gallate. Nutr Cancer 67:167-76|
|Wang, Hong; Zhou, Hong; Liu, Anna et al. (2015) Genetic analysis of colon tumors induced by a dietary carcinogen PhIP in CYP1A humanized mice: Identification of mutation of ?-catenin/Ctnnb1 as the driver gene for the carcinogenesis. Mol Carcinog 54:1264-74|
|Yang, Chung S; Wang, Hong; Chen, Jayson X et al. (2014) Effects of Tea Catechins on Cancer Signaling Pathways. Enzymes 36:195-221|
|Sakamori, Ryotaro; Yu, Shiyan; Zhang, Xiao et al. (2014) CDC42 inhibition suppresses progression of incipient intestinal tumors. Cancer Res 74:5480-92|
|Zhou, Hong; Chen, Jayson X; Yang, Chung S et al. (2014) Gene regulation mediated by microRNAs in response to green tea polyphenol EGCG in mouse lung cancer. BMC Genomics 15 Suppl 11:S3|
|Oh, Sangtaek; Gwak, Jungsug; Park, Seoyoung et al. (2014) Green tea polyphenol EGCG suppresses Wnt/?-catenin signaling by promoting GSK-3?- and PP2A-independent ?-catenin phosphorylation/degradation. Biofactors 40:586-95|
|Dolfi, Sonia C; Yang, Zhihong; Lee, Mao-Jung et al. (2013) Inhibitory effects of different forms of tocopherols, tocopherol phosphates, and tocopherol quinones on growth of colon cancer cells. J Agric Food Chem 61:8533-40|
|Yang, Chung S; Wang, Hong (2013) Cancer therapy combination: green tea and a phosphodiesterase 5 inhibitor? J Clin Invest 123:556-8|
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