In previous studies, we found that oral administration of green or black tea inhibits ultraviolet light (UV)-induced carcinogenesis in mice. In the present proposal, we plan to investigate the effects of orally administered green and black tea, as well as their constituents (-)-epigallocatechin gallate (EGCG) and caffeine, on mechanistically important UV-induced early changes in mouse skin. A major focus will be to test the hypothesis that tea administration upregulates UV-induced increases in wild-type p53 and downstream effectors of p53. We plan to pursue the following specific aims: 1. Determine the effects of oral administration of green and black tea to SKH-1 mice on the time course for effects of single or multiple low- dose exposures to UV on (a) wild-type p53 expression, (b) expression of p300, ARF and MDM-2 (modulators of p53 stability and function), (c) p21(WAF1/CIP1) expression, (d) bromodemyuridine incorporation into DNA, (e) epidermal thickening (hyperplasia), (f) formation of apoptotic sunburn cells and (g) expression of apoptosis related proteins (BAX, BCL-2, Fas, Fas ligand and caspases) that are downstream effectors of p53. The formation of thymine dimers, oxidized bases and strand breaks in DNA will also be determined. If green and black tea are effective, we will determine the effects of the tea constituents EGCG and caffeine on the parameters that are modulated by tea. 2. Determine the effects of oral administration of green or black tea on the formation and elimination of UV-induced persistent patches of p53 positive cells. These patches will be sequenced to determine the effects of tea administration on the profile of p53 mutations. If tea alters the profile of UV-induced mutations, we will evaluate the effects of EGCG and caffeine. 3. Test the importance of wild-type p53 and Bax for the stimulatory effect of green tea on UV-induced increases in apoptotic sunburn cells and for the inhibitory effect of tea on UV-induced carcinogenesis by studies in p53(-/-) and Bax(-/-) knockout mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080759-04
Application #
6607375
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Okano, Paul
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2005-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$245,700
Indirect Cost
Name
Rutgers University
Department
Biology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Conney, Allan H; Lou, You-Rong; Nghiem, Paul et al. (2013) Inhibition of UVB-induced nonmelanoma skin cancer: a path from tea to caffeine to exercise to decreased tissue fat. Top Curr Chem 329:61-72
Conney, Allan H; Kramata, Pavel; Lou, You-Rong et al. (2008) Effect of caffeine on UVB-induced carcinogenesis, apoptosis, and the elimination of UVB-induced patches of p53 mutant epidermal cells in SKH-1 mice. Photochem Photobiol 84:330-8
Lu, Yao-Ping; Lou, You-Rong; Xie, Jian-Guo et al. (2007) Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice. Carcinogenesis 28:199-206
Conney, Allan H; Zhou, Sherry; Lee, Mao-Jung et al. (2007) Stimulatory effect of oral administration of tea, coffee or caffeine on UVB-induced apoptosis in the epidermis of SKH-1 mice. Toxicol Appl Pharmacol 224:209-13
Michna, Laura; Wagner, George C; Lou, You-Rong et al. (2006) Inhibitory effects of voluntary running wheel exercise on UVB-induced skin carcinogenesis in SKH-1 mice. Carcinogenesis 27:2108-15
Lu, Yao-Ping; Lou, You-Rong; Liao, Jie et al. (2005) Administration of green tea or caffeine enhances the disappearance of UVB-induced patches of mutant p53 positive epidermal cells in SKH-1 mice. Carcinogenesis 26:1465-72
Kramata, Pavel; Lu, Yao-Ping; Lou, You-Rong et al. (2005) Patches of mutant p53-immunoreactive epidermal cells induced by chronic UVB Irradiation harbor the same p53 mutations as squamous cell carcinomas in the skin of hairless SKH-1 mice. Cancer Res 65:3577-85
Kramata, Pavel; Lu, Yao-Ping; Lou, You-Rong et al. (2005) Effect of administration of caffeine or green tea on the mutation profile in the p53 gene in early mutant p53-positive patches of epidermal cells induced by chronic UVB-irradiation of hairless SKH-1 mice. Carcinogenesis 26:1965-74
Wogan, Gerald N; Hecht, Stephen S; Felton, James S et al. (2004) Environmental and chemical carcinogenesis. Semin Cancer Biol 14:473-86
Lu, Yao-Ping; Lou, You-Rong; Peng, Qing-Yun et al. (2004) Stimulatory effect of topical application of caffeine on UVB-induced apoptosis in the epidermis of p53 and Bax knockout mice. Cancer Res 64:5020-7

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