Sunlight-induced skin cancer is the most prevalent cancer in the United States. In earlier studies we treated SKH-1 mice with UVB twice a week for 20 weeks. These initiated mice have no tumors, but they have a high risk of developing tumors during the next several months (high risk mice). Topical applications of caffeine 5 days a week to these high risk mice inhibited carcinogenesis and selectively increased apoptosis in the tumors but not in areas of the epidermis away from the tumors. Our leading hypothesis is that caffeine induces apoptosis by inhibition of the ATR/Chk1-dependent G2/M cell cycle checkpoint leading to premature mitosis and cell death. In preparation for translational studies on the effects of caffeine in humans, we evaluated the tumorigenicity of four commercial moisturizing creams that are commonly used by the public. All four had tumorigenic activity when applied topically for several months to high risk mice. To overcome this obstacle, we developed a novel Custom Blend cream that lacks tumorigenic activity and can be used for translational studies in humans. We plan to pursue the following specific aims: 1. Determine the effects of topical applications of caffeine in our newly developed non-tumorigenic Custom Blend cream on carcinogenesis in UVB-pretreated high risk SKH-1 mice and study the effects of the treatment on apoptosis, proliferation and the ATR/Chk1 signal transduction pathway in focal hyperplastic areas of the epidermis and in tumors. The effects of oral administration of caffeine will also be studied. 2. Determine the primary targets or early events for the action of caffeine by studying its effect on key molecular markers based on Aim 1 in epidermal focal hyperplastic areas and tumors after short term treatment (e.g. with topically applied caffeine for 3 hr, 6 hr, 24 hr, 48 hr, 7 days, or 14 days). 3. Initiate a translational study to determine the effects of topical applications of caffeine on apoptosis, proliferation and the ATR/Chk1 pathway in actinic keratoses in human skin. Key molecular markers identified by research in Aim 1 will be determined in biopsies of large keratoses before and after two weeks of topical applications of caffeine or placebo.

Public Health Relevance

Our proposed mechanistic studies on the effects of caffeine on ultraviolet light-induced cancer formation are important steps on the road to the development of a novel approach for the prevention of sunlight-induced skin cancer. Our studies on the effects of caffeine may also have importance for individuals ingesting caffeine-containing beverages and chocolate.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ONC-L (03))
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Perloff, Marjorie
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Rutgers University
Schools of Pharmacy
New Brunswick
United States
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Bernard, Jamie J; Lou, You-Rong; Peng, Qing-Yun et al. (2014) Inverse relationship between p53 and phospho-Chk1 (Ser317) protein expression in UVB-induced skin tumors in SKH-1 mice. Exp Mol Pathol 96:126-31
Lou, Yourong; Peng, Qingyun; Li, Tao et al. (2013) Oral caffeine during voluntary exercise markedly inhibits skin carcinogenesis and decreases inflammatory cytokines in UVB-treated mice. Nutr Cancer 65:1002-13
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
Lu, Yao-Ping; Lou, You-Rong; Bernard, Jamie J et al. (2012) Surgical removal of the parametrial fat pads stimulates apoptosis and inhibits UVB-induced carcinogenesis in mice fed a high-fat diet. Proc Natl Acad Sci U S A 109:9065-70
Lu, Yao-Ping; Lou, You-Rong; Peng, Qing-Yun et al. (2011) Caffeine decreases phospho-Chk1 (Ser317) and increases mitotic cells with cyclin B1 and caspase 3 in tumors from UVB-treated mice. Cancer Prev Res (Phila) 4:1118-25
Kawasumi, Masaoki; Lemos, Bianca; Bradner, James E et al. (2011) Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase. Proc Natl Acad Sci U S A 108:13716-21