Carcinogenesis Advance Access originally published online on January 14, 2008
Carcinogenesis 2008 29(6):1228-1234; doi:10.1093/carcin/bgn016
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Inhibitory effects of caffeine analogues on neoplastic transformation: structure–activity relationship
1 Hormel Institute, University of Minnesota, Austin, MN 55912, USA
2 Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, South Korea
3 Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA
4 Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa 920-1181, Japan
5 Department of Hospital Pharmacy, School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan
6 Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08855-0789, USA
* To whom correspondence should be addressed. Tel: +507 437 9600; Fax: +507 437 9606; Email: zgdong{at}hi.umn.edu
Some xanthine analogues, including 1,3,7-trimethylxanthine (caffeine) and 1,3-dimethylxanthine (theophylline), have been shown to exert anticancer activities in both cell culture and animal models. The present study focused on the relationship of structure and activity of 50 different caffeine analogues in preventing epidermal growth factor (EGF)-induced malignant transformation of mouse epidermal JB6 promotion-sensitive (P+) Cl41 (JB6 P+) cells. Results indicated that the inhibition of cell transformation by the 1,3,7-trialkylxanthines depends on the number of carbons at the alkyl groups R1 and R3, but not R7. Notably, 1-ethyl-3-hexylxanthine (xanthine 70) was the most effective compound for inhibiting EGF-induced neoplastic transformation among the 50 xanthine analogues tested. The 50% inhibition of cell transformation (ICT50) value for xanthine 70 was 48- or 75-fold less than the ICT50 value of caffeine or theophylline, respectively. Further study revealed that xanthine 70 (5–40 µM) dose dependently inhibited EGF-induced transactivation of activator protein 1 (AP-1), whereas theophylline or caffeine (up to 500 µM) had no effect on AP-1 activity. In addition, xanthine 70 (10 µM) inhibited 12-O-tetradecanoylphorbol-13-acetate- or H-Ras-induced neoplastic transformation in JB6 P+ cells by 78.2 or 62.0%, respectively. Collectively, these results indicated that the number of carbons at R1 and R3 is important for the antitumor-promoting activity of the trialkylxanthines and xanthine 70 might be a promising anticancer agent.
Abbreviations: AP-1, activator protein 1; EGF, epidermal growth factor; FBS, fetal bovine serum; ICT50, 50% inhibition of cell transformation; MEM, minimum essential medium; P+, promotion sensitive; TPA, 12-O-tetradecanoylphorbol-13-acetate
These authors contributed equally to this work. Received June 28, 2007; revised January 4, 2008; accepted January 7, 2008.