Inhibitory effects of caffeine analogues on neoplastic transformation: Structure-activity relationship

Evgeny A. Rogozin, Ki Won Lee, Nam Joo Kang, Haoyu Yu, Masaaki Nomura, Ken Ichi Miyamoto, Allan H. Conney, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1228-1234
Number of pages7
Issue number6
StatePublished - Jun 2008

Bibliographical note

Funding Information:
The Hormel Foundation; National Institutes of Health grants (CA120388, CA111536, CA88961, CA81064); BioGreen 21 Program, Rural Development Administration, Republic of Korea (20070301-034-042-007-02-00).


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