title: Inhibitory effects of caffeine analogues on neoplastic transformation: structure-activity relationship.
abstract: 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 (ICT(50)) value for xanthine 70 was 48- or 75-fold less than the ICT(50) value of caffeine or theophylline, respectively. Further study revealed that xanthine 70 (5-40 muM) dose dependently inhibited EGF-induced transactivation of activator protein 1 (AP-1), whereas theophylline or caffeine (up to 500 muM) had no effect on AP-1 activity. In addition, xanthine 70 (10 muM) 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.
authors.affiliation: Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Rogozin
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Kang
authors.forename: Haoyu
authors.initials: H
authors.lastname: Yu
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nomura
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Allan H
authors.initials: AH
authors.lastname: Conney
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002110:Caffeine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D051379:Mice; D013329:Structure-Activity Relationship; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018808:Transcription Factor AP-1; D002110:Caffeine; D004815:Epidermal Growth Factor