Abstract 1600: Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by topical garcinol through inhibition of 5-lipoxygenase

Abstract

Abstract Oral cancer is a common malignancy occurring in developing countries, and remains problematic due to lack of effective strategies of prevention and treatment. Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis, and can be targeted for cancer prevention. In order to develop potent topical agents for oral cancer chemoprevention, five known 5-Lox inhibitors from dietary and synthetic sources were evaluated for their potential efficacy when topically applied on the oral epithelium. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be the most promising agent based on our calculation of a theoretical activity index. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. Furthermore, computer modeling showed that garcinol well fit the active site of 5-Lox, and inhibited enzyme activity through possible interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. These results demonstrated that topical garcinol exerts its chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis by inhibiting 5-Lox, inflammation and cell. Chemical modifications of garcinol may produce more potent 5-Lox inhibitors for topical use in oral cancer chemoprevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1600. doi:1538-7445.AM2012-1600