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. To develop potent topical agents for
oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (
Zileuton,
ABT-761,
licofelone,
curcumin, and
garcinol) were evaluated in silico for their potential efficacy.
Garcinol, a polyisoprenylated
benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that
garcinol well fit the active site of 5-Lox, and potentially inhibited
enzyme activity through interactions between the phenolic
hydroxyl groups and the non-
heme catalytic
iron. 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. These results demonstrated that topical application of a 5-Lox inhibitor,
garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch
carcinogenesis.