Isoflavone genistein inhibits the initiation and promotion of two-stage skin carcinogenesis in mice

Isoflavone genistein is a specific inhibitor of protein tyrosine kinase(PTK) and has been shown to have a variety of anticancer activities incultured cells and animal models. We report here that genisteinsignificantly inhibits 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and12-O-tetradecanoyl phorbol-13-acetate (TPA)-promoted skin tumorigenesis ina two-stage carcinogenesis model. In an initiation study, 10 micromolgenistein was applied daily to female SENCAR mouse skin for 1 week,followed by initiation with 10 nmol DMBA. Mice were then treated with twiceweekly 4 microg TPA. Genistein was shown to reduce tumor incidence andmultiplicity in DMBA-initiated skin tumors by approximately 20 (P <0.05) and 50% (P < 0.01), respectively. Two promotion studies wereconducted using CD-1 and SENCAR mice. In experiment 1, CD-1 mice wereinitiated with 100 nmol DMBA and followed by a twice weekly regimen of 1and 5 micromol genistein/4 microg TPA. In experiment 2, SENCAR mice wereinitiated with 10 nmol DMBA and followed by a regimen of 5, 10 and 20micromol genistein/2 microg TPA. Both studies consistently showed thatgenistein substantially inhibited TPA-promoted skin tumorigenesis byreducing the tumor multiplicity by approximately 60 and 75%, respectively(P < 0.01). However, the tumor incidence appeared to be less affected.Mechanistic studies showed that genistein inhibited DMBA-induced bulky DNAadduct formation and substantially suppressed TPA-stimulated H2O2 andinflammatory responses in mouse skin by >60% (P < 0.01). In contrast,genistein only exhibited a moderate inhibition of TPA-induced ornithinedecarboxylase activity (P > 0.05). Our results suggest that genisteinexerts its anti- initiational and anti-promotional effects on skincarcinogenesis probably through blockage of DNA adduct formation andinhibition of oxidative and inflammatory events in vivo.