Inhibition of 12-O-tetradecanoylphorbol-13-acetate-mediated epidermal ornithine decarboxylase induction and skin tumor promotion by new lipoxygenase inhibitors lacking protein kinase C inhibitory effects

Both 2,3,5-trimethyl-6-(12-hydroxy-5, 10-dodecadiynyl)-l, 4-benzoquinone(AA861) and 3, 4, 2‘, 4’-tetrahydroxychalcone inhibited12-lipoxygenase of mouse epidermis. The IC₅₀ of AA861 and 3,4, 2‘, 4’-tetrahydroxychalcone for epidermal 12-lipoxygenasewere 1.9 and 0.2 µM, respectively. These agents showedvery weak inhibitory actions on epidermal cyclooxygenase, withthe potency of inhibition for cydooxy-genase less than 1/50of that for lipoxygenase. Induction of epidermal ornithine decarboxylaseby 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 10 nmol/mouse)was potently inhibited by these agents in a dose-dependent manner(1–30µmol/mouse). TPA (5 nmol/mouse)-induced skintumor formation was also strongly suppressed by these agents(15 µmol/mouse). Both AA861 and 3, 4, 2‘, 4’-tetrahydroxy-chalconefailed to inhbit partially purified epidermal protein kinaseC activity. These results support the proposed involvement oflipoxygenase product(s) of arachidonic acid in TPA-induced skintumor promotion.