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 inhibited 12-lipoxygenase of mouse epidermis. The IC₅₀ of AA861 and 3, 4, 2', 4'-tetrahydroxychalcone for epidermal 12-lipoxygenase were 1.9 and 0.2 μM, respectively. These agents showed very weak inhibitory actions on epidermal cyclooxygenase, with the potency of inhibition for cydooxy-genase less than 1/50 of that for lipoxygenase. Induction of epidermal ornithine decarboxylase by 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 skin tumor formation was also strongly suppressed by these agents (15 μmol/mouse). Both AA861 and 3, 4, 2', 4'-tetrahydroxy-chalcone failed to inhbit partially purified epidermal protein kinase C activity. These results support the proposed involvement of lipoxygenase product(s) of arachidonic acid in TPA-induced skin tumor promotion.