sn-1,2-Diacylglycerols mimic the effects of 12-O-tetradecanoylphorbol-13-acetate in vivo by inducing biochemical changes associated with tumor promotion in mouse epidermis

Abstract

12-O-Tetradecanoylphorbol-13 acetate (TPA) or various acylglycerols were applied topically to CD-1 mice, and biochemical changes associated with tumor promotion in the epidermis were examined. The topical application of 5 mumol of sn-1,2-didecanoylglycerol caused a 40-fold increase in ornithine decarboxylase activity which was similar to that found after the topical application of 2 nmol of TPA. The time course for the induction of ornithine decarboxylase activity by TPA and the time course for its induction by sn-1,2-didecanoylglycerol were similar; both compounds produced rapid increases in ornithine decarboxylase activity with peak induction occurring 4-6 h after application of the inducing chemical. sn-1,2-Dioctanoylglycerol and sn-1-oleoyl-2-acetylglycerol also increased ornithine decarboxylase activity in mouse epidermis, but sn-1,2-dioleoylglycerol, 1,3-didecanoylglycerol and rac-1-monodecanoylglycerol were inactive at the dose tested. trans-Retinoic acid, a potent inhibitor of tumor promotion, markedly inhibited the epidermal induction of ornithine decarboxylase activity that resulted from the topical administration of sn-1,2-didecanoylglycerol or TPA. The effects of TPA and the acylglycerols on epidermal DNA synthesis in vivo were determined by measuring the incorporation of [3H]thymidine into epidermal DNA. The application of sn-1,2-didecanoylglycerol or TPA to mouse skin stimulated epidermal DNA synthesis. The maximum increase occurred 18 h after administration of the inducing chemical, and the increase in DNA synthesis was proportional to the dose of sn-1,2-didecanoylglycerol. Although sn-1,2-didecanoylglycerol, sn-1,2-dioctanoylglycerol and sn-1,2-dioleoylglycerol stimulated epidermal DNA synthesis, sn-1-oleoyl-2-acetylglycerol, 1,3-didecanoylglycerol and rac-1-monodecanoylglycerol had little or no effect. The increase in epidermal DNA synthesis induced by sn-1,2-didecanoylglycerol or TPA was inhibited by the simultaneous application of fluocinolone acetonide, a potent inhibitor of tumor promotion. The results indicate that several sn-1,2-diacylglycerols mimic TPA in vivo with respect to their effects on certain biochemical parameters associated with tumor promotion in mouse skin.