Does Superoxide Anion Have a Role in Phorbol Ester Tumor Promotion ?

Abstract

Several lines of evidence indicate that TPA stimulates the production of O27, as well as H2O2, although both the metabolic source and biological significance in tumor promotion and progression in mouse skin have not been elucidated. The first approach taken in this study was to compare the efficacy of two structurally different Superoxide dismutase (SOD)-mimetics or -scavengers, copper II (diisopropylsalicylic acid)2 (CuDIPS) and the acyl dehyroalanines AD5 and AD19, on several TPA- induced responses. Both of these compounds reduce O22 production in TPA-treated keratinocytes, however, their effects are dissimilar for other parameters. AD19 does not inhibit ornithine decarboxylase (ODC) induction, while CuDIPS does. CuDIPS has previously been shown to inhibit tumor promotion; however, AD19 completely lacks this inhibitory activity, although it does dramatically reduce hyperplasia and the progression of papillomas to carcinomas. The second approach was to determine whether elevated endogenous SOD would inhibit TPA-induced growth in soft agar in the JB-6 cell line. Transfection with human CuZnSOD cDNA resulted in a number of cell lines in which, unexpectedly, there was no correlation between mRNA levels, SOD activity or colony formation in soft agar. Together these studies suggest that 022 may not play a key role in tumor promotion.