Cell death by reactive oxygen species generated from water-soluble cationic metalloporphyrins as superoxide dismutase mimics

We investigated the effect on cell death of reactive oxygen species induced by water-soluble cationic metalloporphyrins with superoxide dismutase (SOD) activity. The SOD activity of 5,10,15,20-tetrakis(4-N-methylpyridyl)]porphine (MPy4P) containing Fe, Mn or Cu was measured using a cytochrome c assay by the xanthine/xanthine oxidase system and stopped-flow kinetic analysis. Cell viability of four cell lines treated with metalloporphyrins, mitomycin c (MMC), or cisplatin was estimated by a trypan blue exclusion assay. FeMPy4P with a high SOD activity showed a significant cytotoxicity compared with MMC and cisplatin, while CuMPy4P without SOD activity exhibited no cytotoxicity. However, MnMPy4P showing an SOD activity as high as that of FeMPy4P did not indicate cytotoxicity. These findings suggest that FeMPy4P as SOD mimic converts intracellular O2(-) to H2O2 and that it rapidly reacts with H2O2 to form OH, causing DNA damage and inducing cell death. Os the other hand, MnMPy4P did not participate in the Fenton reaction, so that DNA damage in the cells treated with MnMPy4P was not observed. In addition, the cytotoxicity by the metalloporphyrin was inversely correlated with the SOD activity of the cells and the selective damage at cellular and DNA levels was confirmed. We believe that for an anticancer drug with antioxidant ability O-2(-) is useful as a target molecule to induce selective cell death between cancer and normal cells and that metalloporphyrins showing SOD activity and Fenton-like reaction are a new class of anticancer agents. (C) 2001 Elsevier Science B.V. All rights reserved.