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)]porp hine (MPy4P) containing Fe, Mn or Cu was measured using a cytochrome c assa y by the xanthine/xanthine oxidase system and stopped-flow kinetic analysis . Cell viability of four cell lines treated with metalloporphyrins, mitomyc in c (MMC), or cisplatin was estimated by a trypan blue exclusion assay. Fe MPy4P with a high SOD activity showed a significant cytotoxicity compared w ith MMC and cisplatin, while CuMPy4P without SOD activity exhibited no cyto toxicity. However, MnMPy4P showing an SOD activity as high as that of FeMPy 4P did not indicate cytotoxicity. These findings suggest that FeMPy4P as SO D mimic converts intracellular O2(-) to H2O2 and that it rapidly reacts wit h 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 dama ge in the cells treated with MnMPy4P was not observed. In addition, the cyt otoxicity by the metalloporphyrin was inversely correlated with the SOD act ivity 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 betwee n cancer and normal cells and that metalloporphyrins showing SOD activity a nd Fenton-like reaction are a new class of anticancer agents. (C) 2001 Else vier Science B.V. All rights reserved.