Selective cell death by water-soluble Fe-porphyrins with superoxide dismutase (SOD) activity

We investigated the effect on cell death of reactive oxygen species induced by [[5,10 (or 5,15)-bis(N-methyl-4-pyridyl)-15,20 (or 10,20) diphenyl]porphinato] iron (cis-FeMPy2P2P or trans-FeMPy2P2P) with SOD activity. The SOD activities of the cis-FeMPy2P2P and trans-FeMPy2P2P were measured using stopped-flow kinetic analysis. The cell viability of four cell lines treated with cis-Fe-porphyrin, trans-Fe-porphyrin, mitomycin c (MMC), or cisplatin was estimated by the alamar blue exclusion assay of the modified MTT method. The amount of cis-FeMPy2P2P and trans-FeMPy2P2P in the Walker 256 cultured for 24 h was 4.0 and 2.6 fmol cell(-1), respectively, indicating that the plasma membrane permeability of the Fe-porphyrins depended on their structure. Cis-FeMPy2P2P selectively killed Walker 256 and H-4-II-E as cancer cells but not FR and BRL-3A as normal cells and showed a significant cytotoxicity for the cancer cells compared with trans-FeMPy2P2P, MMC and cisplatin. We believe that cis-FeMPy2P2P as an SOD mimic converts intracellular O-2(.-) to H2O2 and that H2O2 or .OH causes DNA damage and induces cell death. This result suggests that for the SOD mimic, O-2(.-) may be useful as a target molecule to induce selective cell death between cancer and normal cells and that a metalloporphyrin having SOD activity is a new class of anticancer agents. (C) 2002 Published by Elsevier Science Inc.