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-FeMPy(2)P(2)P or trans-FeMPy(2)P(2)P) with SOD activity. The SOD activities of the cis-FeMPy(2)P(2)P and trans-FeMPy(2)P(2)P 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-FeMPy(2)P(2)P and trans-FeMPy(2)P(2)P in the Walker 256 cultured for 24 h was 4.0 and 2.6 fmolcell(-1), respectively, indicating that the plasma membrane permeability of the Fe-porphyrins depended on their structure. Cis-FeMPy(2)P(2)P 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-FeMPy(2)P(2)P, MMC and cisplatin. We believe that cis-FeMPy(2)P(2)P as an SOD mimic converts intracellular O(2)(*-) to H(2)O(2) and that H(2)O(2) 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.
Kasugai
Nobuyoshi
N
Department of Applied Chemistry, Tokyo Metropolitan University, Minami-Ogsawa, Hachioji, Tokyo 192-0397, Japan.
Murase
Toru
T
Ohse
Toshiyuki
T
Nagaoka
Shoji
S
Kawakami
Hiroyoshi
H
Kubota
Sunao
S
D000818:Animals; D016923:Cell Death; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D018384:Oxidative Stress; D011166:Porphyrins / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species; D012995:Solubility; D013482:Superoxide Dismutase / Q000494:pharmacology*
D011166:Porphyrins; D017382:Reactive Oxygen Species; D016685:Mitomycin; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D002945:Cisplatin