- Induction of ferroptosis by singlet oxygen generated from naphthalene endoperoxide
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Singlet oxygen causes a cytotoxic process in tumor cells in photodynamic therapy (PDT) and skin photoaging. The mechanism responsible for this cytotoxicity is, however, not fully understood. 1-Methylnaphthalene-4-propionate endoperoxide (MNPE) is a cell-permeable endoperoxide that generates pure singlet oxygen. We previously reported that cell death induced by MNPE did not show the typical profile of apoptosis, and the cause of this cell death remains elusive. We report herein on an investigation of the mechanism for MNPE-induced cell death from the view point of ferroptosis. The findings indicate that the MNPE treatment decreased the viabilities of mouse hepatoma Hepa 1-6 cells in vitro, and that this decrease was accompanied by increases in the concentrations of both intracellular ferrous iron and the level of lipid peroxidation, but that the caspase-mediated apoptotic pathway was not activated. The intracellular levels of cysteine and glutathione were not affected by the MNPE treatment. Importantly, an assay of lactate dehydrogenase activity revealed that the cell death caused by MNPE was suppressed by ferrostatin-1, a ferroptosis-specific inhibitor. Collectively, these results strongly indicate that ferroptosis is the main cell death pathway induced by singlet oxygen.
- Homma, Takujiro,Kobayashi, Sho,Fujii, Junichi
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- Formation of Superoxide Ion via One-Electron Transfer from Electron Donors to Singlet Oxygen
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The formation of superoxide ion (O2-.) via one-electron transfer from substituted N,N-dimethylanilines to singlet oxygen (1O2) was examined in phosphate buffer by employing a water-soluble oxygen source and a combination of p-nitrotetrazolium blue (NBT) and superoxide dismutase (SOD) as a detecting reagent for O2-..When a solution of an electron-donor-substituted N,N-dimethylaniline, NBT, and 3-(1,4-epidioxy-4-methyl-1,4-dihydro-1-naphthyl)propionic acid in phosphate buffer at pH 7.5 was incubated at 35 deg C, NBT was reduced to formazan.The inhibition of the reduction of NBT to formazan by SOD indicated the formation of O2-..Control experiments demonstrated that O2-. is produced by a direct reaction between 1O2 and the amine.Both the yield of O2-. and the quenching rate constants of 1O2 are well correlated with the oxidation potentials of these amines.Tetramethyl-p-phenylenediamine having a quenching rate constant close to a diffusion-controlled limit is the most effective for the generation of O2-. A plot of the log of the quenching rate constant of 1O2 by the amines against the calculated free-energy change (ΔG) for full electron transfer showed a linear relationship with a slope of -0.19 +/- 0.05 mol/kcal.The correlation of the log of the relative yield of O2-. against ΔG strongly supports the electron-transfer mechanism for the formation of O2-..It was demonstrated that an electron-transfer reaction giving rise to O2-. is only possible for aromatic amines with oxidation potentials less than ca. 0.5 V vs.SCE in aqueous media.
- Saito, Isao,Matsuura, Teruo,Inoue, Kenzo
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- Toxicity of singlet oxygen generated thermolytically in Escherichia coli
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Three water-soluble devivatives of naphthalene endoperoxide were prepared to examine the toxicity of singlet oxygen towards Escherichia coli. On incubation without irradiation, these endoperoxides produce singlet oxygen thermolytically in a dose-dependent manner. The amount of singlet oxygen produced per unit time can be controlled by varying both the incubation temperature and the number of methyl substituents of the naphthalene endoperoxide derivatives. 3-(1,4-Dihydro-1,4-epidioxy-4-methyl-1-naphthyl)propionic acid (EP-1), one of the derivatives, inhibited E. coli growth dose- and incubation temperature-dependently and caused E. coli lethality. Furthermore, EP-1 did not induce superoxide dismutase or catalase in E. coli even when the cells were incubated in nutritionally rich medium containing trypticase/soy/yeast extract. Singlet oxygen, one of the reactive oxygen species, did not act as a signal for induction of superoxide dismutase and catalase, in contrast to the actions of superoxide and hydrogen peroxide.
- Nagano,Tanaka,Mizuki,Hirobe
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p. 883 - 887
(2007/10/02)
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