Evidence that oxidative stress-induced apoptosis by menadione involves Fas-dependent and Fas-independent pathways.
Menadione (vitamin K3) a redox cycling quinone, is a clinically important chemotherapeutic agent. The objective of this study was to clarify the cytotoxic mechanisms by which menadione induces cell death in a lymphoblastoid cell line. Our results show that while the Jun kinase cascade and FasL expression may contribute to cell death at lower drug concentrations, a mitochondrial pathway dominates the cytotoxic effect at higher menadione concentrations. Menadione treatment clearly affected the mitochondrial function of Jurkat T cells by inducing a collapse of the inner transmembrane potential (DeltaPsi(m)) and a decrease in inner membrane mass, which could be completely reversed by N-acetylcysteine. Importantly, while a broad range of fmk-derived caspase inhibitors had potent effects on Fas-induced apoptosis, they failed to interfere in menadione cytotoxicity, indicating that menadione-induced cell death is predominantly Fas-independent. In addition, the mitochondrial changes coincided with ATP depletion. The failure in ATP production explains the occurrence of Fas-independent death events.
Laux
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Division of Clinical Immunology and Allergy, Department of Medicine, UCLA, School of Medicine, Los Angeles, California 90095, USA.
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D000933:Antifibrinolytic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D053222:Fas Ligand Protein; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D024483:Vitamin K 3 / Q000633:toxicity*; D019014:fas Receptor / Q000276:immunology*
D000933:Antifibrinolytic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; D024483:Vitamin K 3