DISULFIRAM INHIBITS TNF-α-INDUCED CELL DEATH

Disulfiram, a clinically employed alcohol deterrent, was recently discovered to inhibit caspase-3 and DNA fragmentation. Using LLC-PK1 cells and murine liver as models, we examined if the drug inhibited TNF-α-induced cell death. Disulfiram produced dose-dependent inhibition of TNF-α-induced cell dea...

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Veröffentlicht in:Cytokine (Philadelphia, Pa.) Pa.), 2000-09, Vol.12 (9), p.1356-1367
Hauptverfasser: Zhao, Aiping, Wu, Zheng-Qi, Pollack, Matthew, Rollwagen, Florence M, Hirszel, Przemyslaw, Zhou, Xiaoming
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Sprache:eng
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Zusammenfassung:Disulfiram, a clinically employed alcohol deterrent, was recently discovered to inhibit caspase-3 and DNA fragmentation. Using LLC-PK1 cells and murine liver as models, we examined if the drug inhibited TNF-α-induced cell death. Disulfiram produced dose-dependent inhibition of TNF-α-induced cell death as well as caspase-3-like activity. Disulfiram retained 80% of its effect when added 4h after TNF-α. Disulfiram protected the cells from cytokine-induced death for at least 6 days. The cells rescued by the drug preserved the ability to proliferate. The cells died spontaneously after exposure to TNF-α for just 70min. Co-administration of 15μM disulfiram and TNF-α for 70min prior to their removal abolished TNF-α-induced killing, and this was associated with restoration of mitochondrial membrane potential and suppression of reactive oxygen species. Treatment of mice with TNF-α and D-galactosamine for 5h markedly increased hepatic DNA fragmentation and caspase-3-like activity. Disulfiram at 0.6mmol/kg abolished these effects. We conclude that disulfiram is a potent inhibitor of TNF-α-induced cell death in vitro. The underlying mechanisms include stabilization of mitochondrial membrane potential, suppression of reactive oxygen species, and inhibition of caspase-3-like activity. We further conclude that disulfiram inhibits DNA fragmentation in vivo in association with the blockade of caspase-3-like activity.
ISSN:1043-4666
1096-0023
DOI:10.1006/cyto.2000.0725