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...
Gespeichert in:
Veröffentlicht in: | Cytokine (Philadelphia, Pa.) Pa.), 2000-09, Vol.12 (9), p.1356-1367 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
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 |