Disulfiram inhibits TNF-α-induced cell death

Aiping Zhao, Zheng Qi Wu, Matthew Pollack, Florence M. Rollwagen, Przemyslaw Hirszel, Xiaoming Zhou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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 4 h 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 70 min. Co-administration of 15 μM disulfiram and TNF-α for 70 min 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 5 h markedly increased hepatic DNA fragmentation and caspase-3-like activity. Disulfiram at 0.6 mmol/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.

Original languageEnglish
Pages (from-to)1356-1367
Number of pages12
Issue number9
StatePublished - 2000
Externally publishedYes


  • Apoptosis
  • Caspase-3
  • LLC-PK1 cells
  • Liver
  • Reactive oxygen species


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