Oxidative stress and c-Jun-amino-terminal kinase activation involved in apoptosis of primary astrocytes induced by disulfiram-Cu2+ complex

Sung Ho Chen, Shing Hwa Liu, Yu Chih Liang, Jen Kun Lin, Shoei Yn Lin-Shiau

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Disulfiram is frequently used in the treatment of alcoholism. In this study, we found that CuCl2 (1-10 μM), but not other metal ions (Fe2+, Zn2+, Pb2+), markedly potentiated disulfiram-induced cytotoxicity by 440-fold in primary astrocytes. Thus, the molecular mechanisms of the cytotoxic effects induced by the disulfiram-Cu2+ complex were explored. The changes in morphology (nuclear condensation and apoptotic body formation) and hypodiploidy of DNA suggested that the disulfiram-Cu2+ complex induced an apoptotic process. Our studies of the death-signaling pathway reveal that decreased mitochondrial membrane potential, increased free radical production, and depletion of non-protein-thiols (glutathione) were involved. The disulfiram-Cu2+ complex activated c-Jun-amino-terminal kinase (JNK) and caspase-3 followed by poly (ADP-ribose) polymerase degradation in a time-dependent manner. Moreover, the cellular Cu content was markedly increased and the copper chelator bathocuproine disulfonate abolished all of these cellular events, suggesting that Cu2+ is essential for death signaling. The antioxidants N-acetylcysteine and vitamin C also inhibited the cytotoxic effect. Thus, we conclude that the disulfiram-Cu2+ complex induces apoptosis and perhaps necrosis at a late stage mediated by oxidative stress followed by sequential activation of JNK, caspase-3 and poly (ADP-ribose) polymerase degradation. These findings imply that the axonal degeneration and neurotoxicity observed after the chronic administration of disulfiram are perhaps, at least in part, due to the cytotoxic effect of the disulfiram-Cu2+ complex formed endogenously.

Original languageEnglish
Pages (from-to)177-188
Number of pages12
JournalEuropean Journal of Pharmacology
Volume414
Issue number2-3
DOIs
Publication statusPublished - Mar 2 2001
Externally publishedYes

Keywords

  • Bathocuproine disulfonate
  • c-Jun-amino-terminal kinase (JNK)
  • Caspase-3
  • Disulfiram
  • Membrane potential
  • Oxidative stress

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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