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

研究成果: 雜誌貢獻文章同行評審

36 引文 斯高帕斯(Scopus)


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.
頁(從 - 到)177-188
期刊European Journal of Pharmacology
出版狀態已發佈 - 三月 2 2001

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

指紋 深入研究「Oxidative stress and c-Jun-amino-terminal kinase activation involved in apoptosis of primary astrocytes induced by disulfiram-Cu<sup>2+</sup> complex」主題。共同形成了獨特的指紋。