https://scholars.lib.ntu.edu.tw/handle/123456789/431199
標題: | Oxidative stress and c-Jun-amino-terminal kinase activation involved in apoptosis of primary astrocytes induced by disulfiram-Cu 2+ complex | 作者: | Chen S.H. SHING-HWA LIU Liang Y.-C. Lin J.-K. Lin-Shiau S.-Y. |
公開日期: | 2001 | 卷: | 414 | 期: | 2/3 | 起(迄)頁: | 177-188 | 來源出版物: | European Journal of Pharmacology | 摘要: | 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. ? 2001 Published by Elsevier Science B.V. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-0035794002&doi=10.1016%2fS0014-2999%2801%2900792-0&partnerID=40&md5=5ce0957742ad802365d1937e1f7081c9 https://scholars.lib.ntu.edu.tw/handle/123456789/431199 |
ISSN: | 0014-2999 | DOI: | 10.1016/S0014-2999(01)00792-0 | SDG/關鍵字: | caspase 3; copper complex; disulfiram; disulfiram copper; stress activated protein kinase; unclassified drug; alcoholism; animal cell; apoptosis; article; astrocyte; cell viability; complex formation; concentration response; controlled study; cytopathology; cytotoxicity; drug effect; enzyme activation; enzyme degradation; membrane potential; nerve fiber degeneration; neuropathology; neurotoxicity; nonhuman; oxidative stress; priority journal; rat; signal transduction; Animals; Animals, Newborn; Apoptosis; Astrocytes; Caspase 3; Caspases; Cells, Cultured; Cerebral Cortex; Copper; Disulfiram; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Inhibitors; Free Radicals; Glutathione; JNK Mitogen-Activated Protein Kinases; Membrane Potentials; Mitogen-Activated Protein Kinases; Oxidative Stress; Poly(ADP-ribose) Polymerases; Rats; Rats, Wistar |
顯示於: | 毒理學研究所 |
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