Disulfiram/copper complex activated JNK/c-jun pathway and sensitized cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells.

Abstract

Resistance to chemotherapy and non-specific cytotoxicity are the major challenges to the treatment of acute myeloid leukemia (AML). In this study, we demonstrated that the disulfiram/copper (DS/Cu) complex alone exhibited cytotoxicity to doxorubicin (Dox) resistant leukemia HL60 cells (HL60/Dox) and enhanced cytotoxicity of Dox to HL60/Dox cells. DS/Cu inhibited Bcl-2 expression and enhanced Dox-induced apoptosis. DS/Cu/Dox in combination significantly induced c-Jun expression and JNK and c-Jun phosphorylation. JNK inhibitor Sp600125 attenuated DS/Cu/Dox-induced apoptosis and suppressed DS/Cu/Dox-induced protein expression in JNK/c-jun pathway. This study suggested that DS/Cu complex may re-sensitize HL60/Dox cells to Dox through activating JNK/c-jun as well as inhibiting anti-apoptotic bcl-2 expression.

• Authors: Bing Xu, Pengcheng Shi, Ivo S Fombon, Yanyan Zhang, Fen Huang, Weiguang Wang, Shuyun Zhou
• Journal: Blood cells, molecules & diseases (Blood Cells Mol Dis) Vol. 47 Issue 4 Pg. 264-9 (Dec 15 2011) ISSN: 1096-0961 [Electronic] United States
• PMID: 21911303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Proto-Oncogene Proteins c-jun
• Copper
• Doxorubicin
• JNK Mitogen-Activated Protein Kinases
• Disulfiram

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor
• Copper (toxicity)
• Disulfiram (toxicity)
• Doxorubicin (toxicity)
• Drug Resistance, Neoplasm
• Drug Synergism
• HL-60 Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Leukemia, Myeloid, Acute (enzymology)
• MAP Kinase Signaling System (drug effects)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-jun (metabolism)