title: 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.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China. xubingzhangjian@126.com
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Shi
authors.forename: Ivo S
authors.initials: IS
authors.lastname: Fombon
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fen
authors.initials: F
authors.lastname: Huang
authors.forename: Weiguang
authors.initials: W
authors.lastname: Wang
authors.forename: Shuyun
authors.initials: S
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003300:Copper / Q000633:toxicity*; D004221:Disulfiram / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D003300:Copper; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D004221:Disulfiram