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Apicidin potentiates the imatinib-induced apoptosis of Bcr–Abl-positive human leukaemia cells by enhancing the activation of mitochondria-dependent caspase cascades

 Seung Tae Lee  ;  Jin Seok Kim  ;  Yoo Hong Min  ;  Yun Woong Ko  ;  Jee Sook Hahn  ;  Hoyoung Maeng  ;  June-Won Cheong  ;  Hoi Kyung Jeung 
 BRITISH JOURNAL OF HAEMATOLOGY, Vol.124(2) : 166-178, 2004 
Journal Title
Issue Date
Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Apoptosis/drug effects ; Benzamides ; Blotting, Western ; Caspases/metabolism* ; Drug Synergism ; Enzyme Inhibitors/therapeutic use* ; Genes, abl ; Histone Deacetylase Inhibitors ; Humans ; Imatinib Mesylate ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology ; Mitochondria/enzymology ; Peptides, Cyclic/administration & dosage* ; Piperazines/administration & dosage* ; Pyrimidines/administration & dosage*
imatinib ; apicidin ; histone deacetylase inhibitor ; Bcr–Abl ; leukaemia
Apicidin, a histone deacetylase inhibitor, is a novel cyclic tetrapeptide with potent antiproliferative activity against various cancer cells. We examined whether apicidin potentiates the imatinib-induced apoptosis of Bcr–Abl-positive human leukaemia cells. In K562 cells, the co-administration of minimally toxic concentrations of imatinib and apicidin (imatinib/apicidin) for 48 h produced a marked increase in mitochondrial damage, processing of caspase cascades and apoptosis. Similar results were observed in leukaemic blasts obtained from patients with chronic myeloid leukaemia in blast crisis. Imatinib/apicidin co-treatment for 48 h resulted in a near complete loss of the full-length XIAP (X-linked inhibitor of apoptosis) protein, with a corresponding increase in the 29-kDa XIAP cleavage product. Both the degradation of XIAP and increased release of second mitochondria-derived activator of caspase/direct IAP-binding protein with low pI (Smac/DIABLO) into the cytosol were abrogated by pretreatment with the caspase-3 inhibitor DEVD-CHO. Imatinib/apicidin co-treatment for 48 h produced a prominent decrease in Bcr–Abl protein levels in a caspase-dependent manner. In summary, these data indicate that apicidin potentiates the imatinib-induced apoptosis of Bcr–Abl-positive leukaemia cells through the enhanced activation of the mitochondria-dependent caspase cascades, accompanied by caspase-dependent downregulation of Bcr–Abl and XIAP. These findings generate a rationale for further investigation of apicidin and imatinib as a potential therapeutic strategy in Bcr–Abl-positive leukaemias.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Ko, Yun Woong(고윤웅)
Kim, Jin Seok(김진석) ORCID logo https://orcid.org/0000-0001-8986-8436
Maeng, Ho Young(맹호영)
Min, Yoo Hong(민유홍) ORCID logo https://orcid.org/0000-0001-8542-9583
Lee, Seung Tae(이승태)
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
Jeung, Hoi Kyung(정회경)
Hahn, Jee Sook(한지숙)
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