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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.
Br J Haematol. 2004 Jan; 124(2):166-78.BJ

Abstract

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.

Authors+Show Affiliations

Department of Internal Medicine, National Health Insurance Corporation, Ilsan Hospital, Kyunggi-do, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14687026

Citation

Kim, Jin Seok, et al. "Apicidin Potentiates the Imatinib-induced Apoptosis of Bcr-Abl-positive Human Leukaemia Cells By Enhancing the Activation of Mitochondria-dependent Caspase Cascades." British Journal of Haematology, vol. 124, no. 2, 2004, pp. 166-78.
Kim JS, Jeung HK, Cheong JW, et al. Apicidin potentiates the imatinib-induced apoptosis of Bcr-Abl-positive human leukaemia cells by enhancing the activation of mitochondria-dependent caspase cascades. Br J Haematol. 2004;124(2):166-78.
Kim, J. S., Jeung, H. K., Cheong, J. W., Maeng, H., Lee, S. T., Hahn, J. S., Ko, Y. W., & Min, Y. H. (2004). Apicidin potentiates the imatinib-induced apoptosis of Bcr-Abl-positive human leukaemia cells by enhancing the activation of mitochondria-dependent caspase cascades. British Journal of Haematology, 124(2), 166-78.
Kim JS, et al. Apicidin Potentiates the Imatinib-induced Apoptosis of Bcr-Abl-positive Human Leukaemia Cells By Enhancing the Activation of Mitochondria-dependent Caspase Cascades. Br J Haematol. 2004;124(2):166-78. PubMed PMID: 14687026.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apicidin potentiates the imatinib-induced apoptosis of Bcr-Abl-positive human leukaemia cells by enhancing the activation of mitochondria-dependent caspase cascades. AU - Kim,Jin Seok, AU - Jeung,Hoi Kyung, AU - Cheong,June-Won, AU - Maeng,Hoyoung, AU - Lee,Seung Tae, AU - Hahn,Jee Sook, AU - Ko,Yun Woong, AU - Min,Yoo Hong, PY - 2003/12/23/pubmed PY - 2004/2/12/medline PY - 2003/12/23/entrez SP - 166 EP - 78 JF - British journal of haematology JO - Br J Haematol VL - 124 IS - 2 N2 - 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. SN - 0007-1048 UR - https://www.unboundmedicine.com/medline/citation/14687026/Apicidin_potentiates_the_imatinib_induced_apoptosis_of_Bcr_Abl_positive_human_leukaemia_cells_by_enhancing_the_activation_of_mitochondria_dependent_caspase_cascades_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0007-1048&date=2004&volume=124&issue=2&spage=166 DB - PRIME DP - Unbound Medicine ER -