Histone deacetylase inhibitors induce caspase-dependent apoptosis and downregulation of daxx in acute promyelocytic leukaemia with t(15;17).
Histone deacetylase (HDAC) appears to play an important role in the pathogenesis of acute promyelocytic leukaemia (APL) as it is recruited by both PML-RARalpha and PLZF/RAR alpha in leukaemic cells with t(15;17) and t(11;17) respectively. Recent studies have demonstrated that HDAC inhibitors can be therapeutically used in various neoplastic disorders including APL. Cell differentiation was considered the major mechanism of the anti-leukaemic effects of HDAC inhibitors in APL. However, most of these studies either evaluated the effect of HDAC inhibitors in combination with all-trans retinoic acid (ATRA) or focused on the less common form of APL with t(11;17). To investigate the cellular effects of HDAC inhibitors, including sodium butyrate, trichostatin A, and suberoylanilide hydroxamic acid (SAHA), we used two APL cell lines, NB4 and the ATRA-resistant derivative NB4.306. Moreover, primary cells from five patients with cytogenetic evidence for t(15;17) were also studied. Our results demonstrated that HDAC inhibitors induce distinct caspase-dependent apoptosis in APL, which showed both concentration-and time-dependence. In addition, changes in the apoptosis-regulatory proteins, daxx, bcl-2 and bax were analysed. HDAC inhibitors induced downregulation of daxx, but no significant changes were detected in bcl-2 or bax. In conclusion, apoptosis induced by HDAC inhibitors in APL could provide an effective strategy for treatment of patients with t(15;17).
Amin
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HM
Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA.
Saeed
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Alkan
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D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000502:physiology; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D056970:Co-Repressor Proteins; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002087:Butyrates; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C012589:trichostatin A; D000077337:Vorinostat; D020169:Caspases