title: Histone deacetylase inhibitor depsipeptide (FK228) induces apoptosis in leukemic cells by facilitating mitochondrial translocation of Bax, which is enhanced by the proteasome inhibitor bortezomib.
abstract: Histone deacetylase (HDAC) inhibitors are promising candidates for molecular-targeted therapy for leukemia. In this study, we investigated the mechanisms of cytotoxic effects of depsipeptide (FK228), one of the most effective HDAC inhibitors against leukemia, using human myeloid leukemic cell lines HL-60 and K562. We found that FK228 activated caspase-9 and a subsequent caspase cascade by perturbing the mitochondrial membrane to release cytochrome c, which was almost completely blocked by overexpression of Bcl-2. The mitochondrial damage was caused by the translocation of Bax but not other pro-apoptotic Bcl-2 family proteins to the mitochondria. FK228 did not affect the interaction between Bax and Bax adaptor proteins such as 14-3-3theta and Ku70. FK228-induced apoptosis and mitochondrial translocation of Bax were markedly enhanced by the proteasome inhibitor bortezomib. The synergistic action of FK228 and bortezomib was at least partly mediated through conformational changes in Bax, which facilitate its translocation to the mitochondria. These results suggest that the combination of HDAC inhibitors and proteasome inhibitors is useful in the treatment of leukemia especially in the context of molecular-targeted therapy. The status of Bcl-2 and Bax may influence the sensitivity of tumors to this combination and thus can be a target of further therapeutic intervention.
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
authors.forename: Krittaya
authors.initials: K
authors.lastname: Sutheesophon
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Masa-aki
authors.initials: MA
authors.lastname: Takatoku
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kano
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D000072200:Ku Autoantigen; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D021381:Protein Transport / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D000903:Antibiotics, Antineoplastic; D034961:Antigens, Nuclear; C494826:BAX protein, human; D001897:Boronic Acids; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; C482984:YWHAH protein, human; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; D045304:Cytochromes c; C087123:romidepsin; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen