title: Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells.
abstract: Therapeutic strategies targeting histone deacetylase (HDAC) inhibition have become promising in many human malignancies. Belinostat (PXD101) is a hydroxamate-type HDAC inhibitor tested in phase I and II clinical trials in solid tumors and hematological cancers. However, little is known about the use of belinostat for differentiation therapy against acute myelogenous leukemia. Here, we characterize the antileukemia activity of belinostat as a single drug and in combination with all-trans-retinoic acid (RA) in promyelocytic leukemia HL-60 and NB4 cells. Belinostat exerted dose-dependent growth-inhibitory or proapoptotic effects, promoting cell cycle arrest at the G0/G1 or the S transition. Apoptosis was accompanied by activation of caspase 3, degradation of PARP-1, and cell cycle-dependent changes in the expression of survivin, cyclin E1, and cyclin A2. Belinostat induced a dose-dependent reduction in the expression of EZH2 and SUZ12, HDAC-1, HDAC-2, and histone acetyltransferase PCAF (p300/CBP-associated factor). Belinostat increased acetylation of histone H4, H3 at K9 and H3 at K16 residues in a dose-dependent manner, but did not reduce trimethylation of H3 at K27 at proapoptotic doses. Combined treatment with belinostat and RA dose dependently accelerated and reinforced granulocytic differentiation, accompanied by changes in the expression of CD11b, C/EBPα (CCAAT/enhancer binding protein-α), and C/EBPε. Our results concluded the usefulness of belinostat, as an epigenetic drug, for antileukemia and differentiation therapy.
authors.affiliation: Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Vilnius, Lithuania.
authors.forename: Jurate
authors.initials: J
authors.lastname: Savickiene
authors.forename: Grazina
authors.initials: G
authors.lastname: Treigyte
authors.forename: Giedre
authors.initials: G
authors.lastname: Valiuliene
authors.forename: Ieva
authors.initials: I
authors.lastname: Stirblyte
authors.forename: Ruta
authors.initials: R
authors.lastname: Navakauskiene
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology*; D009363:Neoplasm Proteins; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014157:Transcription Factors; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; C430461:SUZ12 protein, human; D013449:Sulfonamides; D014157:Transcription Factors; D014212:Tretinoin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D006655:Histone Deacetylases; C487081:belinostat