Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells

Autor: Giedre Valiuliene, Ruta Navakauskiene, Grazina Treigyte, Jurate Savickiene, Ieva Stirblyte
Rok vydání: 2014
Předmět:
Acute promyelocytic leukemia
Cancer Research
medicine.drug_class
Antineoplastic Agents
Apoptosis
Tretinoin
Hydroxamic Acids
Histone Deacetylases
Epigenesis
Genetic
Histones
chemistry.chemical_compound
Promyelocytic leukemia protein
Leukemia
Promyelocytic
Acute
Cell Line
Tumor
medicine
Humans
Pharmacology (medical)
Enhancer of Zeste Homolog 2 Protein
Cell Proliferation
Pharmacology
Histone deacetylase 5
Sulfonamides
biology
HDAC11
Histone deacetylase 2
business.industry
Histone deacetylase inhibitor
Polycomb Repressive Complex 2
Acetylation
Cell Differentiation
Drug Synergism
Cell Cycle Checkpoints
medicine.disease
Neoplasm Proteins
Histone Deacetylase Inhibitors
Oncology
chemistry
Cancer research
biology.protein
Histone deacetylase
business
Apoptosis Regulatory Proteins
Belinostat
Granulocytes
Transcription Factors
Zdroj: Anti-cancer drugs. 25(8)
ISSN: 1473-5741
Popis: 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.
Databáze: OpenAIRE
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