title: Response of retinoic acid-resistant KG1 cells to combination of retinoic acid with diverse histone deacetylase inhibitors.
abstract: Acute promyelocytic leukemia KG1 cells with t(11;17) PLZF-RARalpha respond poorly to the differentiation inducer all-trans retinoic acid (RA), and the reason for the RA resistance is the recruitment of histone deacetylase by PLZF-RARalpha. Here, we demonstrate that histone deacetylase inhibitors (HDACIs), FK228, BML-210, phenyl butyrate, and vitamin B3, in different combinations with RA, act as KG1 cell growth inhibitors. Partial differentiation to granulocytes was induced by 3 micromol/L RA, and its combination with HDAC inhibitors did not enhance RA-induced but potentiated apoptosis. HDACIs induced accumulation of hyperacetylated histone H4. Chromatin immunoprecipitation analysis has revealed phenyl butyrate and its combinations with RA and vitamin B3 cause histone H4 acetylation in the p21 promoter regions corresponding to p53 and/or Sp1 sites. This was coincident with the activation of the transcription factor p53-binding activity to the p21 promoter in electrophoretic mobility shift assay. The results indicate the possibility of using the combination of agents for therapeutic strategy in RA-resistant acute myeloid leukemia to produce both differentiation and apoptosis.
authors.affiliation: Department of Developmental Biology, Institute of Biochemistry, Vilnius, Lithuania. savickiene@bchi.lt
authors.forename: Jurate
authors.initials: J
authors.lastname: Savickiene
authors.forename: Grazina
authors.initials: G
authors.lastname: Treigyte
authors.forename: Karl-Eric
authors.initials: KE
authors.lastname: Magnusson
authors.forename: Ruta
authors.initials: R
authors.lastname: Navakauskiene
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D047630:Depsipeptides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D024202:Electrophoretic Mobility Shift Assay; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014212:Tretinoin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014803:Vitamin B Complex / Q000494:pharmacology
chemical_list: D000813:Anilides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C514580:N1-(2-aminophenyl)-N8-phenyloctanediamide; D010654:Phenylbutyrates; D016159:Tumor Suppressor Protein p53; D014803:Vitamin B Complex; D009536:Niacinamide; D014212:Tretinoin; C087123:romidepsin