title: Fetal hemoglobin induction by the histone deacetylase inhibitor, scriptaid.
abstract: Many different classes of drugs induce fetal hemoglobin (HbF) including histone deacetylase (HDAC) inhibitors such as butyrate and trichostatin A. Although these agents induce gamma-globin expression in culture many are ineffective in vivo, therefore research efforts continue to identify clinically useful fetal globin inducers. We and others demonstrated a role for p38 mitogen activated protein kinase (MAPK) in gamma-globin promoter activation by HDAC inhibitors. In this study we determined the ability of scriptaid, a novel HDAC inhibitor, to induce gamma-globin expression via p38 MAPK signaling. Scriptaid induced gamma-globin in K562 cells and human erythroid progenitors. Furthermore the p38-selective inhibitor SB203580 completely reversed the ability of scriptaid to induce HbF. To test the potential efficacy of scriptaid in humans, in vivo studies were completed in beta-YAC transgenic mice where the gamma-gene is completely silenced. Scriptaid induced reticulocytosis and human gamma-globin mRNA synthesis. At a concentration of 1 mg/kg/day given by intraperitoneal injections twice weekly we observed a significant 1.8-fold increase in gamma-globin mRNA transcripts. The potential for scriptaid as a treatment option for sickle cell disease will be discussed.
authors.affiliation: Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75083, USA.
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.forename: R
authors.initials: R
authors.lastname: Hunter
authors.forename: R
authors.initials: R
authors.lastname: McElveen
authors.forename: X H
authors.initials: XH
authors.lastname: Qian
authors.forename: B S
authors.initials: BS
authors.lastname: Baliga
authors.forename: B S
authors.initials: BS
authors.lastname: Pace
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015672:Erythroid Precursor Cells / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D006898:Hydroxylamines / Q000494:pharmacology* / Q000627:therapeutic use; D007093:Imidazoles / Q000494:pharmacology; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D006898:Hydroxylamines; D007093:Imidazoles; D011725:Pyridines; D011804:Quinolines; D012333:RNA, Messenger; C410733:scriptaid; C012589:trichostatin A; D005914:Globins; D005319:Fetal Hemoglobin; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580