Fetal hemoglobin induction by the histone deacetylase inhibitor, scriptaid.
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.
Johnson
J
J
Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75083, USA.
Hunter
R
R
McElveen
R
R
Qian
X H
XH
Baliga
B S
BS
Pace
B S
BS
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
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