trichostatin-a and Anemia--Sickle-Cell

The vascular pathobiology of sickle cell anemia involves inflammation, coagulation, vascular stasis, reperfusion injury, iron-based oxidative biochemistry, deficient nitric oxide (NO) bioavailability, and red cell sickling. These disparate pathobiologies intersect and overlap, so it is probable that multimodality therapy will be necessary for this disease. We have, therefore, tested a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), for efficacy in reducing endothelial activation. We found that pulmonary vascular endothelial VCAM-1 and tissue factor (TF) expression (both are indicators of endothelial activation) are powerfully and significantly inhibited by TSA. This is seen both with pretreatment before the inducing stress of hypoxia/reoxygenation (NY1DD sickle transgenic mouse), and upon longer-term therapy after endothelial activation has already occurred (hBERK1 sickle mouse at ambient air). In addition, TSA prevented vascular stasis in sickle mice, it exhibited activity as an iron chelator, and it induced expression of the antisickling hemoglobin, hemoglobin F. Notably, the TSA analog SAHA (suberoylanilide hydroxaminc acid) that is already approved for human clinical use exhibits the same spectrum of biologic effects as TSA. We suggest that SAHA possibly could provide true, multimodality, salubrious effects for prevention and treatment of the chronic vasculopathy of sickle cell anemia.

Topics: Anemia, Sickle Cell; Animals; beta-Thalassemia; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Enzyme Inhibitors; Fetal Hemoglobin; Hemoglobin A; Hemoglobin, Sickle; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Intercellular Adhesion Molecule-1; Iron Chelating Agents; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pulmonary Veins; Regional Blood Flow; Thromboplastin; Vascular Cell Adhesion Molecule-1; Venules; Vorinostat

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.

Topics: Anemia, Sickle Cell; Animals; Butyrates; Enzyme Inhibitors; Erythroid Precursor Cells; Fetal Hemoglobin; Gene Expression Regulation; Gene Silencing; Globins; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Hydroxylamines; Imidazoles; K562 Cells; Mice; Mice, Transgenic; p38 Mitogen-Activated Protein Kinases; Pyridines; Quinolines; RNA, Messenger; Signal Transduction