Salubrinal induces fetal hemoglobin expression via the stress-signaling pathway in human sickle erythroid progenitors and sickle cell disease mice

• Published in: PloS one 2022-05, Vol.17 (5), p.e0261799-e0261799
• Main Authors: Lopez, Nicole H, Li, Biaoru, Palani, Chithra, Siddaramappa, Umapathy, Takezaki, Mayuko, Xu, Hongyan, Zhi, Wenbo, Pace, Betty S
• Format: Article
• Language: English
• Subjects: Analysis; Anemia; Anemia, Sickle Cell; Animals; Antibodies; Binding sites; Biology and Life Sciences; Biotechnology; Care and treatment; Cinnamates - pharmacology; Cinnamates - therapeutic use; Diagnosis; Drug dosages; Erythrocytes; Eukaryotic Initiation Factor-2 - metabolism; FDA approval; Fetal Hemoglobin - metabolism; Fetuses; Flow cytometry; Gene expression; HBB gene; Hemoglobin; Hemoglobin S; Humans; Hydroxyurea; Hypoxia; Medicine and Health Sciences; Mice; Mutation; Occlusion; Oxidative stress; Oxygen; Phosphoprotein phosphatase; Progenitor cells; Protein folding; Protein phosphatase; Proteins; Reactive oxygen species; Research and Analysis Methods; RNA polymerase; Sickle cell anemia; Sickle cell disease; Signal Transduction; Signaling; Thiourea - analogs & derivatives; Transgenic animals
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0261799

Sickle cell disease (SCD) is an inherited blood disorder caused by a mutation in the HBB gene leading to hemoglobin S production and polymerization under hypoxia conditions leading to vaso-occlusion, chronic hemolysis, and progressive organ damage. This disease affects ~100,000 people in the United States and millions worldwide. An effective therapy for SCD is fetal hemoglobin (HbF) induction by pharmacologic agents such as hydroxyurea, the only Food and Drug Administration-approved drug for this purpose. Therefore, the goal of our study was to determine whether salubrinal (SAL), a selective protein phosphatase 1 inhibitor, induces HbF expression through the stress-signaling pathway by activation of p-eIF2α and ATF4 trans-activation in the γ-globin gene promoter. Sickle erythroid progenitors treated with 24μM SAL increased F-cells levels 1.4-fold (p = 0.021) and produced an 80% decrease in reactive oxygen species. Western blot analysis showed SAL enhanced HbF protein by 1.6-fold (p = 0.0441), along with dose-dependent increases of p-eIF2α and ATF4 levels. Subsequent treatment of SCD mice by a single intraperitoneal injection of SAL (5mg/kg) produced peak plasma concentrations at 6 hours. Chronic treatments of SCD mice with SAL mediated a 2.3-fold increase in F-cells (p = 0.0013) and decreased sickle erythrocytes supporting in vivo HbF induction.