title: Pharmacological Induction of Human Fetal Globin Gene in Hydroxyurea-Resistant Primary Adult Erythroid Cells.
abstract: Pharmacological induction of the fetal γ globin gene and the consequent formation of HbF (α2/γ2) in adult erythroid cells are one feasible therapeutic strategy for sickle cell disease (SCD) and severe β-thalassemias. Hydroxyurea (HU) is the current drug of choice for SCD, but serious side effects limit its clinical use. Moreover, 30 to 50% of patients are irresponsive to HU treatment. We have used high-throughput screening to identify benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one and its derivatives (compounds I to VI) as potent γ globin inducers. Of the compounds, I to V exert superior γ globin induction and have better therapeutic potential than HU, likely because of their activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway and modulation of expression levels and/or chromosome binding of γ globin gene regulators, including BCL11A, and chromatin structure over the γ globin promoter. Unlike sodium butyrate (NaB), the global levels of acetylated histones H3 and H4 are not changed by compound II treatment. Remarkably, compound II induces the γ globin gene in HU-resistant primary human adult erythroid cells, the p38 signaling pathway of which appears to be irresponsive to HU and NaB as well as compound II. This study provides a new framework for the development of new and superior compounds for treating SCD and severe β-thalassemias.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Chou
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Ruei-Lin
authors.initials: RL
authors.lastname: Chen
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Zheng-Sheng
authors.initials: ZS
authors.lastname: Lai
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan ckshen@imb.sinica.edu.tw.
authors.forename: Che-Kun James
authors.initials: CK
authors.lastname: Shen
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D020148:Butyric Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004351:Drug Resistance; D041905:Erythroid Cells / Q000187:drug effects* / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D020014:K562 Cells; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061251:Primary Cell Culture; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D017086:beta-Thalassemia / Q000188:drug therapy / Q000235:genetics; D055545:gamma-Globins / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D055545:gamma-Globins; D020148:Butyric Acid; D005319:Fetal Hemoglobin; D048051:p38 Mitogen-Activated Protein Kinases; D006918:Hydroxyurea