Pharmacological induction of human fetal globin gene in hydroxyurea-resistant primary adult erythroid cells

Yu Chi Chou, Ruei Lin Chen, Zheng Sheng Lai, Jen Shin Song, Yu Sheng Chao, Che Kun James Shen

研究成果: 雜誌貢獻文章同行評審

20 引文 斯高帕斯(Scopus)

摘要

Pharmacological induction of the fetal γ globin gene and the consequent formation of HbF (α22) 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.

原文英語
頁(從 - 到)2541-2553
頁數13
期刊Molecular and Cellular Biology
35
發行號14
DOIs
出版狀態已發佈 - 2015
對外發佈

ASJC Scopus subject areas

  • 分子生物學
  • 細胞生物學

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