Cilostazol-mediated reversion of γ-globin silencing is associated with a high level of HbF production: A potential therapeutic candidate for β-globin disorders

Biomedicine & Pharmacotherapy

Syed Ghulam Musharraf¹  Faisal Khan¹  Hamad Ali¹ 

[1] Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;

关键词: Cilostazol;    HbF inducer;    γ-globin induction;    β-YAC transgenic mice;    β-thalassemia;    sickle cell anemia;   

DOI  :  

来源: DOAJ

【 摘 要 】

Reversal of fetal hemoglobin (HbF) silencing is an attractive therapeutic intervention for β-thalassemia and sickle cell anemia. The current study proposes the therapeutic of repurposing of cilostazol, an FDA-approved antithrombotic agent, as a promising HbF inducer. Preliminary, we report that cilostazol induced erythroid differentiation and hemoglobinization of human erythroleukemia K562 cells. The erythroid differentiation was accompanied by increased expression of γ-globin mRNA transcripts and HbF production. Cilostazol induced erythroid differentiation and HbF production, without significantly affecting proliferation and viability of hemoglobin producing cells at maximum erythroid inducing concentration. Moreover, we investigated the effect of cilostazol on human β- and γ-globin transgenes in in vivo β-YAC transgenic mice, harboring human β-locus along with β-LCR. A good in vitro correlation was found with substantial up-regulation in fetal globin mRNA; whereas, the β-globin gene expression was not significantly changed. F-cells, analysis in the peripheral blood of cilostazol-treated mice, revealed a significant increase in the F-cells population as compared with sham control groups. Together, these findings support the potential of cilostazol as an HbF inducer, which can be evaluated further to develop a new HbF inducer.

【 授权许可】

Unknown