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

• Published in: Biomedicine & pharmacotherapy Vol. 142; p. 112058
• Main Authors: Ali, Hamad, Khan, Faisal, Musharraf, Syed Ghulam
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-10-2021; Elsevier
• Subjects: Anemia, Sickle Cell - drug therapy; Animals; beta-Globins - genetics; beta-Globins - metabolism; beta-Thalassemia - drug therapy; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cilostazol; Cilostazol - pharmacology; Cilostazol - therapeutic use; Drug Repositioning; Erythroid Cells - drug effects; Fetal Hemoglobin - biosynthesis; Fetal Hemoglobin - drug effects; Fetal Hemoglobin - genetics; gamma-Globins - genetics; gamma-Globins - metabolism; HbF inducer; Hemoglobinopathies - drug therapy; Hemoglobins - drug effects; Hemoglobins - metabolism; Humans; K562 Cells; Mice, Transgenic; sickle cell anemia; β-thalassemia; β-YAC transgenic mice; γ-globin induction; HbF inducer; γ-globin induction; β-YAC transgenic mice; Cilostazol; β-thalassemia; sickle cell anemia
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112058

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.
[Display omitted]
•Cilostazol (CTZ) has been discovered as a new potential HbF inducer.•CTZ induced erythroid differentiation of K562 cells without cytotoxicity.•Erythroid induction was related to an increase in γ-globin mRNA and HbF expression.•In vivo efficacy of CTZ in β-YAC mice demonstrated a good in vitro correlation.•This study suggests CTZ as a potential therapeutic candidate for β-hemoglobinopathies.