Synergistic Effect of Simvastatin and Romidepsin on Gamma-globin Gene Induction

Habibi, Hussain; Atashi, Amir; Abroun, Saeid; Noruzinia, Mehrdad

doi:10.22074/cellj.2019.5589

Synergistic Effect of Simvastatin and Romidepsin on Gamma-globin Gene Induction

Document Type : Original Article

Authors

¹ Department of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran

² Department of Medical Genetics, School of Medicine, Tarbiat Modares University, Tehran, Iran

10.22074/cellj.2019.5589

Abstract

Objective
Hemoglobinopathies such as beta-thalassemia and sickle cell disease (SCD) are inherited disorders that are caused by mutations in beta-globin chain. Gamma-globin gene reactivation can ameliorate clinical manifestations of beta- thalassemia and SCD. Drugs that induce fetal hemoglobin (HbF) can be promising tools for treatment of beta-thalassemia and SCD patients. Recently, it has been shown that Simvastatin (SIM) and Romidepsin (ROM) induce HbF. SIM is a BCL11a inhibitor and ROM is a HDAC inhibitor and both of these drugs are Food and Drug Administration (FDA)-approved for hypercholesterolemia and cutaneous T-cell lymphoma respectively. Our aim was to evaluate the synergistic effects of these drugs in inducing HbF.
Materials and Methods
In our experimental study, we isolated CD34+ cells from five cord blood samples that were cultured in erythroid differentiation medium containing ROM and Simvastatin. Then Gamma-globin, BCL11a and HDAC gene expression were evaluated on the 7thand 14thday of erythroid differentiation by real-time polymerase chain reaction (PCR) and immunocytochemistry.
Results
Our results showed that combination of SIM and ROM significantly increased Gamma-globin gene expression and inhibit BCL11a and HDAC expression compared to results of using each of them alone. SIM and ROM lead to 3.09- fold increase in HbF production compared to the control group. Also, SIM inhibited BCL11a expression (0.065-fold) and ROM inhibited HDAC1 expression (0.47-fold) as two important inhibitors of HbF production after birth.
Conclusion
We propose combination therapy of these drugs may be ameliorate clinical manifestation in beta-thalassemia and SCD with at least side effects and reduce the need for blood transfusion.

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