Past Issue

Volume 20, Number 4, Jan-Mar(Winter) 2019, Serial Number: 80 Pages: 576-583

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


Hussain Habibi, M.Sc, 1, Amir Atashi, Ph.D, 1, *, Saeid Abroun, Ph.D, 1, Mehrdad Noruzinia, M.D, Ph.D, 2,
Department of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
Department of Medical Genetics, School of Medicine, Tarbiat Modares University, Tehran, Iran
*Corresponding Address: P.O.Box: 141173116 Department of Hematology School of Medical Sciences Tarbiat Modares University Tehran Iran Email:atashia@modares.ac.ir

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.