synergistic effect of simvastatin and romidepsin ongamma-globin gene induction

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 betathalassemia 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 7th and 14th day 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.