Synergistic Effect of Simvastatin and Romidepsin on Gamma-globin Gene Induction.
Synergistic Effect of Simvastatin and Romidepsin on Gamma-globin Gene Induction.
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DOI：
10.22074/cellj.2019.5589
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发表时间：
2019-01
期刊：
影响因子：
2
通讯作者：
Noruzinia M
中科院分区：
文献类型：
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作者：
Habibi H;Atashi A;Abroun S;Noruzinia M
β-地中海贫血和镰状细胞病 (SCD) 等血红蛋白病是由 β-珠蛋白链突变引起的遗传性疾病。 γ-珠蛋白基因再激活可以改善β-地中海贫血和SCD的临床表现。诱导胎儿血红蛋白 (HbF) 的药物可能成为治疗 β 地中海贫血和 SCD 患者的有希望的工具。最近，研究表明辛伐他汀 (SIM) 和罗米地辛 (ROM) 会诱导 HbF。 SIM 是一种 BCL11a 抑制剂，ROM 是一种 HDAC 抑制剂，这两种药物均已获得美国食品和药物管理局 (FDA) 批准，分别用于治疗高胆固醇血症和皮肤 T 细胞淋巴瘤。我们的目的是评估这些药物在诱导 HbF 方面的协同作用。 在我们的实验研究中，我们从五个脐带血样本中分离出 CD34+ 细胞，这些样本在含有 ROM 和辛伐他汀的红系分化培养基中培养。然后通过实时聚合酶链式反应（PCR）和免疫细胞化学评估红系分化第7天和第14天的γ-珠蛋白、BCL11a和HDAC基因表达。 我们的结果表明，与单独使用 SIM 和 ROM 的结果相比，SIM 和 ROM 的组合显着增加了 Gamma 珠蛋白基因表达并抑制了 BCL11a 和 HDAC 表达。与对照组相比，SIM 和 ROM 导致 HbF 产量增加 3.09 倍。此外，SIM 抑制 BCL11a 表达（0.065 倍），ROM 抑制 HDAC1 表达（0.47 倍），作为出生后 HbF 产生的两个重要抑制剂。 我们建议这些药物的联合治疗可能会改善β地中海贫血和SCD的临床表现，至少具有副作用，并减少输血的需要。
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. 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. 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. 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.