Synergistic Effect Of Simvastatin And Romidepsin On Gamma-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 beta- thalassemia and SCD. Drugs that induce fetal hemoglobin (HbF)...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Royan Institute (ACECR), Tehran
2018-08-01
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| Series: | Cell Journal |
| Subjects: | |
| Online Access: | https://celljournal.org/journal/article/abstract/5589 |
| _version_ | 1818503591791427584 |
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| author | Hussain Habibi Amir Atashi Saeid Abroun Mehrdad Noruzinia |
| author_facet | Hussain Habibi Amir Atashi Saeid Abroun Mehrdad Noruzinia |
| author_sort | Hussain Habibi |
| collection | DOAJ |
| description | 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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| format | Article |
| id | doaj.art-3b3a6203bee34c4396b713297f5cf6f3 |
| institution | Directory Open Access Journal |
| issn | 2228-5806 2228-5814 |
| language | English |
| last_indexed | 2024-12-10T21:26:00Z |
| publishDate | 2018-08-01 |
| publisher | Royan Institute (ACECR), Tehran |
| record_format | Article |
| series | Cell Journal |
| spelling | doaj.art-3b3a6203bee34c4396b713297f5cf6f32022-12-22T01:32:59ZengRoyan Institute (ACECR), TehranCell Journal2228-58062228-58142018-08-0120456758310.22074/cellj.2019.5589Synergistic Effect Of Simvastatin And Romidepsin On Gamma-Globin Gene InductionHussain Habibi0Amir Atashi1Saeid Abroun2Mehrdad Noruzinia3Department of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, IranDepartment of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, IranDepartment of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, IranDepartment of Medical Genetics, School of Medicine, Tarbiat Modares University, Tehran, IranObjective 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.https://celljournal.org/journal/article/abstract/5589Beta-ThalassemiaRomidepsinSickle Cell DiseaseSimvastatin |
| spellingShingle | Hussain Habibi Amir Atashi Saeid Abroun Mehrdad Noruzinia Synergistic Effect Of Simvastatin And Romidepsin On Gamma-Globin Gene Induction Cell Journal Beta-Thalassemia Romidepsin Sickle Cell Disease Simvastatin |
| title | Synergistic Effect Of Simvastatin And Romidepsin On Gamma-Globin Gene Induction |
| title_full | Synergistic Effect Of Simvastatin And Romidepsin On Gamma-Globin Gene Induction |
| title_fullStr | Synergistic Effect Of Simvastatin And Romidepsin On Gamma-Globin Gene Induction |
| title_full_unstemmed | Synergistic Effect Of Simvastatin And Romidepsin On Gamma-Globin Gene Induction |
| title_short | Synergistic Effect Of Simvastatin And Romidepsin On Gamma-Globin Gene Induction |
| title_sort | synergistic effect of simvastatin and romidepsin on gamma globin gene induction |
| topic | Beta-Thalassemia Romidepsin Sickle Cell Disease Simvastatin |
| url | https://celljournal.org/journal/article/abstract/5589 |
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