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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)...

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Autores principales: Habibi, Hussain, Atashi, Amir, Abroun, Saeid, Noruzinia, Mehrdad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royan Institute 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099151/
https://www.ncbi.nlm.nih.gov/pubmed/30124006
http://dx.doi.org/10.22074/cellj.2019.5589
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author Habibi, Hussain
Atashi, Amir
Abroun, Saeid
Noruzinia, Mehrdad
author_facet Habibi, Hussain
Atashi, Amir
Abroun, Saeid
Noruzinia, Mehrdad
author_sort Habibi, Hussain
collection PubMed
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 7(th)and 14(th)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.
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spelling pubmed-60991512019-01-01 Synergistic Effect of Simvastatin and Romidepsin on Gamma-globin Gene Induction Habibi, Hussain Atashi, Amir Abroun, Saeid Noruzinia, Mehrdad Cell J Original Article 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 7(th)and 14(th)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. Royan Institute 2019 2018-08-07 /pmc/articles/PMC6099151/ /pubmed/30124006 http://dx.doi.org/10.22074/cellj.2019.5589 Text en Any use, distribution, reproduction or abstract of this publication in any medium, with the exception of commercial purposes, is permitted provided the original work is properly cited http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Habibi, Hussain
Atashi, Amir
Abroun, Saeid
Noruzinia, Mehrdad
Synergistic Effect of Simvastatin and Romidepsin on Gamma-globin Gene Induction
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 Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099151/
https://www.ncbi.nlm.nih.gov/pubmed/30124006
http://dx.doi.org/10.22074/cellj.2019.5589
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AT noruziniamehrdad synergisticeffectofsimvastatinandromidepsinongammaglobingeneinduction