Genetically Engineered Mouse Embryonic Stem Cell-Derived Cardiomyocytes as a Suitable Model on Drugs Toxicity Assessment in Vitro

Document Type : Original Article (s)

Authors

1 Instructor, Department of Neurology, Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Ira

2 Assistant Professor, Department of Stem Cell and Molecular Biology, Cell Science Research Center, Royan Institute for Animal Biotechnology, The Academic Center for Education, Culture and Research (ACECR), Isfahan, Iran

3 Associate Professor, Department of Biology, School of Sciences, University of Tehran, Tehran, Iran

4 Assistant Professor, Department of Medical Sciences, School of Medicine, Islamic Azad University, Najafabad Branch, Isfahan, Iran

5 Associate Professor, Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran

Abstract

Background: Doxorubicin (DOX) is a powerful chemotherapeutic agent used in the treatment of solid tumors and malignant hematological diseases. However, cardiac toxicity limits the clinical usefulness of this drug. Previous reports have shown that corticosteroids induce a cytoprotective effect on cardiomyocytes. Mouse transgenic embryonic stem cell-derived pure cardiomyocytes may be considered as a model for assessment pharmacological and toxicological effects of drugs in vitro.Methods: Mouse transgenic embryonic stem cell-derived pure cardiomyocytes were treated by different concentrations of doxorubicin to determine median lethal dose (LD50). Pure cardiomyocytes were evaluated in two groups: treatment by 10 µM dexamethasone (DEX) 24 hours before or before and in continuation with doxorubicin. The percentage of cardiomyocyte viability by MTS assay, the percentage of beating, and quantitative real-time polymerase chain reaction (RT-PCR) for cardiac gene expression (β-MHC) were evaluated in each group.Findings: 5 µM doxorubicin was determined as drug concentration that leads to 50% cardiomyocyte mortality. Cardiotoxicity on mouse transgenic embryonic stem cell-derived pure cardiomyocytes could be ameliorated by treatment with dexamethasone (DEX) when administrated before doxorubicin. The effect of dexamethasone appeared to be mediated via glucocorticoid receptors. Dexamethasone increased cardiomyocyte gene expression and decreased apoptosis.Conclusion: Transgenic embryonic stem cell-derived cardiomyocytes are a model for evaluation of doxorubicin toxicity. Additionally, this model provides us with a clinical suggestion, which proposes that the beneficial effect of dexamethasone is obtained when added only before doxorubicin. In addition, the results of present study were consistent with in vivo result in mice.

Keywords

References

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Journal of Isfahan Medical School
Volume 31, Issue 259 - Serial Number 259
September and October 2014
Pages 1779-1786

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History

  • Receive Date: 26 May 2013
  • Revise Date: 27 May 2024
  • Accept Date: 06 April 2022

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