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A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
New targets and biomarkers for doxorubicin-induced cardiotoxicity in humans: implications drawn from toxicogenomic
Fuat Karakuş1, Abdulilah Ece2, Burak Kuzu3
1Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Van Yuzuncu Yil University, Van, Türkiye.
Abstract:
The doxorubicin-induced cardiotoxicity continues to be a life-threatening adverse effect in the clinic. Doxorubicin-induced acute cardiotoxicity is reversible, whereas chronic cardiotoxicity is irreversible, leading to dilated cardiomyopathy and heart failure. The aim of this study was to identify the molecular mechanisms associated with doxorubicin metabolites in doxorubicin-induced chronic cardiotoxicity. For this purpose, literature searches and in silico toxicogenomic analyses were conducted using various tools, including the Comparative Toxicogenomic Database, GeneMANIA, Metascape, MIENTURNET, ChEA3, and AutoDock. Additionally, molecular dynamics simulations were performed for 500 ns using Schrödinger software to assess the stability and dynamics of the representative docked complexes. We observed that doxorubicin biotransformed into five metabolites in the human heart and identified 11 common genes related to doxorubicin, its metabolites, dilated cardiomyopathy, and heart failure. Our findings revealed that doxorubicin and its metabolites primarily exhibited binding affinity to the beta-1 adrenergic receptor and fatty acid synthase. Furthermore, we identified several key transcription factors, especially the Homeobox protein Nkx-2.6, and hsa-miR-183-3p associated with this cardiotoxicity. Finally, we observed that, in addition to doxorubicinol, 7-deoxidoxorubicinone, another metabolite of doxorubicin, may also contribute to this cardiotoxicity. These findings contribute to our understanding of the processes underlying doxorubicin-induced chronic cardiotoxicity.
Insights
Doxorubicin cardiotoxicity leads to irreversible heart failure. This study identified key molecular mechanisms and metabolites, including 7-deoxidoxorubicinone, contributing to chronic doxorubicin cardiotoxicity.
Area of Science:
- Pharmacology
- Toxicology
- Cardiovascular Medicine
Background:
- Doxorubicin chemotherapy causes life-threatening cardiotoxicity.
- Chronic doxorubicin cardiotoxicity is irreversible, leading to dilated cardiomyopathy and heart failure.
- Understanding the molecular mechanisms of doxorubicin metabolites is crucial.
Purpose of the Study:
- To identify molecular mechanisms of doxorubicin metabolites in doxorubicin-induced chronic cardiotoxicity.
- To investigate the role of specific doxorubicin metabolites in heart failure.
- To uncover key genes, transcription factors, and microRNAs involved in cardiotoxicity.
Main Methods:
- Literature searches and in silico toxicogenomic analyses using multiple databases and tools.
- Molecular dynamics simulations were performed using Schrödinger software.
- Identification of doxorubicin metabolites and their target genes in the human heart.
Main Results:
- Doxorubicin transforms into five metabolites in the human heart.
- Eleven common genes link doxorubicin, its metabolites, dilated cardiomyopathy, and heart failure.
- Doxorubicin and metabolites bind to beta-1 adrenergic receptor and fatty acid synthase.
- Key transcription factors (Nkx-2.6) and microRNAs (hsa-miR-183-3p) were identified.
- 7-deoxidoxorubicinone, alongside doxorubicinol, may contribute to cardiotoxicity.
Conclusions:
- Doxorubicin metabolites play a significant role in chronic cardiotoxicity.
- Specific molecular targets and regulatory factors have been identified.
- Findings advance understanding of doxorubicin-induced heart failure mechanisms.
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