Dasatinib targets c-Src kinase in cardiotoxicity.
Manar Elmadani1, Sami Raatikainen1, Orvokki Mattila1
1Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Toxicology Reports
|May 8, 2023
Summary
Dasatinib, a cancer drug, can harm the heart by affecting cardiomyocytes. This study reveals that the kinase c-Src is a key mediator of dasatinib
Area of Science:
- Cardiology
- Oncology
- Molecular Biology
Background:
- Dasatinib is a kinase inhibitor used to treat leukemia.
- Kinase inhibitors, including dasatinib, can cause cardiotoxicity.
- Reported cardiac side effects include heart failure and pulmonary hypertension.
Purpose of the Study:
- To investigate the molecular mechanisms of dasatinib-induced cardiotoxicity.
- To identify the specific cardiac cell types and molecular targets involved.
Main Methods:
- Assessing dasatinib toxicity in different cardiac cell types.
- Measuring extracellular signal-regulated kinase (ERK) activity.
- Analyzing the role of c-Src kinase through depletion and mutation studies.
Main Results:
- Cardiomyocytes showed the highest sensitivity to dasatinib-induced cell death.
- Dasatinib treatment reduced extracellular signal-regulated kinase (ERK) activity, a target of c-Src.
- Depleting c-Src mimicked dasatinib toxicity, while a resistant c-Src mutant protected cardiomyocytes.
Conclusions:
- c-Src is a critical molecular target mediating dasatinib's cardiotoxicity in cardiomyocytes.
- Findings suggest closer cardiac monitoring for patients on c-Src targeting therapies.
- Results may inform future drug design to mitigate dasatinib-related cardiac adverse effects.
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