University of Oulu

Manar Elmadani, Sami Raatikainen, Orvokki Mattila, Tarja Alakoski, Jarkko Piuhola, Pirjo Åström, Olli Tenhunen, Johanna Magga, Risto Kerkelä, Dasatinib targets c-Src kinase in cardiotoxicity, Toxicology Reports, Volume 10, 2023, Pages 521-528, ISSN 2214-7500,

Dasatinib targets c-Src kinase in cardiotoxicity

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Author: Elmadani, Manar1; Raatikainen, Sami1; Mattila, Orvokki1;
Organizations: 1Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
2Division of Cardiology, Oulu University Hospital, Oulu, Finland
3Biocenter Oulu, University of Oulu, Oulu, Finland
4Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
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Language: English
Published: Elsevier, 2023
Publish Date: 2023-09-19


Dasatinib is a multitargeted kinase inhibitor used for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Unfortunately, treatment of cancer patients with some kinase inhibitors has been associated with cardiotoxicity. Cancer treatment with dasatinib has been reported to be associated with cardiotoxic side effects such as left ventricular dysfunction, heart failure, pericardial effusion and pulmonary hypertension. Here we aimed to investigate the molecular mechanisms underlying the cardiotoxicity of dasatinib. We found that among the resident cardiac cell types, cardiomyocytes were most sensitive to dasatinib-induced cell death. Exposure of cardiomyocytes to dasatinib attenuated the activity of extracellular signal-regulated kinase (ERK), which is a downstream target of dasatinib target kinase c-Src. Similar to dasatinib, c-Src depletion in cardiomyocytes compromised cardiomyocyte viability. Overexpression of dasatinib-resistant mutant of c-Src rescued the toxicity of dasatinib on cardiomyocytes, whereas forced expression of wild type c-Src did not have protective effect. Collectively, our results show that c-Src is a key target of dasatinib mediating the toxicity of dasatinib to cardiomyocytes. These findings may influence future drug design and suggest closer monitoring of patients treated with agents targeting c-Src for possible adverse cardiac effects.

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Series: Toxicology reports
ISSN: 2214-7500
ISSN-E: 2214-7500
ISSN-L: 2214-7500
Volume: 10
Pages: 521 - 528
DOI: 10.1016/j.toxrep.2023.04.013
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: This work was supported by research funding from the Academy of Finland grants 297094 and 333284 (R.K.), Sigrid Juselius Foundation (R.K.) and the Finnish Foundation for Cardiovascular Research (M.E., S.R., T.A., J.M., R.K.).
Academy of Finland Grant Number: 297094
Detailed Information: 297094 (Academy of Finland Funding decision)
333284 (Academy of Finland Funding decision)
Copyright information: © 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (