Dasatinib targets c-Src kinase in cardiotoxicity
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 asso...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Toxicology Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214750023000495 |
| _version_ | 1797798879208407040 |
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| author | Manar Elmadani Sami Raatikainen Orvokki Mattila Tarja Alakoski Jarkko Piuhola Pirjo Åström Olli Tenhunen Johanna Magga Risto Kerkelä |
| author_facet | Manar Elmadani Sami Raatikainen Orvokki Mattila Tarja Alakoski Jarkko Piuhola Pirjo Åström Olli Tenhunen Johanna Magga Risto Kerkelä |
| author_sort | Manar Elmadani |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T04:10:25Z |
| format | Article |
| id | doaj.art-78ac950203a444f3a338fbcbb7c674d4 |
| institution | Directory Open Access Journal |
| issn | 2214-7500 |
| language | English |
| last_indexed | 2024-03-13T04:10:25Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Toxicology Reports |
| spelling | doaj.art-78ac950203a444f3a338fbcbb7c674d42023-06-21T06:55:11ZengElsevierToxicology Reports2214-75002023-01-0110521528Dasatinib targets c-Src kinase in cardiotoxicityManar Elmadani0Sami Raatikainen1Orvokki Mattila2Tarja Alakoski3Jarkko Piuhola4Pirjo Åström5Olli Tenhunen6Johanna Magga7Risto Kerkelä8Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, FinlandResearch Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, FinlandResearch Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, FinlandResearch Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, FinlandDivision of Cardiology, Oulu University Hospital, Oulu, FinlandResearch Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, FinlandResearch Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, FinlandResearch Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, FinlandResearch Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland; Correspondence to: Research Unit of Biomedicine and Internal Medicine, University of Oulu, P.O.BOX 5000, FIN-90014 Oulu, Finland.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.http://www.sciencedirect.com/science/article/pii/S2214750023000495CardiotoxicityTyrosine kinase inhibitorCell deathProto-oncogene tyrosine-protein kinase Src |
| spellingShingle | 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 Cardiotoxicity Tyrosine kinase inhibitor Cell death Proto-oncogene tyrosine-protein kinase Src |
| title | Dasatinib targets c-Src kinase in cardiotoxicity |
| title_full | Dasatinib targets c-Src kinase in cardiotoxicity |
| title_fullStr | Dasatinib targets c-Src kinase in cardiotoxicity |
| title_full_unstemmed | Dasatinib targets c-Src kinase in cardiotoxicity |
| title_short | Dasatinib targets c-Src kinase in cardiotoxicity |
| title_sort | dasatinib targets c src kinase in cardiotoxicity |
| topic | Cardiotoxicity Tyrosine kinase inhibitor Cell death Proto-oncogene tyrosine-protein kinase Src |
| url | http://www.sciencedirect.com/science/article/pii/S2214750023000495 |
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