Sunitinib malate induces cell death in adult human cardiac progenitor cells
Sunitinib malate is known to cause cardiotoxicity in a sub-population of patients, with heart failure seen in more severe cases. Cardiac progenitor cells (CPCs) have been identified in adult human myocardium and contribute to overall tissue maintenance, with previous work identifying negative impact...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Current Research in Toxicology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666027X24000203 |
| _version_ | 1827226461261529088 |
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| author | Robert Walmsley Derek S. Steele Sotiris Papaspyros Andrew J. Smith |
| author_facet | Robert Walmsley Derek S. Steele Sotiris Papaspyros Andrew J. Smith |
| author_sort | Robert Walmsley |
| collection | DOAJ |
| description | Sunitinib malate is known to cause cardiotoxicity in a sub-population of patients, with heart failure seen in more severe cases. Cardiac progenitor cells (CPCs) have been identified in adult human myocardium and contribute to overall tissue maintenance, with previous work identifying negative impacts of sunitinib on these cells. This study aimed to characterise the toxic effects of sunitinib in human CPCs, applying sunitinib concentrations equivalent to clinical plasma levels to these cells in vitro. Cell viability was reduced by 26.5 ± 6.6 % by 2 μM sunitinib for 24 h (p < 0.01); this concentration also induced fold-change increases in gene expression of: calpain (3.1 ± 0.73, p < 0.05), FAS (2.3 ± 0.8, p < 0.05) and BAX (1.9 ± 0.2, p < 0.05), and a decrease in BCL-2 (3.5 ± 0.0, p < 0.001), vs. control (1.0 ± 0.0). This was affirmed by sunitinib inducing fold changes in protein expression of: calpain-1 (2.5 ± 0.5, p < 0.05); FAS receptor (2.1 ± 0.2, p < 0.05) and BAX (2.1 ± 0.2, p < 0.05) vs. control (1.0 ± 0.0). These results indicated that sunitinib induced apoptosis in CPCs, but negative annexin V staining and lack of protection by caspase inhibitors indicated this was not the cell death pathway activated. Further investigation found sunitinib was concentrated in the lysosomes and autophagosomes within CPCs, but did not induce accumulation of acidic organelles. In conclusion, these data confirm that cell death is caused by sunitinib in CPCs at concentrations equivalent to clinical plasma levels, inducing cell death pathway signals that lead to non-apoptotic cell death. |
| first_indexed | 2024-04-24T07:05:12Z |
| format | Article |
| id | doaj.art-355f9cffb2ab46de90044301e66494da |
| institution | Directory Open Access Journal |
| issn | 2666-027X |
| language | English |
| last_indexed | 2025-03-21T17:42:26Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Toxicology |
| spelling | doaj.art-355f9cffb2ab46de90044301e66494da2024-06-12T04:47:23ZengElsevierCurrent Research in Toxicology2666-027X2024-01-016100167Sunitinib malate induces cell death in adult human cardiac progenitor cellsRobert Walmsley0Derek S. Steele1Sotiris Papaspyros2Andrew J. Smith3School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United KingdomSchool of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United KingdomDepartment of Cardiac Surgery, Yorkshire Heart Centre, Leeds General Infirmary, Leeds LS1 3EX, United KingdomSchool of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom; Corresponding author.Sunitinib malate is known to cause cardiotoxicity in a sub-population of patients, with heart failure seen in more severe cases. Cardiac progenitor cells (CPCs) have been identified in adult human myocardium and contribute to overall tissue maintenance, with previous work identifying negative impacts of sunitinib on these cells. This study aimed to characterise the toxic effects of sunitinib in human CPCs, applying sunitinib concentrations equivalent to clinical plasma levels to these cells in vitro. Cell viability was reduced by 26.5 ± 6.6 % by 2 μM sunitinib for 24 h (p < 0.01); this concentration also induced fold-change increases in gene expression of: calpain (3.1 ± 0.73, p < 0.05), FAS (2.3 ± 0.8, p < 0.05) and BAX (1.9 ± 0.2, p < 0.05), and a decrease in BCL-2 (3.5 ± 0.0, p < 0.001), vs. control (1.0 ± 0.0). This was affirmed by sunitinib inducing fold changes in protein expression of: calpain-1 (2.5 ± 0.5, p < 0.05); FAS receptor (2.1 ± 0.2, p < 0.05) and BAX (2.1 ± 0.2, p < 0.05) vs. control (1.0 ± 0.0). These results indicated that sunitinib induced apoptosis in CPCs, but negative annexin V staining and lack of protection by caspase inhibitors indicated this was not the cell death pathway activated. Further investigation found sunitinib was concentrated in the lysosomes and autophagosomes within CPCs, but did not induce accumulation of acidic organelles. In conclusion, these data confirm that cell death is caused by sunitinib in CPCs at concentrations equivalent to clinical plasma levels, inducing cell death pathway signals that lead to non-apoptotic cell death.http://www.sciencedirect.com/science/article/pii/S2666027X24000203CardiotoxicityReceptor tyrosine kinaseCardiac progenitor cellsApoptosis |
| spellingShingle | Robert Walmsley Derek S. Steele Sotiris Papaspyros Andrew J. Smith Sunitinib malate induces cell death in adult human cardiac progenitor cells Current Research in Toxicology Cardiotoxicity Receptor tyrosine kinase Cardiac progenitor cells Apoptosis |
| title | Sunitinib malate induces cell death in adult human cardiac progenitor cells |
| title_full | Sunitinib malate induces cell death in adult human cardiac progenitor cells |
| title_fullStr | Sunitinib malate induces cell death in adult human cardiac progenitor cells |
| title_full_unstemmed | Sunitinib malate induces cell death in adult human cardiac progenitor cells |
| title_short | Sunitinib malate induces cell death in adult human cardiac progenitor cells |
| title_sort | sunitinib malate induces cell death in adult human cardiac progenitor cells |
| topic | Cardiotoxicity Receptor tyrosine kinase Cardiac progenitor cells Apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2666027X24000203 |
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