Burke, MJ, Walmsley, R, Munsey, TS et al. (1 more author) (2019) Receptor tyrosine kinase inhibitors cause dysfunction in adult rat cardiac fibroblasts in vitro. Toxicology in Vitro, 58. pp. 178-186. ISSN 0887-2333
Abstract
The anti-cancer receptor tyrosine kinase inhibitors include known cardiotoxins: a component of this toxicity may be mediated by effects on cardiac fibroblasts (CFs). We hypothesised that imatinib mesylate (imatinib) and sunitinib malate (sunitinib) cause significant dysfunction in adult CFs. Following in vitro treatments with imatinib or sunitinib, adult rat CF viability was assessed by fluorescein diacetate assay, proliferation measured by bromodeoxyuridine nuclear incorporation and changes to the expression of CF secretome components determined by real time quantitative RT-PCR. Imatinib and sunitinib significantly reduced cell viability over 48 h, with EC50 values of 11.0 μM (imatinib) and 4.5 μM (sunitinib) respectively. Imatinib reduced CF proliferation from 35.5 ± 3.2% in control to 23.0 ± 5.5% (3 μM; p < 0.001) and to 9.4 ± 2.5% (10 μM; p < 0.001), whereas sunitinib reduced proliferation to 22.9 ± 3.1% (1 μM; p < 0.001) and to 15 ± 1.0% (3 μM; p < 0.001). Further, 10 μM imatinib increased mRNA expression of TGFB1 7-fold, (p < 0.01), IL6 6-fold (p < 0.01), and IL1B 7-fold (p < 0.05) and reduced PDGFD 15-fold (p < 0.01); whereas sunitinib specifically reduced IL1B mRNA expression 17-fold (p < 0.01). Overall, these findings show tyrosine kinase inhibitors cause significant dysfunction in CFs. These data point to an important role for the PDGF pathway in governing CF functions, including survival and proliferation.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 Published by Elsevier Ltd. This is an author produced version of a paper published in Toxicology in Vitro. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Fibroblasts; Protein kinase inhibitors; Cardiotoxins; Platelet-derived growth factor receptors (PDGFRs); Interleukin (IL)-1β; Transforming growth factor (TGF)-β1; Cytokines |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 02 Apr 2019 14:46 |
Last Modified: | 22 Mar 2020 01:38 |
Status: | Published |
Publisher: | Elsevier BV |
Identification Number: | 10.1016/j.tiv.2019.03.026 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:144367 |
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Licence: CC-BY-NC-ND 4.0