Receptor tyrosine kinase inhibitors cause dysfunction in adult rat cardiac fibroblasts in vitro.

Toxicol In Vitro 2019 Aug 22;58:178-186. Epub 2019 Mar 22.

School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, United Kingdom; Centre for Human and Applied Physiological Sciences, Centre for Stem Cell and Regenerative Medicine, King's College London, Guy's Campus, London SE1 1UL, United Kingdom. Electronic address:

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 EC 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.

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http://dx.doi.org/10.1016/j.tiv.2019.03.026DOI Listing
August 2019
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