Receptor tyrosine kinase inhibitors cause dysfunction in adult rat cardiac fibroblasts in vitro.
Toxicol In Vitro
; 58: 178-186, 2019 Aug.
Article
in En
| MEDLINE
| ID: mdl-30910525
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 48â¯h, with EC50 values of 11.0⯵M (imatinib) and 4.5⯵M (sunitinib) respectively. Imatinib reduced CF proliferation from 35.5⯱â¯3.2% in control to 23.0⯱â¯5.5% (3⯵M; pâ¯<â¯0.001) and to 9.4⯱â¯2.5% (10⯵M; pâ¯<â¯0.001), whereas sunitinib reduced proliferation to 22.9⯱â¯3.1% (1⯵M; pâ¯<â¯0.001) and to 15⯱â¯1.0% (3⯵M; pâ¯<â¯0.001). Further, 10⯵M imatinib increased mRNA expression of TGFB1 7-fold, (pâ¯<â¯0.01), IL6 6-fold (pâ¯<â¯0.01), and IL1B 7-fold (pâ¯<â¯0.05) and reduced PDGFD 15-fold (pâ¯<â¯0.01); whereas sunitinib specifically reduced IL1B mRNA expression 17-fold (pâ¯<â¯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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Kinase Inhibitors
/
Fibroblasts
/
Imatinib Mesylate
/
Sunitinib
Limits:
Animals
Language:
En
Journal:
Toxicol In Vitro
Journal subject:
TOXICOLOGIA
Year:
2019
Document type:
Article
Affiliation country:
Reino Unido