An exploration of sunitinb‐induced cardiotoxicity in male Sprague‐Dawley rats

Abstract

Sunitinib (STB) inhibits tyrosine kinase and certain growth factors and has been associated with cardiotoxicity as an unexpected adverse effect. The characteristics of STB‐induced myocardial alterations have not been completely defined. The current study evaluated the effects of STB on serum troponin levels and myocardial histology in male Sprague‐Dawley rats (SD). Groups of 7–9 SD received daily oral doses of 12.5, 25.0 or 50.0 mg/kg STB for 14 days. Tissue and blood samples were taken 24 hours after the last dose. Serum levels of cardiac troponin I (cTnI) were monitored using the Erenna immunoassay system. STB‐induced changes in myocyte morphology (autophagy, necrosis and apoptosis) were evaluated (blinded) by light microscopy using a 0–3 scale. The most frequent alteration was an increased presence of autophagic vesicles. Mean autophagy lesion scores of 1.1, 1.6 and 2.5 occurred at doses of 12.5, 25 and 50 mg/kg, respectively. Myocyte necrosis and apoptosis were detected mainly after the high STB dose (mean severity scores of 1.5 and 1.4, respectively). Minor changes in cTnI levels occurred only at 50 mg/kg STB (3.3 vs 6.3 pg/ml in control and treated SD, p >; 0.05). These results indicate that STB induces myocyte alterations over a 2 week treatment period and the most prominent effect, increased autophagy, was not associated with significant changes in serum levels of the cardiac biomarker cTnI.