Sunitinib causes dose-dependent negative functional effects on myocardium and cardiomyocytes Journal Article

Authors: Rainer, P. P.; Doleschal, B.; Kirk, J. A.; Sivakumaran, V.; Saad, Z.; Groschner, K.; Maechler, H.; Hoefler, G.; Bauernhofer, T.; Samonigg, H.; Hutterer, G.; Kass, D. A.; Pieske, B.; von Lewinski, D.; Pichler, M.
Article Title: Sunitinib causes dose-dependent negative functional effects on myocardium and cardiomyocytes
Abstract: OBJECTIVES: To examine the acute effects of sunitinib on inotropic function, intracellular Ca(2+) transients, myofilament Ca(2+) sensitivity and generation of reactive oxygen species (ROS) in human multicellular myocardium and isolated mouse cardiomyocytes. To search for microRNAs as suitable biomarkers for indicating toxic cardiac effects. PATIENTS AND METHODS: After exposure to sunitinib (0.1-10 microg/mL) developed force, diastolic tension and kinetic variables were assessed in isolated human myocardium. Changes in myocyte sarcomere length, whole-cell calcium transients, myofilament force-Ca(2+) relationship, and ROS generation were examined in isolated ventricular mouse cardiomyocytes. Microarray and realtime-PCR were used to screen for differentially expressed microRNAs in cultured cardiomyocytes that were exposed for 24 h to sunitinib. RESULTS: We found that higher concentrations of sunitinib (1 and 10 microg/mL) decreased developed force at 30 minutes 76.9 + 2.8 and 54.5 + 6.3%, compared to 96.1 + 2.6% in controls (P 0.01). Sunitinib exposure significantly decreased sarcomere shortening and Ca2+ transients. Myofilament Ca(2+) sensitivity was not altered, while ROS levels were significantly increased after exposure to the drug. MicroRNA expression patterns were not altered by sunitinib. CONCLUSIONS: Sunitinib elicits a dose-dependent negative inotropic effect in myocardium, accompanied by a decline in intracellular Ca(2+) and increased ROS generation. In clinical practice, these cardiotoxic effects should be considered in cases where cardiac concentrations of sunitinib could be increased.
Journal Title: BJU international
Volume: 110
Issue: 10
ISSN: 1464-410X; 1464-4096
Publisher: Unknown  
Journal Place: England
Date Published: 2012
Start Page: 1455
End Page: 1462
Language: eng
Notes: LR: 20141120; CI: (c) 2012; JID: 100886721; 0 (Antineoplastic Agents); 0 (Indoles); 0 (Protein Kinase Inhibitors); 0 (Pyrroles); 0 (Reactive Oxygen Species); 0 (sunitinib); SY7Q814VUP (Calcium); 2012/04/17 [aheadofprint]; ppublish