title: Sunitinib causes dose-dependent negative functional effects on myocardium and cardiomyocytes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  After exposure to sunitinib (0.1-10 µg/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 µg/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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Medical University Graz, Austria.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Rainer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Doleschal
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kirk
authors.forename: Vidhya
authors.initials: V
authors.lastname: Sivakumaran
authors.forename: Zora
authors.initials: Z
authors.lastname: Saad
authors.forename: Klaus
authors.initials: K
authors.lastname: Groschner
authors.forename: Heinrich
authors.initials: H
authors.lastname: Maechler
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.forename: Thomas
authors.initials: T
authors.lastname: Bauernhofer
authors.forename: Hellmut
authors.initials: H
authors.lastname: Samonigg
authors.forename: Georg
authors.initials: G
authors.lastname: Hutterer
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.forename: Dirk
authors.initials: D
authors.lastname: von Lewinski
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011758:Pyrroles / Q000009:adverse effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012518:Sarcomeres / Q000187:drug effects; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D017382:Reactive Oxygen Species; D002118:Calcium; D000077210:Sunitinib