title: Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin-dependent protein kinase II.
abstract: OBJECTIVE
  Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac contractile function and dysfunction and may be an unwanted secondary target for anti-cancer drugs such as sunitinib and imatinib that have been reported to alter cardiac performance. This study aimed to determine whether anti-cancer kinase inhibitors may affect CaMKII activity and expression when administered in vivo.
  
  
  METHODS
  Cardiovascular haemodynamics in response to acute and chronic sunitinib treatment, and chronic imatinib treatment, were assessed in guinea pigs and the effects compared with those of the known positive and negative inotropes, isoprenaline and verapamil. Parallel studies from the same animals assessed CaMKIIδ expression and CaMKII activity following drug treatments.
  
  
  RESULTS
  Acute administration of sunitinib decreased left ventricular (LV) dP/dtmax. Acute administration of isoprenaline increased LVdP/dtmax dose-dependently, while LVdP/dtmax was decreased by verapamil. CaMKII activity was decreased by acute administration of sunitinib and was increased by acute administration of isoprenaline, and decreased by acute administration of verapamil. CaMKIIδ expression following all acute treatments remained unchanged. Chronic imatinib and sunitinib treatments did not alter fractional shortening; however, both CaMKIIδ expression and CaMKII activity were significantly increased. Chronic administration of isoprenaline and verapamil decreased LV fractional shortening with parallel increases in CaMKIIδ expression and CaMKII activity.
  
  
  CONCLUSIONS
  Chronic sunitinib and imatinib treatment increased CaMKIIδ expression and CaMKII activity. As these compounds are associated with cardiac dysfunction, increased CaMKII expression could be an early indication of cellular cardiotoxicity marking potential progression of cardiac contractile dysfunction.
authors.affiliation: Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, UK.
authors.forename: L
authors.initials: L
authors.lastname: Mooney
authors.affiliation: Safety Assessment UK, AstraZeneca R&D, Macclesfield, UK.
authors.forename: M
authors.initials: M
authors.lastname: Skinner
authors.affiliation: Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Coker
authors.affiliation: Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, UK.
authors.forename: S
authors.initials: S
authors.lastname: Currie
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis*; D004334:Drug Administration Schedule; D006168:Guinea Pigs; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D011758:Pyrroles; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000077210:Sunitinib