Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin‐dependent protein kinase II

Abstract

BACKGROUND AND PURPOSECalcium/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. EXPERIMENTAL APPROACHCardiovascular 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. KEY RESULTSAcute 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 AND IMPLICATIONSChronic 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.

Cobalt Administration Causes Reduced Contractility with Parallel Increases in TRPC6 and TRPM7 Transporter Protein Expression in Adult Rat Hearts

“…injections of distilled water ( n = 3) or 1 mg/kg CoCl 2 ( n = 6) in distilled water daily for 7 days and 28 days. The animals were subjected to echocardiography (short-axis view) as previously described [19] at both 7 days and 28 days and then euthanised on the same day as the final injection. Procedures complied with the ARRIVE guidelines and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No.…”

“…Samples (homogenised cardiac tissue or CFs) were analysed by immunoblotting using the NuPAGE system as previously described [19, 20]. DMT1 protein was detected using an overnight incubation in anti-DMT1 (rabbit polyclonal, Sigma-Aldrich) at 1:800 dilution.…”

The effect of adenosine triphosphate on sunitinib-induced cardiac injury in rats

“…These serious adverse events such as the development of hypertension and angina pectoris might be resulted with acute ischemic myocardial damage, QT prolongation, symptomatic congestive heart failure, left ventricular systolic dysfunction, and sudden death. 10,11,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] The underlying molecular mechanisms involved in the pathogenesis of these cardiotoxic effects are still unclear, but dependence of cardiomyocytes to aerobic metabolism and ATP was reported as an important factor for cardiotoxicity of sunitinib. 11,34,35 It was determined that being an ATP analog, sunitinib competitively inhibits the ATP binding domain of its target proteins.…”

Sunitinib and Imatinib Display Differential Cardiotoxicity in Adult Rat Cardiac Fibroblasts That Involves a Role for Calcium/Calmodulin Dependent Protein Kinase II

“…Sunitinib has been suggested to have a number of off-target effects that can adversely affect the heart. Examples of off-target effects include inhibition of AMP-activated protein kinase ( 21 ) and activation of calcium/calmodulin dependent protein kinase (CaMKII) ( 22 ), both of which, if chronically affected, can result in cardiac dysfunction.…”

“…Previous work by our group has highlighted that CaMKII activation occurs in guinea pig hearts following chronic administration of clinically relevant concentrations of either imatinib or sunitinib ( 22 ). Increased cardiac CaMKIIδ expression and CaMKII activity were shown to occur in the absence of any overt cardiac dysfunction.…”