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Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin‐dependent protein kinase II
Author(s) -
Mooney L,
Skinner M,
Coker S J,
Currie S
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13213
Subject(s) - sunitinib , verapamil , medicine , isoprenaline , imatinib , pharmacology , endocrinology , cardiac function curve , heart failure , calcium , cancer , stimulation , myeloid leukemia
Background and Purpose Calcium/calmodulin‐dependent protein kinase II δ ( CaMKII δ) 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 Approach 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 CaMKII δ expression and CaMKII activity following drug treatments.Key Results Acute administration of sunitinib decreased left ventricular ( LV ) d P /dt max . Acute administration of isoprenaline increased LVdP /dt max dose‐dependently, while LVdP /dt max 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. CaMKII δ expression following all acute treatments remained unchanged. Chronic imatinib and sunitinib treatments did not alter fractional shortening; however, both CaMKII δ expression and CaMKII activity were significantly increased. Chronic administration of isoprenaline and verapamil decreased LV fractional shortening with parallel increases in CaMKII δ expression and CaMKII activity. Conclusions and Implications Chronic sunitinib and imatinib treatment increased CaMKII δ 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.