Key result
Sunitinib and imatinib increase cardiac CaMKIIδ expression and CaMKII activity without overt cardiac dysfunction.
Why the study?
Anti-cancer kinase inhibitors such as sunitinib and imatinib may affect CaMKII activity and expression, potentially altering cardiac performance and causing cardiotoxicity.
Chronic TKI use may flag early cardiotoxicity via CaMKII rise; leaves open whether this precedes clinical HF in patients.
BACKGROUND AND PURPOSE: 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. 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 CaMKIIδ expression and CaMKII activity following drug treatments. KEY 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 AND IMPLICATIONS: 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.
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Mooney et al. (2015) studied Cardiotoxicity (n=50). Sunitinib and imatinib vs. Vehicle was evaluated on CaMKII activity and CaMKIIδ expression. Chronic treatment with sunitinib and imatinib significantly increased cardiac CaMKIIδ expression and CaMKII activity in guinea pigs in the absence of overt cardiac dysfunction.
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