L Mooney1, M Skinner2, S J Coker1, S Currie1. 1. Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, UK. 2. Safety Assessment UK, AstraZeneca R&D, Macclesfield, UK.
Abstract
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.
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.
Authors: Michael Markert; Thomas Trautmann; Marcus Groß; Anja Ege; Karin Mayer; Brian Guth Journal: J Pharmacol Toxicol Methods Date: 2012-04-23 Impact factor: 1.950
Authors: E Blasi; J Heyen; S Patyna; M Hemkens; D Ramirez; A John-Baptiste; J Steidl-Nichols; A McHarg Journal: Cardiovasc Ther Date: 2011-05-31 Impact factor: 3.023
Authors: Risto Kerkela; Kathleen C Woulfe; Jean-Bernard Durand; Ronald Vagnozzi; David Kramer; Tammy F Chu; Cara Beahm; Ming Hui Chen; Thomas Force Journal: Clin Transl Sci Date: 2009-02 Impact factor: 4.689
Authors: Laura Mooney; Louise Marks; Karen L Philp; Matthew Skinner; Susan J Coker; Susan Currie Journal: J Pharmacol Toxicol Methods Date: 2012-05-30 Impact factor: 1.950
Authors: Tamara P Martin; Ahmed Lawan; Emma Robinson; David J Grieve; Robin Plevin; Andrew Paul; Susan Currie Journal: Pflugers Arch Date: 2013-07-24 Impact factor: 3.657
Authors: Mei-Ling A Joiner; Olha M Koval; Jingdong Li; B Julie He; Chantal Allamargot; Zhan Gao; Elizabeth D Luczak; Duane D Hall; Brian D Fink; Biyi Chen; Jinying Yang; Steven A Moore; Thomas D Scholz; Stefan Strack; Peter J Mohler; William I Sivitz; Long-Sheng Song; Mark E Anderson Journal: Nature Date: 2012-10-10 Impact factor: 49.962
Authors: Adam J Pawson; Joanna L Sharman; Helen E Benson; Elena Faccenda; Stephen P H Alexander; O Peter Buneman; Anthony P Davenport; John C McGrath; John A Peters; Christopher Southan; Michael Spedding; Wenyuan Yu; Anthony J Harmar Journal: Nucleic Acids Res Date: 2013-11-14 Impact factor: 16.971
Authors: Giuseppe Caruso; Anna Privitera; Barbara Moura Antunes; Giuseppe Lazzarino; Susan Marie Lunte; Giancarlo Aldini; Filippo Caraci Journal: Molecules Date: 2022-07-12 Impact factor: 4.927