Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations

• Published in: Toxicology and applied pharmacology Vol. 257; no. 1; pp. 74 - 83
• Main Authors: Cohen, J.D., Babiarz, J.E., Abrams, R.M., Guo, L., Kameoka, S., Chiao, E., Taunton, J., Kolaja, K.L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.11.2011; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; AMP; AMPK; APOPTOSIS; ATP; Biological and medical sciences; Blotting, Western; CARCINOMAS; Cardiotoxicity; Cell Survival - drug effects; Electrophysiological Phenomena - drug effects; Enzyme Activation - drug effects; GLUTATHIONE; Human stem cell derived cardiomyocytes; Humans; IN VITRO; Indoles - toxicity; Induced pluripotent stem cells; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - physiology; INHIBITION; KIDNEYS; Medical sciences; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; OXIDATION; PHOSPHORYLATION; PHOSPHOTRANSFERASES; Protein Kinases - metabolism; Pyrroles - toxicity; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 90-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RODENTS; RSK; STEM CELLS; Sunitinib; TOXICITY; Toxicology; TYROSINE; Human stem cell derived cardiomyocytes; AMPK; Sunitinib; RSK; Cardiotoxicity; Induced pluripotent stem cells; Antineoplastic agent; Human; Enzyme; Tyrosine kinase inhibitor; Toxicity; Transferases; Stem cell; Enzyme inhibitor; Electrophysiology; Induced pluripotent stem cell; Cardiovascular disease; cAMP-dependent protein kinase; Cardiomyocyte; Heart disease; Multikinase inhibitor; Antiangiogenic agent; Protein-tyrosine kinase
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2011.08.020

Sunitinib, an oral tyrosine kinase inhibitor approved to treat advanced renal cell carcinoma and gastrointestinal stroma tumor, is associated with clinical cardiac toxicity. Although the precise mechanism of sunitinib cardiotoxicity is not known, both the key metabolic energy regulator, AMP-activated protein kinase (AMPK), and ribosomal S 6 kinase (RSK) have been hypothesized as causative, albeit based on rodent models. To study the mechanism of sunitinib-mediated cardiotoxicity in a human model, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) having electrophysiological and contractile properties of native cardiac tissue were investigated. Sunitinib was cardiotoxic in a dose-dependent manner with an IC 50 in the low micromolar range, observed by a loss of cellular ATP, an increase in oxidized glutathione, and induction of apoptosis in iPSC-CMs. Pretreatment of iPSC-CMs with AMPK activators AICAR or metformin, increased the phosphorylation of pAMPK-T172 and pACC-S79, but only marginally attenuated sunitinib mediated cell death. Furthermore, additional inhibitors of AMPK were not directly cytotoxic to iPSC-CMs up to 250 μM concentrations. Inhibition of RSK with a highly specific, irreversible, small molecule inhibitor (RSK-FMK-MEA) did not induce cytotoxicity in iPSC-CMs below 250 μM. Extensive electrophysiological analysis of sunitinib and RSK-FMK-MEA mediated conduction effects were performed. Taken together, these findings suggest that inhibition of AMPK and RSK are not a major component of sunitinib-induced cardiotoxicity. Although the exact mechanism of cardiotoxicity of sunitinib is not known, it is likely due to inhibition of multiple kinases simultaneously. These data highlight the utility of human iPSC-CMs in investigating the potential molecular mechanisms underlying drug-induced cardiotoxicity. ► Cytoxic effect of sunitinib on human stem cell derived cardiomyocytes ► Sunitinib causes ATP depletion, LDH release, GSH oxidation, and apoptosis ► In vitro effects of sunitinib include changes in beat rate and amplitude ► Sunitinib inhibits hERG and Nav1.5. ► AMPK and RSK do not mediate sunitinib cardiotoxicity