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

Journal Article · Tue Nov 15 00:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2011.08.020· OSTI ID:22212553

Cohen, J.D., E-mail: [e-mail] ^[1]; Babiarz, J.E., E-mail: [e-mail] ^[1]; Abrams, R.M., E-mail: [e-mail] ^[1]; Guo, L., E-mail: [e-mail] ^[1]; Kameoka, S., E-mail: [e-mail] ^[1]; Chiao, E., E-mail: [e-mail] ^[1]; Taunton, J., E-mail: [e-mail] ^[2]; Kolaja, K.L., E-mail: [e-mail] ^[1]

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1. Early and Investigative Safety, Nonclinical Safety, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110 (United States)
2. Howard Hughes Medical Institute, Cellular and Molecular Pharmacology, University California San Francisco, San Francisco, CA 94158 (United States)

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{sub 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 {mu}M concentrations. Inhibition of RSK with a highly specific, irreversible, small molecule inhibitor (RSK-FMK-MEA) did not induce cytotoxicity in iPSC-CMs below 250 {mu}M. 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. -- Highlights: Black-Right-Pointing-Pointer Cytoxic effect of sunitinib on human stem cell derived cardiomyocytes Black-Right-Pointing-Pointer Sunitinib causes ATP depletion, LDH release, GSH oxidation, and apoptosis Black-Right-Pointing-Pointer In vitro effects of sunitinib include changes in beat rate and amplitude Black-Right-Pointing-Pointer Sunitinib inhibits hERG and Nav1.5. Black-Right-Pointing-Pointer AMPK and RSK do not mediate sunitinib cardiotoxicity.

• OSTI ID: 22212553
• Journal Information: Toxicology and Applied Pharmacology, Vol. 257, Issue 1; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMP
APOPTOSIS
ATP
CARCINOMAS
GLUTATHIONE
IN VITRO
INHIBITION
KIDNEYS
OXIDATION
PHOSPHORYLATION
PHOSPHOTRANSFERASES
RODENTS
STEM CELLS
TOXICITY
TYROSINE