ArticleToxicology and applied pharmacology2011
Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations.
Article in Toxicology and applied pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 78 citations in OpenAlex.
- Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes as an in vitro model in toxicology: strengths and weaknesses for hazard identification and risk characterization.Expert opinion on drug metabolism & toxicology · 2021Pooled it
- Electromechanical modelling and simulation of human-induced pluripotent stem cell-derived cardiomyocytes predict drug-induced contractility effects.The Journal of physiology · 2026Article
- Article
- Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation.Pharmaceutics · 2022Review
- Antiviral and anti-inflammatory drugs to combat COVID-19: Effects on cardiac ion channels and risk of ventricular arrhythmias.BioImpacts : BI · 2022Review
- Computational model of cardiomyocyte apoptosis identifies mechanisms of tyrosine kinase inhibitor-induced cardiotoxicity.Journal of molecular and cellular cardiology · 2021Article
- Modeling Precision Cardio-Oncology: Using Human-Induced Pluripotent Stem Cells for Risk Stratification and Prevention.Current oncology reports · 2021Review
- Relationships between constituents of energy drinks and beating parameters in human induced pluripotent stem cell (iPSC)-Derived cardiomyocytes.Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · 2021Article
- Human Induced Pluripotent Stem Cells as a Disease Model System for Heart Failure.Current heart failure reports · 2021Review
- Polydatin Reduces Cardiotoxicity and Enhances the Anticancer Effects of Sunitinib by Decreasing Pro-Oxidative Stress, Pro-Inflammatory Cytokines, and NLRP3 Inflammasome Expression.Frontiers in oncology · 2021Article
- Downregulation of long noncoding RNA SNHG6 rescued propofol-induced cytotoxicity in human induced pluripotent stem cell-derived cardiomyocytes.Cardiovascular diagnosis and therapy · 2020Article
- Pluripotent Stem Cell Modeling of Anticancer Therapy-Induced Cardiotoxicity.Current cardiology reports · 2020Review
- Human In Vitro Models for Assessing the Genomic Basis of Chemotherapy-Induced Cardiovascular Toxicity.Journal of cardiovascular translational research · 2020Review
- Workshop Report: FDA Workshop on Improving Cardiotoxicity Assessment With Human-Relevant Platforms.Circulation research · 2019Review
- Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology.Stem cells translational medicine · 2019Review
- hiPSCs in cardio-oncology: deciphering the genomics.Cardiovascular research · 2019Review
- Increased Afterload Augments Sunitinib-Induced Cardiotoxicity in an Engineered Cardiac Microtissue Model.JACC. Basic to translational science · 2018Article
- Exaggerated Cardiotoxicity of Sunitinib in Stressed 3-Dimensional Heart Muscles.JACC. Basic to translational science · 2018Article
- Cytotoxicity of propofol in human induced pluripotent stem cell-derived cardiomyocytes.Journal of anesthesia · 2018Article
- Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
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 IC₅₀ 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.