A multi-parameter in vitro screen in human stem cell-derived cardiomyocytes identifies ponatinib-induced structural and functional cardiac toxicity
| Autor: | Sarah S. Bacus, Dominique R. Talbert, Scott A. Shell, Kimberly R. Doherty, Diarmuid M. Moran, Patricia Trusk |
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| Rok vydání: | 2014 |
| Předmět: |
Time Factors
Heart Diseases Cell hERG Induced Pluripotent Stem Cells Antineoplastic Agents Pharmacology Toxicology Risk Assessment Mitochondria Heart Cell Line chemistry.chemical_compound Heart Rate Toxicity Tests medicine Humans Myocytes Cardiac Protein Kinase Inhibitors Cardiotoxicity biology Cell Death Dose-Response Relationship Drug Ponatinib In vitro toxicology Imidazoles Cell Differentiation Actin cytoskeleton Troponin Pyridazines Actin Cytoskeleton Oxidative Stress medicine.anatomical_structure chemistry Toxicity biology.protein Stem cell Signal Transduction |
| Zdroj: | Toxicological sciences : an official journal of the Society of Toxicology. 143(1) |
| ISSN: | 1096-0929 |
| Popis: | Ponatinib, a multi-targeted TKI and potent pan-ABL inhibitor, approved for the treatment of Ph þ ALL and CML, was temporarily withdrawn from the U.S. market due to severe vascular adverse events. Cardiac-specific toxicities including myocardial infarction, severe congestive heart failure, and cardiac arrhythmias have also been shown with ponatinib. Targeted oncology agents such as ponatinib have transformed cancer treatment but often induce toxicity due to inhibition of survival pathways shared by both cancer and cardiac cells. These toxicities are often missed by the standard preclinical toxicity assessment methods, which include human Ether-a`-go-go-related gene (hERG) and animal toxicity testing. In this study, we show that a multiparameter in vitro toxicity screening approach using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) accurately predicted the cardiac toxicity potential of ponatinib. This in vitro model evaluated ponatinib’s effect on the overall cell health, mitochondrial stress, and function of hiPSC-CM and also provided mechanistic insight into the signaling pathways and cellular structures altered with treatment. We show here that ponatinib rapidly inhibits prosurvival signaling pathways, induces structural cardiac toxicity (as shown by actin cytoskeleton damage, mitochondrial stress, cell death, and troponin secretion), and disrupts cardiac cell beating. Most of these effects occurred at doses between 10� and 50� ponatinib’s Cmax, a dose range shown to be relevant for accurate prediction of in vivo toxicity. Together these studies show that a comprehensive in vitro screening tool in a more relevant human cardiac cell model can improve the detection of cardiac toxicity with targeted oncology agents such as ponatinib. |
| Databáze: | OpenAIRE |
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