Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types
| Autor: | Patricia Trusk, Diarmuid M. Moran, Scott A. Shell, Dominique R. Talbert, Kimberly R. Doherty, Sarah S. Bacus |
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| Rok vydání: | 2015 |
| Předmět: |
Drug
Time Factors Heart Diseases Cell Survival media_common.quotation_subject Induced Pluripotent Stem Cells Antineoplastic Agents Pharmacology Toxicology Risk Assessment Structure-Activity Relationship Toxicity Tests Humans Medicine Myocytes Cardiac Induced pluripotent stem cell Cells Cultured media_common Cardiotoxicity Dose-Response Relationship Drug Molecular Structure biology business.industry Mechanism (biology) Safety pharmacology Troponin I Reproducibility of Results Lipid Metabolism Troponin High-Throughput Screening Assays Oxidative Stress Drug development biology.protein Stem cell Reactive Oxygen Species business Biomarkers |
| Zdroj: | Toxicology and Applied Pharmacology. 285:51-60 |
| ISSN: | 0041-008X |
| Popis: | Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks. Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug-induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability. |
| Databáze: | OpenAIRE |
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