{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T17:36:12Z","timestamp":1788802572331,"version":"build-2803163510"},"reference-count":81,"publisher":"Oxford University Press (OUP)","issue":"1","funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01HL140493"],"award-info":[{"award-number":["R01HL140493"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Center for Toxicological Research"},{"name":"ORISE Research Participation Program"},{"DOI":"10.13039\/100000038","name":"Food and Drug Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006229","name":"Oak Ridge Institute for Science and Education","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006229","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Energy and FDA\/Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anticancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for exploring the interindividual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intraindividual variability of iPSC-CM-related assays and presented a proof of concept to prospectively predict doxorubicin (DOX)-induced cardiotoxicity (DIC) using donor-specific iPSC-CMs. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intraindividual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice and largely replicated the reported mechanisms. By categorizing iPSC-CMs into resistant and sensitive cell lines based on their time- and concentration-related phenotypic responses to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we identified a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. Our results support the utilization of donor-specific iPSC-CMs in assessing interindividual differences in DIC. Further studies will encompass a large panel of donor-specific iPSC-CMs to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae041","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T19:37:34Z","timestamp":1711654654000},"page":"79-94","source":"Crossref","is-referenced-by-count":6,"title":["Predicting oncology drug-induced cardiotoxicity with donor-specific iPSC-CMs\u2014a proof-of-concept study with doxorubicin"],"prefix":"10.1093","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0212-2090","authenticated-orcid":false,"given":"Li","family":"Pang","sequence":"first","affiliation":[{"name":"Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration , Jefferson, Arkansas 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengzhong","family":"Cai","sequence":"additional","affiliation":[{"name":"Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration , Jefferson, Arkansas 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praful","family":"Aggarwal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Section of Genomic Pediatrics, Medical College of Wisconsin , Milwaukee, Wisconsin 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration , Jefferson, Arkansas 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikrant","family":"Vijay","sequence":"additional","affiliation":[{"name":"Division of Systems 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School of Public Health, University of Alabama at Birmingham , Birmingham, Alabama 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemant K","family":"Tiwari","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, University of Alabama at Birmingham , Birmingham, Alabama 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3427-0565","authenticated-orcid":false,"given":"Xi","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Pharmacology & Toxicology, Office of Cardiology, Hematology, Endocrinology, & Nephrology, Office of New Drug, Center for Drug Evaluation and Research, U.S. Food and Drug Administration , Silver Spring, Maryland 20903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Schnackenberg","sequence":"additional","affiliation":[{"name":"Division of Systems Biology, National Center for 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