We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Predicting oncology drug-induced cardiotoxicity with donor-specific iPSC-CMs—a proof-of-concept study with doxorubicin.
- Authors
Pang, Li; Cai, Chengzhong; Aggarwal, Praful; Wang, Dong; Vijay, Vikrant; Bagam, Prathyusha; Blamer, Jacob; Matter, Andrea; Turner, Amy; Ren, Lijun; Papineau, Katy; Srinivasasainagendra, Vinodh; Tiwari, Hemant K; Yang, Xi; Schnackenberg, Laura; Mattes, William; Broeckel, Ulrich
- Abstract
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.
- Subjects
DOXORUBICIN; CARDIOTOXICITY; DRUG side effects; PROOF of concept; GENE expression; CYTOTOXINS
- Publication
Toxicological Sciences, 2024, Vol 200, Issue 1, p79
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/kfae041