03159nas a2200505   4500000000100000000000100001008004100002260001500043653003200058653002600090653001900116653003700135653001600172653001100188653003500199653002200234653002700256653004500283653002600328653006800354653003200422653002800454100001200482700001900494700002000513700001400533700001800547700002100565700001700586700001800603700001500621700001400636700001800650700003200668700002100700700001200721700002400733700001900757700002000776245012300796300001000919490000800929520170200937022001402639       2024                            d  c2024-06-2610aAntibiotics, Antineoplastic10aAntineoplastic Agents10aCardiotoxicity10aDose-Response Relationship, Drug10aDoxorubicin10aHumans10ainduced pluripotent stem cells10aMyocytes, Cardiac10aProof of Concept Study10adoxorubicin-induced cardiotoxicity (DIC)10ain vitro cytotoxicity10ainduced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)10ainterindividual variability10atranscriptome profiling1 aLi Pang1 aChengzhong Cai1 aPraful Aggarwal1 aDong Wang1 aVikrant Vijay1 aPrathyusha Bagam1 aJacob Blamer1 aAndrea Matter1 aAmy Turner1 aLijun Ren1 aKaty Papineau1 aVinodh Srinivasasainagendra1 aHemant K. Tiwari1 aXi Yang1 aLaura Schnackenberg1 aWilliam Mattes1 aUlrich Broeckel00aPredicting oncology drug-induced cardiotoxicity with donor-specific iPSC-CMs-a proof-of-concept study with doxorubicin  a79-940 v2003 aMany 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.  a1096-0929