TY - JOUR
KW - Antibiotics, Antineoplastic
KW - Antineoplastic Agents
KW - Cardiotoxicity
KW - Dose-Response Relationship, Drug
KW - Doxorubicin
KW - Humans
KW - induced pluripotent stem cells
KW - Myocytes, Cardiac
KW - Proof of Concept Study
KW - doxorubicin-induced cardiotoxicity (DIC)
KW - in vitro cytotoxicity
KW - induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)
KW - interindividual variability
KW - transcriptome profiling
AU - Li Pang
AU - Chengzhong Cai
AU - Praful Aggarwal
AU - Dong Wang
AU - Vikrant Vijay
AU - Prathyusha Bagam
AU - Jacob Blamer
AU - Andrea Matter
AU - Amy Turner
AU - Lijun Ren
AU - Katy Papineau
AU - Vinodh Srinivasasainagendra
AU - Hemant K. Tiwari
AU - Xi Yang
AU - Laura Schnackenberg
AU - William Mattes
AU - Ulrich Broeckel
AB - 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.
BT - Toxicological Sciences: An Official Journal of the Society of Toxicology
DA - 2024-06-26
DO - 10.1093/toxsci/kfae041
IS - 1
LA - eng
N2 - 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.
PY - 2024
SP - 79
EP - 94
T2 - Toxicological Sciences: An Official Journal of the Society of Toxicology
TI - Predicting oncology drug-induced cardiotoxicity with donor-specific iPSC-CMs-a proof-of-concept study with doxorubicin
VL - 200
SN - 1096-0929
ER -