Faculty Collaboration Database

Predicting oncology drug-induced cardiotoxicity with donor-specific iPSC-CMs-a proof-of-concept study with doxorubicin. Toxicol Sci 2024 Jun 26;200(1):79-94

Date

03/28/2024

Pubmed ID

38547396

Pubmed Central ID

PMC11199917

DOI

10.1093/toxsci/kfae041

Scopus ID

2-s2.0-85197340912 (requires institutional sign-in at Scopus site)   4 Citations

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.

Author List

Pang L, Cai C, Aggarwal P, Wang D, Vijay V, Bagam P, Blamer J, Matter A, Turner A, Ren L, Papineau K, Srinivasasainagendra V, Tiwari HK, Yang X, Schnackenberg L, Mattes W, Broeckel U

Author

Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antibiotics, Antineoplastic
Antineoplastic Agents
Cardiotoxicity
Dose-Response Relationship, Drug
Doxorubicin
Humans
Induced Pluripotent Stem Cells
Myocytes, Cardiac
Proof of Concept Study