A safety screening platform for individualized cardiotoxicity assessment

Verena Schwach*, Rolf H. Slaats, Carla Cofiño-Fabres, Simone A. ten Den, José M. Rivera-Arbeláez, Maureen Dannenberg, Chiara van Boheemen, Marcelo Ribeiro, Sabina Y. van der Zanden, Edgar E. Nollet, Jolanda van der Velden, Jacques Neefjes, Lu Cao, Robert Passier*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin, Aclarubicin, and Amrubicin. Doxorubicin and Aclarubicin unlike Amrubicin substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated annually.

Original languageEnglish
Article number109139
Number of pages40
JournaliScience
Volume27
Issue number3
Early online date6 Feb 2024
DOIs
Publication statusPublished - 15 Mar 2024

Keywords

  • UT-Gold-D

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