TY - JOUR
T1 - A safety screening platform for individualized cardiotoxicity assessment
AU - Schwach, Verena
AU - Slaats, Rolf H.
AU - Cofiño-Fabres, Carla
AU - ten Den, Simone A.
AU - Rivera-Arbeláez, José M.
AU - Dannenberg, Maureen
AU - van Boheemen, Chiara
AU - Ribeiro, Marcelo
AU - van der Zanden, Sabina Y.
AU - Nollet, Edgar E.
AU - van der Velden, Jolanda
AU - Neefjes, Jacques
AU - Cao, Lu
AU - Passier, Robert
PY - 2024/3/15
Y1 - 2024/3/15
N2 - 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.
AB - 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.
KW - UT-Gold-D
U2 - 10.1016/j.isci.2024.109139
DO - 10.1016/j.isci.2024.109139
M3 - Article
SN - 2589-0042
VL - 27
JO - iScience
JF - iScience
IS - 3
M1 - 109139
ER -