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Sci Rep. 2016 May 4;6:25333. doi: 10.1038/srep25333.

Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes.

Author information

1
Translational Laboratory in Genetic Medicine, National University of Singapore and the Agency for Science Technology and Research (A*STAR), Singapore.
2
Center for Computational Biology, Duke-NUS Graduate Medical School, Singapore.
3
National Heart Research Institute, National Heart Centre Singapore, Singapore.
4
Cardiovascular Academic Clinical Program, DUKE-NUS Graduate Medical School, Singapore.
5
Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
6
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
7
Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore.
8
Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.

Abstract

Doxorubicin is a highly efficacious anti-cancer drug but causes cardiotoxicity in many patients. The mechanisms of doxorubicin-induced cardiotoxicity (DIC) remain incompletely understood. We investigated the characteristics and molecular mechanisms of DIC in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). We found that doxorubicin causes dose-dependent increases in apoptotic and necrotic cell death, reactive oxygen species production, mitochondrial dysfunction and increased intracellular calcium concentration. We characterized genome-wide changes in gene expression caused by doxorubicin using RNA-seq, as well as electrophysiological abnormalities caused by doxorubicin with multi-electrode array technology. Finally, we show that CRISPR-Cas9-mediated disruption of TOP2B, a gene implicated in DIC in mouse studies, significantly reduces the sensitivity of hPSC-CMs to doxorubicin-induced double stranded DNA breaks and cell death. These data establish a human cellular model of DIC that recapitulates many of the cardinal features of this adverse drug reaction and could enable screening for protective agents against DIC as well as assessment of genetic variants involved in doxorubicin response.

PMID:
27142468
PMCID:
PMC4855185
DOI:
10.1038/srep25333
[Indexed for MEDLINE]
Free PMC Article

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