Please use this identifier to cite or link to this item: https://doi.org/10.1038/srep25333
Title: Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes
Authors: Maillet, A 
Tan, K
Chai, X 
Sadananda, S.N
Mehta, A 
Ooi, J
Hayden, M.R 
Pouladi, M.A 
Ghosh, S 
Shim, W 
Brunham, L.R 
Keywords: antineoplastic antibiotic
doxorubicin
biological model
cardiac muscle cell
cardiotoxicity
cell culture
cell survival
drug effects
electrophysiology
gene expression profiling
human
physiology
pluripotent stem cell
Antibiotics, Antineoplastic
Cardiotoxicity
Cell Survival
Cells, Cultured
Doxorubicin
Electrophysiological Phenomena
Gene Expression Profiling
Humans
Models, Biological
Myocytes, Cardiac
Pluripotent Stem Cells
Issue Date: 2016
Citation: Maillet, A, Tan, K, Chai, X, Sadananda, S.N, Mehta, A, Ooi, J, Hayden, M.R, Pouladi, M.A, Ghosh, S, Shim, W, Brunham, L.R (2016). Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes. Scientific Reports 6 : 25333. ScholarBank@NUS Repository. https://doi.org/10.1038/srep25333
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. © 2016 Nature Publishing Group. All rights reserved.
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/174014
ISSN: 20452322
DOI: 10.1038/srep25333
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