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Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes
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Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes
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Journal Article
Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes
2016
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/106
/ 13/109
/ 13/2
/ 13/31
/ 13/44
/ 13/51
/ 14
/ 14/19
/ 38
/ 38/91
/ 45/41
/ Antibiotics, Antineoplastic - adverse effects
/ Cancer
/ Cell Survival - drug effects
/ CRISPR
/ Disseminated intravascular coagulation
/ Doxorubicin - adverse effects
/ Electrophysiological Phenomena - drug effects
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Myocytes, Cardiac - drug effects
/ Myocytes, Cardiac - physiology
/ Pluripotent Stem Cells - drug effects
/ Pluripotent Stem Cells - physiology
/ RNA
/ Rodents
/ Science
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