Identification of the molecular basis of doxorubicin-induced cardiotoxicity

Sui Zhang; Xiaobing Liu; Tasneem Bawa-Khalfe; Long Sheng Lu; Yi Lisa Lyu; Leroy-Fong Liu; Edward T H Yeh

doi:10.1038/nm.2919

Identification of the molecular basis of doxorubicin-induced cardiotoxicity

Sui Zhang, Xiaobing Liu, Tasneem Bawa-Khalfe, Long Sheng Lu, Yi Lisa Lyu, Leroy-Fong Liu, Edward T H Yeh

Research output: Contribution to journal › Article › peer-review

1451 Citations (Scopus)

Abstract

Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.

Original language	English
Pages (from-to)	1639-1642
Number of pages	4
Journal	Nature Medicine
Volume	18
Issue number	11
DOIs	https://doi.org/10.1038/nm.2919
Publication status	Published - Nov 2012
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

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10.1038/nm.2919

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@article{6efcd444a9c845508ee4ee0fca05902f,

title = "Identification of the molecular basis of doxorubicin-induced cardiotoxicity",

abstract = "Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.",

author = "Sui Zhang and Xiaobing Liu and Tasneem Bawa-Khalfe and Lu, {Long Sheng} and Lyu, {Yi Lisa} and Leroy-Fong Liu and Yeh, {Edward T H}",

note = "Funding Information: We thank C.H. Ren for expert technical assistance and F.M. Lin and H. Dou for conducting studies on mitochondria DNA. W.C. Claycomb (Louisiana State University Health Science Center) provided HL-1 cells. This study is supported by the Cancer Prevention Research Institute of Texas and McNair Medical Institute (E.T.H.Y.), US National Institutes of Health grant CA102463 (to L.F.L.), the New Jersey Commission on Cancer Research Grant 06-2419-CCR-EO, US Department of Defense Idea Award W81XWH-07-1-0407 and Concept Award W81XWH06-1-0514 (to Y.L.L.).",

year = "2012",

month = nov,

doi = "10.1038/nm.2919",

language = "English",

volume = "18",

pages = "1639--1642",

journal = "Nature Medicine",

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AU - Zhang, Sui

AU - Liu, Xiaobing

AU - Bawa-Khalfe, Tasneem

AU - Lu, Long Sheng

AU - Lyu, Yi Lisa

AU - Liu, Leroy-Fong

AU - Yeh, Edward T H

N1 - Funding Information: We thank C.H. Ren for expert technical assistance and F.M. Lin and H. Dou for conducting studies on mitochondria DNA. W.C. Claycomb (Louisiana State University Health Science Center) provided HL-1 cells. This study is supported by the Cancer Prevention Research Institute of Texas and McNair Medical Institute (E.T.H.Y.), US National Institutes of Health grant CA102463 (to L.F.L.), the New Jersey Commission on Cancer Research Grant 06-2419-CCR-EO, US Department of Defense Idea Award W81XWH-07-1-0407 and Concept Award W81XWH06-1-0514 (to Y.L.L.).

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N2 - Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.

AB - Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes.

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Identification of the molecular basis of doxorubicin-induced cardiotoxicity

Abstract

ASJC Scopus subject areas

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