Type IIB DNA topoisomerase is downregulated by trastuzumab and doxorubicin to synergize cardiotoxicity

Oncotarget
Jiangsong JiangWen Jin Wu

Abstract

Despite heightened risk of cardiotoxicity associated with combination therapy of anthracyclines and trastuzumab in HER2-positive breast cancer patients, little research effort has been invested in exploring the molecular mechanisms of cardiotoxicity induced by this combination therapy. In this study, we demonstrate that trastuzumab downregulates both gene and protein expressions of type IIB DNA topoisomerase/DNA topoisomerase IIB (TOP2B), a major intracellular target mediating doxorubicin-induced cardiotoxicity, in human primary cardiomyocytes. This in turn induces DNA damage activity and DNA double strand breaks, which is indicated by the enhanced phosphorylation of H2AX (γH2AX) and ataxia telangiectasia and Rad3-related protein (ATR pS428) in trastuzumab-treated cardiomyocytes. Furthermore, concurrent or sequential treatment of doxorubicin and trastuzumab significantly increases the downregulation of the protein levels of TOP2B, enhances apoptosis and cell growth inhibition, and promotes production of reactive oxidative and nitrative species in human cardiomyocytes as compared to either trastuzumab or doxorubicin treatment, indicating augmentation of cardiotoxicity in combination therapy. Additionally, our data reveal that do...Continue Reading

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References

Oct 24, 2001·The Journal of Biological Chemistry·I M Ward, J Chen
Jun 4, 2002·Nature Reviews. Molecular Cell Biology·James C Wang
Jan 30, 2004·Recent Progress in Hormone Research·Alejandra NegroKuo-Fen Lee
Oct 21, 2005·The New England Journal of Medicine·Martine J Piccart-GebhartUNKNOWN Herceptin Adjuvant (HERA) Trial Study Team
Feb 6, 2007·Free Radical Biology & Medicine·Shiwei DengLeszek Wojnowski
Aug 10, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Melinda L TelliAlice E Guardino
Dec 17, 2008·Breast Cancer Research and Treatment·Deepa WadhwaDavinder S Jassal
Apr 21, 2009·Nature Reviews. Cancer·John L Nitiss
Aug 4, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Daniela CardinaleCarlo M Cipolla
Mar 15, 2012·Biochemical Pharmacology·Robert A ForrestSuzanne M Cutts
Sep 27, 2012·The Journal of Biological Chemistry·Stefanie C HuelsenbeckGerhard Fritz
Oct 30, 2012·Nature Medicine·Sui ZhangEdward T H Yeh
Sep 5, 2013·Cold Spring Harbor Perspectives in Biology·Alexandre Maréchal, Lee Zou
Jan 3, 2014·The Journal of Clinical Investigation·Yoshihiko IchikawaHossein Ardehali
Apr 22, 2015·Trends in Pharmacological Sciences·Luc RochetteCatherine Vergely
May 13, 2015·Nature Reviews. Cardiology·Michael S Ewer, Steven M Ewer
Aug 2, 2015·Advances in Clinical Chemistry·Milos Dokmanovic, Wen Jin Wu
Nov 12, 2015·Breast Care·Amelie SchrammJens Huober
Apr 20, 2016·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Paaladinesh ThavendiranathanDouglas S Lee
Oct 8, 2016·British Journal of Pharmacology·Balazs T NemethPal Pacher
Nov 2, 2016·Proceedings of the National Academy of Sciences of the United States of America·Markus RäsänenKari Alitalo
Nov 16, 2016·ESMO Open·Noam F PondéEvandro de Azambuja
Feb 7, 2017·Reviews on Recent Clinical Trials·Rachel Wuerstlein, Nadia Harbeck

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Citations

Jan 29, 2020·Antioxidants & Redox Signaling·Valentina SalaAlessandra Ghigo
Jun 26, 2020·Frontiers in Cell and Developmental Biology·Wanjun MaWenqun Li
Apr 26, 2019·Stem Cells Translational Medicine·Pooja NairIoannis Karakikes
Sep 15, 2018·Antibody Therapeutics·Nishant MohanWen Jin Wu
Jul 18, 2020·Clinical Science·Keith DadsonFilio Billia
Jan 2, 2021·Neoplasia : an International Journal for Oncology Research·Eshita KheraGreg M Thurber

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Methods Mentioned

BETA
flow cytometry
confocal microscopy
ELISA

Software Mentioned

Morpheus
ImageJ
Excel
GraphPad Prism

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