Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

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

Journal Article · · Oncotarget
 [1];  [2];  [2];  [2];  [2]
  1. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research. Office of Pharmaceutical Quality. Office of Biotechnology Products. Division of Biotechnology Research and Review I; DOE/OSTI
  2. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research. Office of Pharmaceutical Quality. Office of Biotechnology Products. Division of Biotechnology Research and Review I
+ Show Author Affiliations
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 doxorubicininduced 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 doxorubicin treatment increases the levels of ErbB2/HER2 expression in human cardiomyocytes as compared with that in cells not treated with doxorubicin, leading to the enhanced activity downstream of HER2 signaling. Consequently, this may render the cardiomyocytes to become addicted to HER2 signaling for survival under stressed conditions. Enhanced HER2 protein expression leaves cardiomyocytes more sensitive to trastuzumab treatment after doxorubicin exposure. This study provides molecular basis for significantly increased cardiotoxicity in cancer patients who are treated with anthracyclines and trastuzumab-based combination regimens.
Research Organization:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
SC0014664
OSTI ID:
1629899
Journal Information:
Oncotarget, Journal Name: Oncotarget Journal Issue: 5 Vol. 9; ISSN 1949-2553
Publisher:
Impact JournalsCopyright Statement
Country of Publication:
United States
Language:
English

References (29)

DNA topoisomerase II and its growing repertoire of biological functions journal April 2009
Erratum: Cardiotoxicity of anticancer treatments journal August 2015
Neoadjuvant Therapy for HER2-positive Breast Cancer journal May 2017
Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study journal December 2008
Different patterns of gene expression of topoisomerase II isoforms in differentiated tissues during murine development journal August 1992
Activation of DNA damage response pathways as a consequence of anthracycline-DNA adduct formation journal June 2012
Gp91phox-containing NAD(P)H oxidase increases superoxide formation by doxorubicin and NADPH journal February 2007
Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms journal June 2015
Identification of the molecular basis of doxorubicin-induced cardiotoxicity journal October 2012
Cardiotoxicity of anticancer treatments journal May 2015
Cellular roles of DNA topoisomerases: a molecular perspective journal June 2002
Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2 journal March 2001
Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer journal October 2005
VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection journal October 2016
Histone H2AX Is Phosphorylated in an ATR-dependent Manner in Response to Replicational Stress journal October 2001
Rac1 Protein Signaling Is Required for DNA Damage Response Stimulated by Topoisomerase II Poisons journal November 2012
Rac1 signalling mediates doxorubicin-induced cardiotoxicity through both reactive oxygen species-dependent and -independent pathways journal October 2012
DNA Damage Sensing by the ATM and ATR Kinases journal September 2013
Trastuzumab cardiotoxicity: from clinical trials to experimental studies journal November 2016
Twenty years of anti-HER2 therapy-associated cardiotoxicity journal January 2016
Topoisomerase IIβ–Mediated DNA Double-Strand Breaks: Implications in Doxorubicin Cardiotoxicity and Prevention by Dexrazoxane journal September 2007
Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes journal June 2016
Targeted Therapies in HER2-Positive Breast Cancer - a Systematic Review journal January 2015
Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation journal January 2014
Trastuzumab-Related Cardiotoxicity: Calling Into Question the Concept of Reversibility journal August 2007
Trastuzumab-Induced Cardiotoxicity: Clinical and Prognostic Implications of Troponin I Evaluation journal September 2010
Breast Cancer Therapy–Related Cardiac Dysfunction in Adult Women Treated in Routine Clinical Practice: A Population-Based Cohort Study journal July 2016
Essential Roles of Her2/erbB2 in Cardiac Development and Function journal January 2004
Trastuzumab Alters the Expression of Genes Essential for Cardiac Function and Induces Ultrastructural Changes of Cardiomyocytes in Mice journal November 2013

Cited By (2)

Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology journal April 2019
PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With Right Ventricular Dysfunction journal May 2019

Similar Records

HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity
Journal Article · Sun Jul 01 00:00:00 EDT 2012 · Toxicology and Applied Pharmacology · OSTI ID:22215342
Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice
Journal Article · Wed Apr 15 00:00:00 EDT 2015 · Toxicology and Applied Pharmacology · OSTI ID:22465732
Long non-coding RNA UCA1 desensitizes breast cancer cells to trastuzumab by impeding miR-18a repression of Yes-associated protein 1
Journal Article · Wed Feb 14 23:00:00 EST 2018 · Biochemical and Biophysical Research Communications · OSTI ID:23137349

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES