ArticleOncotarget2018
Type IIB DNA topoisomerase is downregulated by trastuzumab and doxorubicin to synergize cardiotoxicity.
Article in Oncotarget, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Genetic and RNA-related molecular markers of trastuzumab-chemotherapy-associated cardiotoxicity in HER2 positive breast cancer: a systematic review.BMC cancer · 2022Pooled it
- Pegylated Liposomal Doxorubicin (CaelyxCurrent oncology (Toronto, Ont.) · 2021Trial
- Cardioprotective Potential of Grape-Derived Polyphenols in Cancer Therapy-Related Cardiotoxicity.International journal of molecular sciences · 2026Review
- Novel Mechanism of and Therapeutic Approach for Anthracycline-Induced Cardiotoxicity.Cancer research communications · 2026Article
- Understanding the Mechanisms of Chemotherapy-Related Cardiotoxicity Employing hiPSC-Derived Cardiomyocyte Models for Drug Screening and the Identification of Genetic and Epigenetic Variants.International journal of molecular sciences · 2025Review
- Reevaluating Anti-Inflammatory Therapy: Targeting Senescence to Balance Anti-Cancer Efficacy and Vascular Disease.Arteriosclerosis, thrombosis, and vascular biology · 2025Review
- Targeting metabolic vulnerabilities in breast cancer cells by combining PEDF and doxorubicin: pathway insights from GC/MS-based metabolomics.EXCLI journal · 2025Article
- Neutrophil Biomarkers Can Predict Cardiotoxicity of Anthracyclines in Breast Cancer.International journal of molecular sciences · 2024Article
- Doxorubicin-induced cardiotoxicity and risk factors.International journal of cardiology. Heart & vasculature · 2024Article
- Structural and functional characterization of IgG- and non-IgG-based T-cell-engaging bispecific antibodies.Frontiers in immunology · 2024Article
- An integrative review of nonobvious puzzles of cellular and molecular cardiooncology.Cellular & molecular biology letters · 2023Review
- Mitigation of Cardiovascular Disease and Toxicity through NRF2 Signalling.International journal of molecular sciences · 2023Review
- Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis.International journal of molecular sciences · 2022Review
- Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity.Frontiers in cell and developmental biology · 2020Review
- Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology.Stem cells translational medicine · 2019Review
- PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With Right Ventricular Dysfunction.Journal of the American Heart Association · 2019Article
- Trastuzumab-mediated cardiotoxicity: current understanding, challenges, and frontiers.Antibody therapeutics · 2018Article
- Heart Failure in Relation to Tumor-Targeted Therapies and Immunotherapies.Methodist DeBakey cardiovascular journalReview
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.