ArticleInternational journal of molecular sciences2022
Trastuzumab and Doxorubicin Sequential Administration Increases Oxidative Stress and Phosphorylation of Connexin 43 on Ser368.
Article in International journal of molecular sciences, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 13 citations in OpenAlex.
- Trajectory and Determinants of Left Ventricular Dysfunction Following Anthracycline-Based Therapy Among Breast Cancer Patients: A Three-Year Cohort Analysis in Indonesia.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Sympathetic Neural Overactivation, Vascular Dysfunction, and Exercise Intolerance in Long-Term Survivors of Breast Cancer Treated With Doxorubicin and Trastuzumab-Based Chemotherapy.Journal of the American Heart Association · 2026Article
- Nuclear translocation of Cx43 promotes to CRC progression and associates with β-catenin accumulation.Cancer biology & therapy · 2025Article
- Characterization of anticancer therapy-induced microvascular dysfunction in patients with breast cancer supports targeted intervention.JCI insight · 2025Article
- Cardioprotective Effects of Simvastatin in Doxorubicin-Induced Acute Cardiomyocyte Injury.International journal of molecular sciences · 2025Article
- PCSK9 Inhibitor Inclisiran Attenuates Cardiotoxicity Induced by Sequential Anthracycline and Trastuzumab Exposure via NLRP3 and MyD88 Pathway Inhibition.International journal of molecular sciences · 2025Article
- Simvastatin Enhances the Cytotoxic Effects of Doxorubicin in a Mammary Adenocarcinoma Cell Model by Involving Connexin 43.Journal of biochemical and molecular toxicology · 2025Article
- Dissection of triple-negative breast cancer microenvironment and identification of potential therapeutic drugs using single-cell RNA sequencing analysis.Journal of pharmaceutical analysis · 2024Article
- Simvastatin Reduces Doxorubicin-Induced Cardiotoxicity: Effects beyond Its Antioxidant Activity.International journal of molecular sciences · 2023Article
- Vx-809, a CFTR Corrector, Acts through a General Mechanism of Protein Folding and on the Inflammatory Process.International journal of molecular sciences · 2023Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancer cases, causing a more aggressive tumour growth and poor prognosis. Trastuzumab, the humanized antibody targeted to HER2, increased the life expectancy of patients, but severe cardiotoxicity emerged as a long-term adverse effect. Clinical evidence highlights that Trastuzumab-induced cardiotoxicity drastically increases in association with Doxorubicin; however, the exact mechanisms involved remain incompletely understood. In order to analyse the molecular mechanisms involved and the possible adaptative responses to Trastuzumab and Doxorubicin treatment, in this study, H9c2 cardiomyoblasts were used. Results showed that Trastuzumab and Doxorubicin sequential administration in cardiomyoblast increased cytosolic and mitochondrial ROS production, intracellular calcium dysregulation, mitochondrial membrane depolarization, and the consequent apoptosis, induced by both Trastuzumab and Doxorubicin alone. Furthermore, in these conditions, we observed increased levels of Connexin43 phosphorylated on Ser368 (pCx43). Since phosphorylation on Ser368 decreases gap junction intracellular communication, thus reducing the spread of death signals to adjacent cells, we hypothesized that the increase in pCx43 could be an adaptative response implemented by cells to defend neighbouring cells by Trastuzumab and Doxorubicin sequential administration. However, the other side of the coin is the resulting conduction abnormalities.
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