ArticleMolecular pharmacology2014
Adverse effects of doxorubicin and its metabolic product on cardiac RyR2 and SERCA2A.
Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 156 citations in OpenAlex.
- βNaunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Glucagon-like peptide-1 receptor agonists are associated with cardiac, cancer- and mortality-related benefits in diabetic patients treated with anthracyclines.European heart journal open · 2026Article
- QT Prolongation and Arrhythmias in Cancer Therapy: A Narrative Review of Mechanistic and Clinical Studies.Cardiovascular toxicology · 2026Review
- Empagliflozin Mitigates Doxorubicin-Induced Cardiotoxicity in Rats: Electrocardiographic, Biochemical, and Histopathological Evidence.International journal of molecular sciences · 2026Article
- Persistently increased CaMKIIδ autophosphorylation mediates pathologic SR Ca loss in a murine model of Doxorubicin-induced cardiomyopathy.Journal of molecular and cellular cardiology plus · 2026Article
- Discovery of Zidovudine as a cardiomyocyte protectant for doxorubicin-induced toxicity through high-throughput phenotypic drug screening.Fundamental research · 2026Article
- Emerging Mechanisms and Therapeutic Strategies in Dilated Cardiomyopathy.Biomedicines · 2026Review
- Doxorubicin-Induced Cardiac Remodeling: Mechanisms and Mitigation Strategies.Cardiovascular drugs and therapy · 2026Review
- Chemo-/radiotherapy-induced cardiomyopathy: roles of mitochondria and endoplasmic reticulum.Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] · 2026Review
- Integrated Omics Approach to Delineate the Mechanisms of Doxorubicin-Induced Cardiotoxicity.Pharmaceuticals (Basel, Switzerland) · 2026Article
- The mechanisms and therapeutic advances of interactions between breast cancer and cardiovascular diseases.Frontiers in pharmacology · 2026Review
- Novel 2D/3D Hybrid Organoid System for High-Throughput Drug Screening in iPSC Cardiomyocytes.Therapeutics · 2025Article
- A recent decade update on combating doxorubicin-induced toxicities.Archives of toxicology · 2025Review
- Article
- Lifestyle and Pharmacological Interventions to Prevent Anthracycline-Related Cardiotoxicity in Cancer Patients.Journal of cardiovascular development and disease · 2025Review
- Metformin Alleviates Doxorubicin-Induced Cardiotoxicity via Preserving Mitochondrial Dynamics Balance and Calcium Homeostasis.Applied biochemistry and biotechnology · 2025Article
- Pathophysiology of dilated cardiomyopathy: from mechanisms to precision medicine.Nature reviews. Cardiology · 2025Review
- Doxorubicin induces cardiotoxicity by enhancing autophagy via mTOR signaling in hiPSC- and hESC-derived cardiomyocytes.Frontiers in cell and developmental biology · 2025Article
- Mechanistic Insights into Flavonoid Subclasses as Cardioprotective Agents Against Doxorubicin-Induced Cardiotoxicity: A Comprehensive Review.Drug design, development and therapy · 2025Review
- Concomitant Administration of Dantrolene is Sufficient to Protect Against Doxorubicin-Induced Cardiomyopathy.JACC. CardioOncology · 2025Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The use of anthracycline chemotherapeutic drugs is restricted owing to potentially fatal cardiotoxic side effects. It has been hypothesized that anthracycline metabolites have a primary role in this cardiac dysfunction; however, information on the molecular interactions of these compounds in the heart is scarce. Here we provide novel evidence that doxorubicin and its metabolite, doxorubicinol, bind to the cardiac ryanodine receptor (RyR2) and to the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA2A) and deleteriously alter their activity. Both drugs (0.01 μM-2.5 μM) activated single RyR2 channels, and this was reversed by drug washout. Both drugs caused a secondary inhibition of RyR2 activity that was not reversed by drug washout. Preincubation with the reducing agent dithiothreitol (DTT, 1 mM) prevented drug-induced inhibition of channel activity. Doxorubicin and doxorubicinol reduced the abundance of thiol groups on RyR2, further indicating that oxidation reactions may be involved in the actions of the compounds. Ca(2+) uptake into sarcoplasmic reticulum vesicles by SERCA2A was inhibited by doxorubicinol, but not doxorubicin. Unexpectedly, in the presence of DTT, doxorubicinol enhanced the rate of Ca(2+) uptake by SERCA2A. Together the evidence provided here shows that doxorubicin and doxorubicinol interact with RyR2 and SERCA2A in similar ways, but that the metabolite acts with greater efficacy than the parent compound. Both compounds modify RyR2 and SERCA2A activity by binding to the proteins and also act via thiol oxidation to disrupt SR Ca(2+) handling. These actions would have severe consequences on cardiomyocyte function and contribute to clinical symptoms of acute anthracycline cardiotoxicity.
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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.