ArticleProceedings of the National Academy of Sciences of the United States of America2021
Targeting OCT3 attenuates doxorubicin-induced cardiac injury.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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The trial behind it
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Who cites it
34 citing papers in PubMed, 64 citations in OpenAlex.
- Role of solute carrier transporters in the biodistribution and toxicity of chemotherapeutic drugs.Pharmacological reviews · 2026Review
- Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants.Research square · 2026Article
- Insights and perspectives into the etiology of TKI-induced cardiotoxicity.ASPET discovery · 2026Article
- Shared Mechanisms in Cancer and Cardiovascular Disease: S100A8/9 and the NLRP3 Inflammasome: JACC: CardioOncology State-of-the-Art Review.JACC. CardioOncology · 2025Review
- Applications of Green Carbon Dots in Personalized Diagnostics for Precision Medicine.International journal of molecular sciences · 2025Review
- Tetrahedral Framework Nucleic Acids Inhibit Oxidative Stress and Cardiomyocyte Apoptosis in Doxorubicin-Induced Cardiotoxicity.International journal of nanomedicine · 2025Article
- Review
- CRISPRi/a screens in human iPSC-cardiomyocytes identify glycolytic activation as a druggable target for doxorubicin-induced cardiotoxicity.Cell stem cell · 2024Article
- Systematic Evaluation of Tyrosine Kinase Inhibitors as OATP1B1 Substrates Using a Competitive Counterflow Screen.Cancer research communications · 2024Article
- Unheralded Adrenergic Receptor Signaling in Cellular Oxidative Stress and Death.Current opinion in physiology · 2024Article
- Cardiac Uptake of the Adrenergic Imaging AgentDrug metabolism and disposition: the biological fate of chemicals · 2024Article
- Membrane transporters in drug development and as determinants of precision medicine.Nature reviews. Drug discovery · 2024Review
- Low-intensity pulsed ultrasound alleviates doxorubicin-induced cardiotoxicity via inhibition of S100a8/a9-mediated cardiac recruitment of neutrophils.Bioengineering & translational medicine · 2023Article
- Doxorubicin-Induced Cardiomyopathy: A Preliminary Study on the Cardioprotective Benefits of 7-Hydroxyflavanone.International journal of molecular sciences · 2023Article
- Interaction of ALK Inhibitors with Polyspecific Organic Cation Transporters and the Impact of Substrate-Dependent Inhibition on the Prediction of Drug-Drug Interactions.Pharmaceutics · 2023Article
- MicroRNA-Based Discovery of Biomarkers, Therapeutic Targets, and Repositioning Drugs for Breast Cancer.Cells · 2023Article
- Determination and disposition of meta-iodobenzylguanidine in plasma and heart of transporter-deficient mice by UPLC-MS/MS.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences · 2023Article
- Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis-Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1.Pharmaceuticals (Basel, Switzerland) · 2023Article
- The Role of Organic Cation Transporters in the Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of Tyrosine Kinase Inhibitors.International journal of molecular sciences · 2023Review
- Article
Corrections and comments
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Authors and funding
32 authors at 8 institutions in 2 countries.
Funding
Abstract
Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies offer only modest protection. Using stem-cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified organic cation transporter 3 (OCT3) (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in heterologous overexpression models confirmed that doxorubicin is transported into cardiomyocytes by OCT3 and that deficiency of OCT3 protected mice from acute and chronic doxorubicin-related changes in cardiovascular function and genetic pathways associated with cardiac damage. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we identified several pharmacological inhibitors of OCT3, including nilotinib, and found that pharmacological targeting of OCT3 can also preserve cardiovascular function following treatment with doxorubicin without affecting its plasma levels or antitumor effects in multiple models of leukemia and breast cancer. Finally, we identified a previously unrecognized, OCT3-dependent pathway of doxorubicin-induced cardiotoxicity that results in a downstream signaling cascade involving the calcium-binding proteins S100A8 and S100A9. These collective findings not only shed light on the etiology of doxorubicin-induced cardiotoxicity, but also are of potential translational relevance and provide a rationale for the implementation of a targeted intervention strategy to prevent this debilitating side effect.
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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.