ArticleJournal of clinical medicine2020
Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway.
Article in Journal of clinical medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- The Role of the Notch1 Signaling Pathway in the Pathogenesis and Treatment of Diabetic Foot: A Review.Diabetes therapy : research, treatment and education of diabetes and related disorders · 2026Review
- Precision Medicine in Hematologic Malignancies: Evolving Concepts and Clinical Applications.Biomedicines · 2025Review
- SGLT2 inhibitors as a novel senotherapeutic approach.npj aging · 2025Review
- KAT7 contributes to ponatinib-induced hypertension by promoting endothelial senescence and inflammatory responses through activating NF-κB signaling pathway.Journal of hypertension · 2025Article
- Article
- Ponatinib Induces a Procoagulant Phenotype in Human Coronary Endothelial Cells via Inducing Apoptosis.Pharmaceutics · 2024Article
- Cardiovascular Toxicity of Antineoplastic Treatments in Hematological Diseases: Focus on Molecular Mechanisms to Improve Therapeutic Management.Journal of clinical medicine · 2024Review
- Case report: Three characteristics of tyrosine kinase inhibitor-associated cerebrovascular stenosis. High threshold for infarction, atypical infarct area, and vascular recoverability under the use of ponatinib.Frontiers in stroke · 2024Article
- Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications.Frontiers in cardiovascular medicine · 2023Review
- Loss of primary cilia promotes inflammation and carcinogenesis.EMBO reports · 2022Article
- Reengineering Ponatinib to Minimize Cardiovascular Toxicity.Cancer research · 2022Article
- Sex-related differential susceptibility to ponatinib cardiotoxicity and differential modulation of the Notch1 signalling pathway in a murine model.Journal of cellular and molecular medicine · 2022Article
- Connexin 43 and Connexin 26 Involvement in the Ponatinib-Induced Cardiomyopathy: Sex-Related Differences in a Murine Model.International journal of molecular sciences · 2021Article
- Multi-Target Drugs for Blood Cancer in the Elderly: Implications of Damage and Repair in the Cardiovascular Toxicity.Frontiers in physiology · 2021Article
- Evaluation of CML TKI Induced Cardiovascular Toxicity and Development of Potential Rescue Strategies in a Zebrafish Model.Frontiers in pharmacology · 2021Article
- Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes.Journal of cellular and molecular medicine · 2020 · on this mapArticle
- Cardiotoxicity of the BCR-ABL1 tyrosine kinase inhibitors: Emphasis on ponatinib.International journal of cardiology · 2020Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ponatinib, a third-generation tyrosine kinase inhibitor (TKI), is the only approved TKI that is effective against T315I mutations in patients with chronic myeloid leukemia (CML). Specific activation of Notch signaling in CML cells by ponatinib can be considered as the "on-target effect" on the tumor and represents a therapeutic approach for CML. Nevertheless, ponatinib-induced vascular toxicity remains a serious concern, with underlying mechanisms being poorly understood. We aimed to determine the mechanisms of ponatinib-induced vascular toxicity, defining associated signaling pathways and identifying potential rescue strategies. We exposed human umbilical endothelial cells (HUVECs) to ponatinib or vehicle in the presence or absence of the neutralizing factor anti-Notch-1 antibody for exposure times of 0-72 h. Label-free proteomics and network analysis showed that protein cargo of HUVECs treated with ponatinib triggered apoptosis and inhibited vasculature development. We validated the proteomic data showing the inhibition of matrigel tube formation, an up-regulation of cleaved caspase-3 and a downregulation of phosphorylated AKT and phosphorylated eNOS. We delineated the signaling of ponatinib-induced vascular toxicity, demonstrating that ponatinib inhibits endothelial survival, reduces angiogenesis and induces endothelial senescence and apoptosis via the Notch-1 pathway. Ponatinib induced endothelial toxicity in vitro. Hyperactivation of Notch-1 in the vessels can lead to abnormal vascular development and vascular dysfunction. By hyperactivating Notch-1 in the vessels, ponatinib exerts an "on-target off tumor effect", which leads to deleterious effects and may explain the drug's vasculotoxicity. Selective blockade of Notch-1 prevented ponatinib-induced vascular toxicity.
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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.