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Open AccessArticle

Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway

1
Institute of Cardiology, University of Pisa, 56124 Pisa, Italy
2
Department of Internal Medicine, Cardiology Division, McGovern School of Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
3
Department of Medical, Oral and Biotechnological Sciences, University ‘‘G. D’Annunzio’’ of Chieti-Pescara, 66100 Chieti, Italy
4
Analytical Biochemistry and Proteomics Laboratory, Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
5
Department of Pharmacy, University ‘‘G. d’Annunzio’’ of Chieti-Pescara, 66100 Chieti, Italy
6
Institute of Cardiology, University “G. d’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
7
Department of Medical Sciences and Public Health, University of Cagliari, 09042 Cagliari, Italy
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(3), 820; https://doi.org/10.3390/jcm9030820
Received: 22 February 2020 / Revised: 4 March 2020 / Accepted: 8 March 2020 / Published: 18 March 2020
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. View Full-Text
Keywords: tyrosine kinase inhibitors; ponatinib; vascular toxicity; Notch-1 tyrosine kinase inhibitors; ponatinib; vascular toxicity; Notch-1
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Madonna, R.; Pieragostino, D.; Cufaro, M.C.; Doria, V.; Del Boccio, P.; Deidda, M.; Pierdomenico, S.D.; Dessalvi, C.C.; De Caterina, R.; Mercuro, G. Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway. J. Clin. Med. 2020, 9, 820.

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