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Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway

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...

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Autores principales: Madonna, Rosalinda, Pieragostino, Damiana, Cufaro, Maria Concetta, Doria, Vanessa, Del Boccio, Piero, Deidda, Martino, Pierdomenico, Sante Donato, Dessalvi, Christian Cadeddu, De Caterina, Raffaele, Mercuro, Giuseppe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141219/
https://www.ncbi.nlm.nih.gov/pubmed/32197359
http://dx.doi.org/10.3390/jcm9030820
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author Madonna, Rosalinda
Pieragostino, Damiana
Cufaro, Maria Concetta
Doria, Vanessa
Del Boccio, Piero
Deidda, Martino
Pierdomenico, Sante Donato
Dessalvi, Christian Cadeddu
De Caterina, Raffaele
Mercuro, Giuseppe
author_facet Madonna, Rosalinda
Pieragostino, Damiana
Cufaro, Maria Concetta
Doria, Vanessa
Del Boccio, Piero
Deidda, Martino
Pierdomenico, Sante Donato
Dessalvi, Christian Cadeddu
De Caterina, Raffaele
Mercuro, Giuseppe
author_sort Madonna, Rosalinda
collection PubMed
description 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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spelling pubmed-71412192020-04-10 Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway Madonna, Rosalinda Pieragostino, Damiana Cufaro, Maria Concetta Doria, Vanessa Del Boccio, Piero Deidda, Martino Pierdomenico, Sante Donato Dessalvi, Christian Cadeddu De Caterina, Raffaele Mercuro, Giuseppe J Clin Med Article 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. MDPI 2020-03-18 /pmc/articles/PMC7141219/ /pubmed/32197359 http://dx.doi.org/10.3390/jcm9030820 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Madonna, Rosalinda
Pieragostino, Damiana
Cufaro, Maria Concetta
Doria, Vanessa
Del Boccio, Piero
Deidda, Martino
Pierdomenico, Sante Donato
Dessalvi, Christian Cadeddu
De Caterina, Raffaele
Mercuro, Giuseppe
Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway
title Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway
title_full Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway
title_fullStr Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway
title_full_unstemmed Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway
title_short Ponatinib Induces Vascular Toxicity through the Notch-1 Signaling Pathway
title_sort ponatinib induces vascular toxicity through the notch-1 signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141219/
https://www.ncbi.nlm.nih.gov/pubmed/32197359
http://dx.doi.org/10.3390/jcm9030820
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