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The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Impairs the Vascular Development of Zebrafish Larvae

Ibrutinib is an orally bioavailable, irreversible selective Bruton’s tyrosine kinase inhibitor that has demonstrated impressive therapeutic effects in patients with B cell malignancies. However, adverse effects, such as bleeding and hypertension, are also reported, implying that studies on the toxic...

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Detalles Bibliográficos
Autores principales: Wang, Kun, Xu, Qiushi, Zhong, Hanbing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838594/
https://www.ncbi.nlm.nih.gov/pubmed/33519491
http://dx.doi.org/10.3389/fphar.2020.625498
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author Wang, Kun
Xu, Qiushi
Zhong, Hanbing
author_facet Wang, Kun
Xu, Qiushi
Zhong, Hanbing
author_sort Wang, Kun
collection PubMed
description Ibrutinib is an orally bioavailable, irreversible selective Bruton’s tyrosine kinase inhibitor that has demonstrated impressive therapeutic effects in patients with B cell malignancies. However, adverse effects, such as bleeding and hypertension, are also reported, implying that studies on the toxicological effect of ibrutinib on living organisms are needed. Here, we have used zebrafish, a successful model organism for studying toxicology, to investigate the influence of ibrutinib during embryogenesis. We found that ibrutinib had potent toxicity on embryonic development, especially vascular development in zebrafish embryos. We also revealed that ibrutinib perturbed vascular formation by suppressing angiogenesis, rather than vasculogenesis. In addition, ibrutinib exposure led to the collapse of the vascular lumen, as well as reduced proliferation and enhanced apoptosis of vascular endothelial cells. Moreover, the expression of vascular development-related genes was also altered in ibrutinib-treated embryos. To our knowledge, this is the first study to describe the vascular toxicity of ibrutinib in an animal model, providing a theoretical basis for clinical safety guidelines in ibrutinib treatment.
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spelling pubmed-78385942021-01-28 The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Impairs the Vascular Development of Zebrafish Larvae Wang, Kun Xu, Qiushi Zhong, Hanbing Front Pharmacol Pharmacology Ibrutinib is an orally bioavailable, irreversible selective Bruton’s tyrosine kinase inhibitor that has demonstrated impressive therapeutic effects in patients with B cell malignancies. However, adverse effects, such as bleeding and hypertension, are also reported, implying that studies on the toxicological effect of ibrutinib on living organisms are needed. Here, we have used zebrafish, a successful model organism for studying toxicology, to investigate the influence of ibrutinib during embryogenesis. We found that ibrutinib had potent toxicity on embryonic development, especially vascular development in zebrafish embryos. We also revealed that ibrutinib perturbed vascular formation by suppressing angiogenesis, rather than vasculogenesis. In addition, ibrutinib exposure led to the collapse of the vascular lumen, as well as reduced proliferation and enhanced apoptosis of vascular endothelial cells. Moreover, the expression of vascular development-related genes was also altered in ibrutinib-treated embryos. To our knowledge, this is the first study to describe the vascular toxicity of ibrutinib in an animal model, providing a theoretical basis for clinical safety guidelines in ibrutinib treatment. Frontiers Media S.A. 2021-01-13 /pmc/articles/PMC7838594/ /pubmed/33519491 http://dx.doi.org/10.3389/fphar.2020.625498 Text en Copyright © 2021 Wang, Xu and Zhong http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Wang, Kun
Xu, Qiushi
Zhong, Hanbing
The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Impairs the Vascular Development of Zebrafish Larvae
title The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Impairs the Vascular Development of Zebrafish Larvae
title_full The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Impairs the Vascular Development of Zebrafish Larvae
title_fullStr The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Impairs the Vascular Development of Zebrafish Larvae
title_full_unstemmed The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Impairs the Vascular Development of Zebrafish Larvae
title_short The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Impairs the Vascular Development of Zebrafish Larvae
title_sort bruton’s tyrosine kinase inhibitor ibrutinib impairs the vascular development of zebrafish larvae
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838594/
https://www.ncbi.nlm.nih.gov/pubmed/33519491
http://dx.doi.org/10.3389/fphar.2020.625498
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