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The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatele...

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Autores principales: Barrachina, María N., Izquierdo, Irene, Hermida-Nogueira, Lidia, Morán, Luis A., Pérez, Amparo, Arroyo, Ana B., García-Barberá, Nuria, González-Conejero, Rocío, Troitiño, Sara, Eble, Johannes A., Rivera, José, Martínez, Constantino, Loza, María I., Domínguez, Eduardo, García, Ángel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037016/
https://www.ncbi.nlm.nih.gov/pubmed/33804911
http://dx.doi.org/10.3390/ijms22073304
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author Barrachina, María N.
Izquierdo, Irene
Hermida-Nogueira, Lidia
Morán, Luis A.
Pérez, Amparo
Arroyo, Ana B.
García-Barberá, Nuria
González-Conejero, Rocío
Troitiño, Sara
Eble, Johannes A.
Rivera, José
Martínez, Constantino
Loza, María I.
Domínguez, Eduardo
García, Ángel
author_facet Barrachina, María N.
Izquierdo, Irene
Hermida-Nogueira, Lidia
Morán, Luis A.
Pérez, Amparo
Arroyo, Ana B.
García-Barberá, Nuria
González-Conejero, Rocío
Troitiño, Sara
Eble, Johannes A.
Rivera, José
Martínez, Constantino
Loza, María I.
Domínguez, Eduardo
García, Ángel
author_sort Barrachina, María N.
collection PubMed
description Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. Results: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. Conclusion: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans.
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spelling pubmed-80370162021-04-12 The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential Barrachina, María N. Izquierdo, Irene Hermida-Nogueira, Lidia Morán, Luis A. Pérez, Amparo Arroyo, Ana B. García-Barberá, Nuria González-Conejero, Rocío Troitiño, Sara Eble, Johannes A. Rivera, José Martínez, Constantino Loza, María I. Domínguez, Eduardo García, Ángel Int J Mol Sci Article Background: Clinical management of ischemic events and prevention of vascular disease is based on antiplatelet drugs. Given the relevance of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) as a candidate target in thrombosis, the main goal of the present study was to identify novel antiplatelet agents within the existing inhibitors blocking PI3K isoforms. Methods: We performed a biological evaluation of the pharmacological activity of PI3K inhibitors in platelets. The effect of the inhibitors was evaluated in intracellular calcium release and platelet functional assays, the latter including aggregation, adhesion, and viability assays. The in vivo drug antithrombotic potential was assessed in mice undergoing chemically induced arterial occlusion, and the associated hemorrhagic risk evaluated by measuring the tail bleeding time. Results: We show that PI3K Class IA inhibitors potently block calcium mobilization in human platelets. The PI3K p110δ inhibitor Idelalisib inhibits platelet aggregation mediated by ITAM receptors GPVI and CLEC-2, preferentially by the former. Moreover, Idelalisib also inhibits platelet adhesion and aggregation under shear and adhesion to collagen. Interestingly, an antithrombotic effect was observed in mice treated with Idelalisib, with mild bleeding effects at high doses of the drug. Conclusion: Idelalisib may have antiplatelet effects with minor bleeding effects, which provides a rationale to evaluate its antithrombotic efficacy in humans. MDPI 2021-03-24 /pmc/articles/PMC8037016/ /pubmed/33804911 http://dx.doi.org/10.3390/ijms22073304 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Barrachina, María N.
Izquierdo, Irene
Hermida-Nogueira, Lidia
Morán, Luis A.
Pérez, Amparo
Arroyo, Ana B.
García-Barberá, Nuria
González-Conejero, Rocío
Troitiño, Sara
Eble, Johannes A.
Rivera, José
Martínez, Constantino
Loza, María I.
Domínguez, Eduardo
García, Ángel
The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential
title The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential
title_full The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential
title_fullStr The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential
title_full_unstemmed The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential
title_short The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential
title_sort pi3kδ inhibitor idelalisib diminishes platelet function and shows antithrombotic potential
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037016/
https://www.ncbi.nlm.nih.gov/pubmed/33804911
http://dx.doi.org/10.3390/ijms22073304
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