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

doi:10.3390/ijms22073304

Open AccessArticle

The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

by

María N. Barrachina

^1,†

,

Irene Izquierdo

^1,†,

Lidia Hermida-Nogueira

¹,

Luis A. Morán

¹

,

Amparo Pérez

^2,3

,

Ana B. Arroyo

⁴

,

Nuria García-Barberá

⁴,

Rocío González-Conejero

⁴

,

Sara Troitiño

¹,

Johannes A. Eble

⁵,

José Rivera

⁴

,

Constantino Martínez

⁴

,

María I. Loza

^2,3,

Eduardo Domínguez

^2,3,‡

and

Ángel García

^1,*,‡

¹

Platelet Proteomics Group, Center for Research in Molecular Medicine and Chronic Diseases, Universidade Santiago de Compostela and Instituto de Investigación Sanitaria de Santiago, 15706 Santiago de Compostela, Spain

²

Pharmacology Applied to Drug Discovery Group, Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas, Universidade Santiago de Compostela, 15705 Santiago de Compostela, Spain

³

Grupo Biofarma, Instituto de Investigación Sanitaria de Santiago, 15706 Santiago de Compostela, Spain

⁴

Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, 30003 Murcia, Spain

⁵

Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, 48149 Münster, Germany

^*

Author to whom correspondence should be addressed.

^†

These two authors contributed equally to the work.

^‡

These two authors contributed equally to the work.

Int. J. Mol. Sci. 2021, 22(7), 3304; https://doi.org/10.3390/ijms22073304

Submission received: 18 February 2021 / Revised: 16 March 2021 / Accepted: 19 March 2021 / Published: 24 March 2021

(This article belongs to the Special Issue Novel Molecular Targets in Cardiovascular Diseases)

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Abstract

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.

Keywords: platelets; Idelalisib; PI3K inhibitors

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MDPI and ACS Style

Barrachina, M.N.; Izquierdo, I.; Hermida-Nogueira, L.; Morán, L.A.; Pérez, A.; Arroyo, A.B.; García-Barberá, N.; González-Conejero, R.; Troitiño, S.; Eble, J.A.; et al. The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential. Int. J. Mol. Sci. 2021, 22, 3304. https://doi.org/10.3390/ijms22073304

AMA Style

Barrachina MN, Izquierdo I, Hermida-Nogueira L, Morán LA, Pérez A, Arroyo AB, García-Barberá N, González-Conejero R, Troitiño S, Eble JA, et al. The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential. International Journal of Molecular Sciences. 2021; 22(7):3304. https://doi.org/10.3390/ijms22073304

Chicago/Turabian Style

Barrachina, María N., Irene Izquierdo, Lidia Hermida-Nogueira, Luis A. Morán, Amparo Pérez, Ana B. Arroyo, Nuria García-Barberá, Rocío González-Conejero, Sara Troitiño, Johannes A. Eble, and et al. 2021. "The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential" International Journal of Molecular Sciences 22, no. 7: 3304. https://doi.org/10.3390/ijms22073304

APA Style

Barrachina, M. N., Izquierdo, I., Hermida-Nogueira, L., Morán, L. A., Pérez, A., Arroyo, A. B., García-Barberá, N., González-Conejero, R., Troitiño, S., Eble, J. A., Rivera, J., Martínez, C., Loza, M. I., Domínguez, E., & García, Á. (2021). The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential. International Journal of Molecular Sciences, 22(7), 3304. https://doi.org/10.3390/ijms22073304

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The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential

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