The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential
Year: 2021
Type: article
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.
DOI: 10.3390/ijms22073304
Institutions: Universidade de Santiago de Compostela, Center for Research in Molecular Medicine and Chronic Diseases, Instituto de Investigación Sanitaria de Santiago, Hospital General Universitario Morales Meseguer, Centro Regional de Hemodonación, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, University of Münster
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,160
Funders: European Commission, Deutsche Forschungsgemeinschaft, Ministerio de Ciencia e Innovación, Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia, Xunta de Galicia, Universidade de Santiago de Compostela, Centro Singular de Investigación de Galicia, Instituto de Salud Carlos III, European Regional Development Fund
Awards: G1086277346, G1244566133, G128883266, G1299844349, G1388518385, TArgeting Platelet Adhesion receptors in thrombosiS, Regulación de la función de neutrófilos y plaquetas por miR-146a en NETosis; consecuencias en trombogénesis y potencial terapéutico, G1869016439, Caracterización funcional, molecular y desarrollo de un modelo de complementación génica en trastornos plaquetarios congénitos, G2238108805, G2376970883, G2538972755, G2673512141, G2826832531, G3325634151, G3671390842, G3690828678, G3809793926, G3876637791, G4063934198, G4180404498, G4747059148, G4912030886, G5285838445, G5970400361, G6857042362, G692825579, G7163626064, G7542015120, G786174116
OpenAlex ID: W3136531285