RT Journal Article
T1 The PI3Kδ Inhibitor Idelalisib Diminishes Platelet Function and Shows Antithrombotic Potential
A1 Barrachina, María N.
A1 Izquierdo, Irene
A1 Hermida Nogueira, Lidia
A1 Morán, Luis A.
A1 Pérez, Amparo
A1 Arroyo, Ana B.
A1 García Barberá, Nuria
A1 González Conejero, Rocío
A1 Troitiño, Sara
A1 Eble, Johannes A.
A1 Rivera, José
A1 Martínez, Constantino
A1 Loza García, María Isabel
A1 Domínguez, Eduardo
A1 García Alonso, Ángel
K1 platelets
K1 Idelalisib
K1 PI3K inhibitors
AB 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.
PB MDPI
SN 1661-6596
YR 2021
FD 2021-03-24
LK https://hdl.handle.net/10347/45317
UL https://hdl.handle.net/10347/45317
LA eng
NO Int. J. Mol. Sci. 2021, 22(7), 3304; https://doi.org/10.3390/ijms22073304
DS Minerva
RD 27 abr 2026