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Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo.

Abstract：

BACKGROUND AND PURPOSE:Mast cells are important in allergic reactions. Here, we assessed the anti-allergic effects of the anti-cancer drug tozasertib specifically regarding regulatory effects on mast cell activation. EXPERIMENTAL APPROACH:Tozasertib effects on mast cell degranulation were determined by measuring β-hexosaminidase and histamine release and by assessing morphological changes in RBL-2H3 and mouse bone marrow-derived mast cells (BMMCs) stimulated with mouse anti-dinitrophenyl (DNP)-IgE/DNP-human serum albumin or human LAD2 cells activated with phorbol-12-myristate 13-acetate plus calcium ionophore (PMACI). Western blots were performed to detect the expression of molecules involved in NF-κB, MAPK, and Aurora kinase signalling. in vivo anti-allergic effects of tozasertib were determined in the murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models. KEY RESULTS:Tozasertib treatment decreased high-affinity IgE receptor (FcεRI) or PMACI-mediated degranulation in RBL-2H3 cells and in BMMCs or LAD2 cells as shown by β-hexosaminidase or histamine levels. Similarly, tozasertib prevented morphological changes in mast cells, such as particle release and F-actin reorganization. In addition, tozasertib markedly decreased expression of phosphorylated (p)-NF-κB p65, p-Erk1/2, p-p38, and p-Aurora A/B, indicating that tozasertib can inhibit the signalling pathway mediating mast cell activation. Tozasertib attenuated IgE/Ag-induced PCA dose-dependently, as shown by reduced Evans blue staining. Similarly, tozasertib reduced body temperature levels and serum histamine levels in OVA-challenged ASA mice. CONCLUSION AND IMPLICATIONS:The Aurora kinase inhibitor tozasertib suppressed mast cell activation in vitro and in vivo. Tozasertib may be a potential drug, targeting mast cell activation, to treat allergic diseases or mastocytosis.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Zhang LN,Ji K,Sun YT,Hou YB,Chen JJ

doi

10.1111/bph.15012

subject

Has Abstract

pub_date

2020-06-01 00:00:00

pages

2848-2859

issue

eissn

0007-1188

issn

1476-5381

journal_volume

177

pub_type

杂志文章

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Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo.