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 antiallergic 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 OVAchallenged 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.

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

“…Our results showing that T-5224 reduced FcεRI-mediated degranulation in MCs were similar to previously reported effects of palbociclib (cyclin-dependent kinase inhibitor) and tozasertib (Aurora kinase inhibitor) [ 22 , 52 ]. Mechanistically, T-5224 decreased IgE/Ag-induced expression of EGR1 and IL4 and also blocked MAPK activation in activated MCs.…”

“…Mechanistically, T-5224 decreased IgE/Ag-induced expression of EGR1 and IL4 and also blocked MAPK activation in activated MCs. A variety of established medicines, including omeprazole (proton pump inhibitor) [ 7 ], tozasertib [ 52 ], and berberine (adenosine monophosphate-activated protein kinase stimulator) [ 53 ] inhibit MC activation-associated MAPK signaling. Meanwhile, T-5224 did not affect maturation of precursor cells into MCs (Additional file 1 : Figure S5).…”

Vorinostat (SAHA) and Breast Cancer: An Overview

“…MK-0457 (VX-680) is a small-molecule aurora kinase (AK) inhibitor [142,143] with preclinical anticancer activity [144]. MK-0457 has been assessed in phase II clinical trials in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) with the T315I mutation or treatment-refractory chronic myelogenous leukemia (CML) [145].…”

Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells

“…The function of Aurora C kinase is not well established, but studies suggested it has similar function to Aurora B kinase ( Sasai et al, 2004 ; Yan et al, 2005 ). There are several Aurora kinase inhibitors that have progressed to clinical development, including tozasertib ( Zhang et al, 2020 ), barasertib ( Floc’h et al, 2019 ) and MK-5108 ( Amin et al, 2016 ). Previous studies showed that GSK-1070916 has a broad antitumor effect on cancer cell lines and in tumor xenograft models including lung, breast, colorectal, and leukemia ( Hardwicke et al, 2009 ).…”