PMID- 32017040
OWN - NLM
STAT- MEDLINE
DCOM- 20210621
LR  - 20220601
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 177
IP  - 12
DP  - 2020 Jun
TI  - Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and 
      in vivo.
PG  - 2848-2859
LID - 10.1111/bph.15012 [doi]
AB  - 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 beta-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-kappaB, 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 (FcepsilonRI) or PMACI-mediated degranulation in RBL-2H3 
      cells and in BMMCs or LAD2 cells as shown by beta-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-kappaB 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.
CI  - (c) 2020 The British Pharmacological Society.
FAU - Zhang, Li-Na
AU  - Zhang LN
AUID- ORCID: 0000-0003-4837-3810
AD  - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen 
      University, Shenzhen, China.
FAU - Ji, Kunmei
AU  - Ji K
AUID- ORCID: 0000-0002-5754-8697
AD  - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen 
      University, Shenzhen, China.
FAU - Sun, Yue-Tong
AU  - Sun YT
AUID- ORCID: 0000-0002-6691-1283
AD  - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen 
      University, Shenzhen, China.
FAU - Hou, Yi-Bo
AU  - Hou YB
AUID- ORCID: 0000-0001-5582-5243
AD  - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen 
      University, Shenzhen, China.
FAU - Chen, Jia-Jie
AU  - Chen JJ
AUID- ORCID: 0000-0002-1372-8450
AD  - Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen 
      University, Shenzhen, China.
LA  - eng
GR  - Shenzhen City 2016 Biochemistry Discipline Construction/
GR  - JCYJ20170818142053544/Natural Science Foundation of Shenzhen City/
GR  - JCYJ20180305163311448/Natural Science Foundation of Shenzhen City/
GR  - 2016A030313039/Natural Science Foundation of Guangdong Province/
GR  - 2017A010105014/Natural Science Foundation of Guangdong Province/
GR  - 2018A050506083/Natural Science Foundation of Guangdong Province/
GR  - 81571570/National Natural Science Foundation of China/
GR  - 81602595/National Natural Science Foundation of China/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200406
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Piperazines)
RN  - 234335M86K (tozasertib)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - EC 2.7.11.1 (Aurora Kinases)
SB  - IM
MH  - Animals
MH  - Aurora Kinases
MH  - Cell Degranulation
MH  - *Immunoglobulin E
MH  - *Mast Cells
MH  - Mice
MH  - Passive Cutaneous Anaphylaxis
MH  - Piperazines
PMC - PMC7236079
COIS- The authors declare no conflicts of interest.
EDAT- 2020/02/06 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/06/01
CRDT- 2020/02/05 06:00
PHST- 2019/06/18 00:00 [received]
PHST- 2019/12/15 00:00 [revised]
PHST- 2020/01/22 00:00 [accepted]
PHST- 2020/02/06 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/02/05 06:00 [entrez]
PHST- 2021/06/01 00:00 [pmc-release]
AID - BPH15012 [pii]
AID - 10.1111/bph.15012 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2020 Jun;177(12):2848-2859. doi: 10.1111/bph.15012. Epub 2020 Apr 
      6.