Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen, China.
Br J Pharmacol. 2020 Jun;177(12):2848-2859. doi: 10.1111/bph.15012. Epub 2020 Apr 6.
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.
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.
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.
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.
肥大细胞在过敏反应中起着重要作用。在这里，我们评估了抗癌药物托扎替尼（tozasertib）的抗过敏作用，特别是其对肥大细胞激活的调节作用。
通过测量β-己糖胺酶和组胺释放，以及评估 RBL-2H3 细胞和小鼠骨髓来源的肥大细胞（BMMCs）在小鼠抗二硝基苯（DNP）-IgE/DNP-人血清白蛋白或人 LAD2 细胞被佛波醇 12-肉豆蔻酸 13-乙酸酯加钙离子载体（PMACI）激活后形态学变化来确定托扎替尼对肥大细胞脱颗粒的影响。通过蛋白质印迹法检测参与 NF-κB、MAPK 和 Aurora 激酶信号通路的分子的表达。在小鼠 IgE 介导的被动皮肤过敏反应（PCA）和卵清蛋白（OVA）诱导的主动全身性过敏反应（ASA）模型中，研究了托扎替尼的体内抗过敏作用。
托扎替尼治疗降低了高亲和力 IgE 受体（FcεRI）或 PMACI 介导的 RBL-2H3 细胞和 BMMC 或 LAD2 细胞中的脱颗粒作用，表现为β-己糖胺酶或组胺水平降低。同样，托扎替尼防止了肥大细胞的形态变化，如颗粒释放和 F-肌动蛋白重排。此外，托扎替尼显著降低了磷酸化（p）-NF-κB p65、p-Erk1/2、p-p38 和 p-Aurora A/B 的表达，表明托扎替尼可以抑制介导肥大细胞激活的信号通路。托扎替尼以剂量依赖性方式减弱 IgE/Ag 诱导的 PCA，如 Evans 蓝染色减少所示。同样，托扎替尼降低了 OVA 挑战的 ASA 小鼠的体温水平和血清组胺水平。
Aurora 激酶抑制剂托扎替尼抑制了体外和体内肥大细胞的激活。托扎替尼可能是一种潜在的药物，可靶向肥大细胞激活，用于治疗过敏疾病或肥大细胞增多症。
