Bafetinib inhibits functional responses of human eosinophils in vitro

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• 作者：Javier Milara ; Maleles Martinez-Losa ; Celia Sanz ; Patricia Almud¨¦ver ; Teresa Peir¨® ; Adela Serrano ; Esteban Jesus Morcillo ; Crist¨®bal Zaragoz¨¢ ; Julio Cortijo
• 关键词：Bafetinib ; Eosinophils ; Protein tyrosine kinase ; Inflammation
• 刊名：European Journal of Pharmacology
• 出版年：2013
• 出版时间：5 September, 2013
• 年：2013
• 卷：715
• 期：1-3
• 页码：172-180
• 全文大小：1957 K

文摘

Eosinophils play a prominent role in the process of allergic inflammation. Non-receptor associated Lyn tyrosine kinases generate key initial signals in eosinophils. Bafetinib, a specific Abl/Lyn tyrosine kinase inhibitor has shown a potent antiproliferative activity in leukemic cells, but its effects on eosinophils have not been reported. Therefore, we studied the effects of bafetinib on functional and mechanistic responses of isolated human eosinophils. Bafetinib was more potent than non-specific tyrosin kinase comparators genistein and tyrphostin inhibiting superoxide anion triggered by N-formyl-Met-Leu-Phe (fMLF; 100 nM) (?log IC₅₀=7.25¡À0.04 M; 6.1¡À0.04 M; and 6.55¡À0.03 M, respectively). Bafetinib, genistein and tyrphostin did not modify the [Ca²⁺]_i responses to fMLF. Bafetinib inhibited the release of EPO induced by fMLF with higher potency than genistein and tyrphostin (?log IC₅₀=7.24¡À0.09 M; 5.36¡À0.28 M; and 5.37¡À0.19 M, respectively), and nearly suppressed LTC₄, ECP and chemotaxis. Bafetinib, genistein and tyrphostin did not change constitutive apoptosis. However bafetinib inhibited the ability of granulocyte-monocyte colony-stimulating factor to prevent apoptosis. The activation of Lyn tyrosine kinase, p-ERK1/2 and p-38 induced by fMLF was suppressed by bafetinib and attenuated by genistein and tyrphostin. In conclusion, bafetinib inhibits oxidative burst and generation of inflammatory mediators, and reverses the eosinophil survival. Therefore, future anti-allergic therapies based on bafetinib, could help to suppress excessive inflammatory response of eosinophils at inflammatory sites.