Bafetinib inhibits functional responses of human eosinophils in vitro

[EN] 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 +/- 0.04 M; 6.1 +/- 0.04 M; and 6.55 +/- 0.03 M, respectively). Bafetinib, genistein and tyrphostin did not modify the [Ca2+](i); responses to tMLF. Bafetinib inhibited the release of EPO induced by tMLF with higher potency than genistein and tyrphostin (-log IC50=7.24 +/- 0.09 M; 5.36 +/- 0.28 M; and 5.37 +/- 0.19 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 tMLF 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. This work was supported by grants SAF2011-26443 (JC), SAF2012-31042 (EM), FIS CP11/00293(JM), CIBERES (CB06/06/0027), ADE10/00020 and research grants from Regional Government (Prometeo/2008/045, 'Generalitat Valenciana'. TP received a research grant from Conselleria de Educacion, Generalitat Valenciana ACIF/2010/114. Support from the CENIT programme (Spanish Government) was obtained. Milara, J.; Martínez -Losa, M.; Sanz, C.; Almudéver-Folch, P.; Peiró, T.; Serrano, A.; Morcillo, EJ... (2013). Bafetinib inhibits functional responses of human eosinophils in vitro. European Journal of Pharmacology. 715(1-3):172-180. https://doi.org/10.1016/j.ejphar.2013.05.025