title: Bafetinib inhibits functional responses of human eosinophils in vitro.
abstract: 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 [Ca(2+)]i responses to fMLF. Bafetinib inhibited the release of EPO induced by fMLF 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 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.
authors.affiliation: Clinical Research Unit (UIC), University General Hospital Consortium, Av. tres cruces s/n, Valencia E-46014, Spain. xmilara@hotmail.com
authors.forename: Javier
authors.initials: J
authors.lastname: Milara
authors.forename: Maleles
authors.initials: M
authors.lastname: Martinez-Losa
authors.forename: Celia
authors.initials: C
authors.lastname: Sanz
authors.forename: Patricia
authors.initials: P
authors.lastname: Almudéver
authors.forename: Teresa
authors.initials: T
authors.lastname: Peiró
authors.forename: Adela
authors.initials: A
authors.lastname: Serrano
authors.forename: Esteban Jesus
authors.initials: EJ
authors.lastname: Morcillo
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Zaragozá
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D047150:Eosinophil Cationic Protein / Q000096:biosynthesis; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology; D017997:Leukotriene C4 / Q000096:biosynthesis; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
chemical_list: D015848:Interleukin-5; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013481:Superoxides; D017997:Leukotriene C4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009195:Peroxidase; D047150:Eosinophil Cationic Protein; C506918:bafetinib; D002118:Calcium
keywords: Bafetinib; Eosinophils; Inflammation; Protein tyrosine kinase