title: Dasatinib inhibits proinflammatory functions of mature human neutrophils.
abstract: Dasatinib is a tyrosine kinase inhibitor used to treat imatinib-resistant chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. At present, little is known about how dasatinib influences nonmalignant cells. In the present study, we tested the effect of dasatinib on functional responses of normal mature human neutrophils. Dasatinib completely blocked integrin- and Fc-receptor-mediated neutrophil functions, with the lowest IC(50) values below 10nM under serum-free conditions. Dasatinib caused a partial inhibition of neutrophil responses triggered by G-protein-coupled receptors and had a moderate effect on neutrophil responses triggered by microbial compounds. Whereas dasatinib inhibited neutrophil chemotaxis under static conditions in 2 dimensions, it did not affect migration under flow conditions or in 3-dimensional environments. Dasatinib did not have any major effect on phagocytosis or killing of bacteria by neutrophils. Adhesion of human neutrophils in the presence of whole serum was significantly inhibited by 50-100nM dasatinib, which corresponds to the reported serum concentrations in dasatinib-treated patients. Finally, ex vivo adhesion of mouse peripheral blood neutrophils was strongly reduced after oral administration of 5 mg/kg of dasatinib. Those results suggest that dasatinib treatment may affect the proinflammatory functions of mature neutrophils and raise the possibility that dasatinib-related compounds may provide clinical benefit in neutrophil-mediated inflammatory diseases.
authors.affiliation: Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Futosi
authors.forename: Tamás
authors.initials: T
authors.lastname: Németh
authors.forename: Robert
authors.initials: R
authors.lastname: Pick
authors.forename: Tibor
authors.initials: T
authors.lastname: Vántus
authors.forename: Barbara
authors.initials: B
authors.lastname: Walzog
authors.forename: Attila
authors.initials: A
authors.lastname: Mócsai
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D016897:Respiratory Burst / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D018836:Inflammation Mediators; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib