The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils.
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Kneidinger M, Schmidt U, Rix U, Gleixner KV, Vales A, Baumgartner C, Lupinek C, Weghofer M, Bennett KL, Herrmann H, Schebesta A, Thomas WR, Vrtala S, Valenta R, Lee FY, Ellmeier W, Superti-Furga G, Valent P
The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils.
Blood. 2008 Mar 15;111(6):3097-107. doi: 10.1182/blood-2007-08-104372. Epub 2008 Jan 7.
- PubMed ID
- 18180381 [ View in PubMed]
- Abstract
Dasatinib is a multitargeted drug that blocks several tyrosine kinases. Apart from its well-known antileukemic activity, the drug has attracted attention because of potential immunosuppressive and anti-inflammatory effects. We report that dasatinib at 1 microM completely blocks anti-IgE-induced histamine release in blood basophils in healthy donors, and allergen-induced release of histamine in sensitized individuals. In addition, dasatinib inhibited FcepsilonRI-mediated release of IL-4 and IgE-mediated up-regulation of CD13, CD63, CD164, and CD203c in basophils. The effects of dasatinib were dose-dependent (IC(50): 50-500 nM) and specific for FcepsilonRI activation in that the drug failed to inhibit C5a-induced or Ca-ionophore-induced histamine release. Interestingly, at lower concentrations, dasatinib even promoted FcepsilonRI-dependent histamine release in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several FcepsilonRI downstream targets in basophils, including Btk. Correspondingly, FcepsilonRI-mediated histamine secretion in basophils was markedly reduced in Btk knockout mice and in a patient with Btk deficiency. However, the remaining "low-level" mediator secretion in Btk-deficient cells was fully blocked down again by 1 muM dasatinib. Together, these data suggest that dasatinib inhibits FcepsilonRI-mediated activation of basophils through multiple signaling molecules including Btk. Dasatinib may be an interesting agent for immunologic disorders involving Btk-dependent responses or/and FcepsilonRI activation of basophils.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Dasatinib Amidophosphoribosyltransferase Protein Humans UnknownBinderDetails Dasatinib Breakpoint cluster region protein Protein Humans YesInhibitorDetails Dasatinib Ephrin type-A receptor 5 Protein Humans UnknownInhibitorDetails Dasatinib Ephrin type-B receptor 4 Protein Humans UnknownInhibitorDetails Dasatinib Heat shock cognate 71 kDa protein Protein Humans UnknownBinderDetails Dasatinib Mitogen-activated protein kinase 14 Protein Humans UnknownBinderDetails Dasatinib Mitogen-activated protein kinase kinase kinase MLT Protein Humans UnknownBinderDetails Dasatinib Tyrosine-protein kinase CSK Protein Humans UnknownInhibitorDetails Dasatinib Tyrosine-protein kinase Fgr Protein Humans UnknownInhibitorDetails Dasatinib Tyrosine-protein kinase FRK Protein Humans UnknownBinderDetails Dasatinib Tyrosine-protein kinase Lyn Protein Humans UnknownInhibitorDetails