International immunopharmacology, 2020-06, Vol.83, p.106398-106398, Article 106398
2020
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- Autor(en) / Beteiligte
- Titel
- The suppressive effect of dabrafenib, a therapeutic agent for metastatic melanoma, in IgE-mediated allergic inflammation
- Ist Teil von
- International immunopharmacology, 2020-06, Vol.83, p.106398-106398, Article 106398
- Ort / Verlag
- Netherlands: Elsevier B.V
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- [Display omitted] •Dabrafenib inhibited IgE-induced mast cell activation.•Dabrafenib decreased the activity of signaling molecules (Lyn, Syk, Akt, and PLCγ).•Dabrafenib reduced IL-4 and TNF-α by the inhibition of NF-κB and NFAT.•Dabrafenib ameliorated mast cell-mediated local anaphylaxis. The functional inhibition of mast cells, which serve as a key effector cells in allergic reactions may be a specific target for treating immunoglobulin (Ig)E-mediated allergic reactions, which occur in various allergic diseases including anaphylaxis, asthma, and atopic dermatitis. In this study, we demonstrated the effects of dabrafenib, a therapeutic agent used to treat metastatic melanoma, with a focus on mast cell activation and local cutaneous anaphylaxis. In two types of mast cells (RBL-2H3 and mouse bone marrow-derived mast cells), dabrafenib (0.01, 0.1, 1 μM) pretreatment significantly decreased IgE-induced degranulation, intracellular calcium influx, and the activity of intracellular signaling molecules, such as Lyn, Syk, Akt, and PLCγ. Dabrafenib ameliorated mRNA and protein expression levels of interleukin-4 and tumor necrosis factor-α by the reduction of nuclear localization of nuclear factor-κB and nuclear factor of activated T-cells. In passive cutaneous anaphylaxis, oral administration of dabrafenib (0.1, 1, 10 mg/kg) reduced local pigmentation and ear thickness in a dose-dependent manner. Taken together, these results suggest that dabrafenib is a therapeutic drug candidate that controls IgE-mediated allergic inflammatory diseases through suppression of mast cell activity.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1567-5769eISSN: 1878-1705DOI: 10.1016/j.intimp.2020.106398Titel-ID: cdi_proquest_miscellaneous_2381629360
- Format
- –
- Schlagworte
- AKT protein, Allergic diseases, Allergic reactions, Anaphylaxis, Anaphylaxis - drug therapy, Animals, Antineoplastic Agents - therapeutic use, Asthma, Atopic dermatitis, Bone marrow, Calcium, Calcium (intracellular), Calcium influx, Calcium Signaling, Cell activation, Cell Degranulation - drug effects, Chemical compounds, Dabrafenib, Degranulation, Dermatitis, Disease Models, Animal, Effector cells, Gene expression, Histamine, Humans, Hypersensitivity, IgE-mediated allergic inflammation, IL-4, Imidazoles - therapeutic use, Immunoglobulin E, Immunoglobulin E - metabolism, Inflammatory diseases, Interleukin 4, Interleukin-4 - metabolism, Intracellular, Intracellular signalling, Localization, Lyn protein, Male, Mast cells, Mast Cells - drug effects, Mast Cells - immunology, Melanoma, Melanoma - drug therapy, Metastases, Metastasis, Mice, Mice, Inbred ICR, mRNA, Neoplasm Metastasis, NF-kappa B - metabolism, Oximes - therapeutic use, Pharmacology, Pigmentation, Skin - pathology, T-Lymphocytes - immunology