The suppressive effect of dabrafenib, a therapeutic agent for metastatic melanoma, in IgE-mediated allergic inflammation
- Authors
- Choi Y.-A.; Lee S.; Choi J.K.; Kang B.-C.; Kim M.-J.; Dhakal H.; Kwon T.K.; Khang D.; Kim S.-H.
- Issue Date
- Jun-2020
- Publisher
- Elsevier B.V.
- Keywords
- Dabrafenib; Histamine; IgE-mediated allergic inflammation; IL-4; Mast cells
- Citation
- International Immunopharmacology, v.83
- Journal Title
- International Immunopharmacology
- Volume
- 83
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/26429
- DOI
- 10.1016/j.intimp.2020.106398
- ISSN
- 1567-5769
- Abstract
- 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. © 2020 Elsevier B.V.
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