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The suppressive effect of dabrafenib, a therapeutic agent for metastatic melanoma, in IgE-mediated allergic inflammation
- Source :
- International Immunopharmacology. 83:106398
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
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.
- Subjects :
- Male
0301 basic medicine
T-Lymphocytes
Immunology
Antineoplastic Agents
Cell Degranulation
Allergic inflammation
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Oximes
medicine
Animals
Humans
Immunology and Allergy
Calcium Signaling
Mast Cells
Neoplasm Metastasis
Anaphylaxis
Melanoma
Skin
Pharmacology
Mice, Inbred ICR
biology
business.industry
Imidazoles
NF-kappa B
Degranulation
Dabrafenib
Immunoglobulin E
Mast cell
medicine.disease
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
chemistry
030220 oncology & carcinogenesis
Cancer research
biology.protein
Tumor necrosis factor alpha
Interleukin-4
Antibody
business
Histamine
medicine.drug
Subjects
Details
- ISSN :
- 15675769
- Volume :
- 83
- Database :
- OpenAIRE
- Journal :
- International Immunopharmacology
- Accession number :
- edsair.doi.dedup.....8fbb8497e47a283556d5b9f91d159ae3