The suppressive effect of dabrafenib, a therapeutic agent for metastatic melanoma, in IgE-mediated allergic inflammation.

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.

• Authors: Young-Ae Choi, Soyoung Lee, Jin Kyeong Choi, Byeong-Cheol Kang, Min-Jong Kim, Hima Dhakal, Taeg Kyu Kwon, Dongwoo Khang, Sang-Hyun Kim
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 83 Pg. 106398 (Jun 2020) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 32197228 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Imidazoles
• NF-kappa B
• Oximes
• Interleukin-4
• Immunoglobulin E
• dabrafenib

Topics

• Anaphylaxis (drug therapy)
• Animals
• Antineoplastic Agents (therapeutic use)
• Calcium Signaling
• Cell Degranulation (drug effects)
• Disease Models, Animal
• Humans
• Imidazoles (therapeutic use)
• Immunoglobulin E (metabolism)
• Interleukin-4 (metabolism)
• Male
• Mast Cells (drug effects, immunology)
• Melanoma (drug therapy)
• Mice
• Mice, Inbred ICR
• NF-kappa B (metabolism)
• Neoplasm Metastasis
• Oximes (therapeutic use)
• Skin (pathology)
• T-Lymphocytes (immunology)