Anti-inflammatory effects of dabrafenib in vitro and in vivo
- Authors
- Lee, In-Chul; Kim, Jongdoo; Bae, Jong-Sup
- Issue Date
- Jun-2017
- Publisher
- CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS
- Keywords
- drug repositioning; dabrafenib; lipopolysaccharide; inflammation; barrier integrity
- Citation
- CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, v.95, no.6, pp.697 - 707
- Journal Title
- CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
- Volume
- 95
- Number
- 6
- Start Page
- 697
- End Page
- 707
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/6074
- DOI
- 10.1139/cjpp-2016-0519
- ISSN
- 0008-4212
- Abstract
- The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases (drug repositioning). Drug repositioning refers to the development of existing drugs for new indications. Dabrafenib (DAB) is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. Here, we tested the possible use of DAB in the treatment of lipopolysaccharide (LPS)-mediated vascular inflammatory responses. The anti-inflammatory activities of DAB were determined by measuring permeability, neutrophils adhesion and migration, and activation of pro-inflammatory proteins in LPS-activated human umbilical vein endothelial cells (HUVECs) and mice. We found that DAB inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs), and adhesion and transendothelial migration of neutrophils to human endothelial cells. DAB also suppressed LPS-induced hyperpermeability and leukocytes migration in vivo. Furthermore, DAB suppressed the production of tumor necrosis factor-alpha (TNF-alpha) or interleukin (IL)-6 and the activation of nuclear factor-kappa B (NF-kappa B) or extracellular regulated kinases (ERK) 1/2 by LPS. Moreover, treatment with DAB resulted in reduced LPS-induced lethal endotoxemia. These results suggest that DAB possesses anti-inflammatory functions by inhibiting hyperpermeability, expression of CAMs, and adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases.
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