Anti-inflammatory effects of dabrafenib in vitro and in vivo.
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-α (TNF-α) or interleukin (IL)-6 and the activation of nuclear factor-κB (NF-κB) 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.
a Department of Cosmetic Science and Technology, Seowon University, Cheongju 28674, Republic of Korea.
In-Chul
IC
Lee
b Cancer Control Team, Gachon University Gil Medical Center, Incheon 21565, Republic of Korea.
Jongdoo
J
Kim
c College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.
Jong-Sup
JS
Bae
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D019446:Endotoxemia / Q000139:chemically induced / Q000517:prevention & control; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D007093:Imidazoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010091:Oximes; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; C561627:dabrafenib
barrier integrity; dabrafenib; dabrafénib; drug repositioning; inflammation; intégrité de la barrière; lipopolysaccharide; repositionnement des médicaments