PMID- 28177661
OWN - NLM
STAT- MEDLINE
DCOM- 20180109
LR  - 20180109
IS  - 1205-7541 (Electronic)
IS  - 0008-4212 (Linking)
VI  - 95
IP  - 6
DP  - 2017 Jun
TI  - Anti-inflammatory effects of dabrafenib in vitro and in vivo.
PG  - 697-707
LID - 10.1139/cjpp-2016-0519 [doi]
AB  - 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-kappaB (NF-kappaB) 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.
FAU - Lee, In-Chul
AU  - Lee IC
AD  - a Department of Cosmetic Science and Technology, Seowon University, Cheongju 
      28674, Republic of Korea.
FAU - Kim, Jongdoo
AU  - Kim J
AD  - b Cancer Control Team, Gachon University Gil Medical Center, Incheon 21565, 
      Republic of Korea.
FAU - Bae, Jong-Sup
AU  - Bae JS
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20170203
PL  - Canada
TA  - Can J Physiol Pharmacol
JT  - Canadian journal of physiology and pharmacology
JID - 0372712
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Imidazoles)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-kappa B)
RN  - 0 (Oximes)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - QGP4HA4G1B (dabrafenib)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology/therapeutic use
MH  - Blood Vessels/drug effects/metabolism
MH  - Cell Adhesion/drug effects
MH  - Cell Adhesion Molecules/metabolism
MH  - Cell Movement/drug effects
MH  - Endotoxemia/chemically induced/prevention & control
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Human Umbilical Vein Endothelial Cells/drug effects/metabolism
MH  - Humans
MH  - Imidazoles/*pharmacology/therapeutic use
MH  - Interleukin-6/biosynthesis
MH  - Lipopolysaccharides/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NF-kappa B/metabolism
MH  - Neutrophils/cytology/drug effects
MH  - Oximes/*pharmacology/therapeutic use
MH  - Tumor Necrosis Factor-alpha/biosynthesis
OTO - NOTNLM
OT  - barrier integrity
OT  - dabrafenib
OT  - dabrafenib
OT  - drug repositioning
OT  - inflammation
OT  - integrite de la barriere
OT  - lipopolysaccharide
OT  - repositionnement des medicaments
EDAT- 2017/02/09 06:00
MHDA- 2018/01/10 06:00
CRDT- 2017/02/09 06:00
PHST- 2017/02/09 06:00 [pubmed]
PHST- 2018/01/10 06:00 [medline]
PHST- 2017/02/09 06:00 [entrez]
AID - 10.1139/cjpp-2016-0519 [doi]
PST - ppublish
SO  - Can J Physiol Pharmacol. 2017 Jun;95(6):697-707. doi: 10.1139/cjpp-2016-0519. 
      Epub 2017 Feb 3.