RT Journal Article
SR Electronic
T1 AGIX-4207 [2-[4-[[1-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic Acid], a Novel Antioxidant and Anti-Inflammatory Compound: Cellular and Biochemical Characterization of Antioxidant Activity and Inhibition of Redox-Sensitive Inflammatory Gene Expression
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 492
OP 501
DO 10.1124/jpet.104.080804
VO 313
IS 2
A1 Charles Kunsch
A1 Jayraz Luchoomun
A1 Xi-lin Chen
A1 Geraldine L. Dodd
A1 Kanika S. Karu
A1 Charles Q. Meng
A1 Elaine M. Marino
A1 Lyn K. Olliff
A1 J. Daniel Piper
A1 Fei-Hua Qiu
A1 James A. Sikorski
A1 Patricia K. Somers
A1 Ki-Ling Suen
A1 Suzanne Thomas
A1 Anne M. Whalen
A1 Martin A. Wasserman
A1 Cynthia L. Sundell
YR 2005
UL http://jpet.aspetjournals.org/content/313/2/492.abstract
AB The pathogenesis of chronic inflammatory diseases, including rheumatoid arthritis, is regulated, at least in part, by modulation of oxidation-reduction (redox) homeostasis and the expression of redox-sensitive inflammatory genes including adhesion molecules, chemokines, and cytokines. AGIX-4207 [2-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetic acid] is a novel, orally active, phenolic antioxidant and anti-inflammatory compound with antirheumatic properties. To elucidate its anti-inflammatory mechanisms, we evaluated AGIX-4207 for a variety of cellular, biochemical, and molecular properties. AGIX-4207 exhibited potent antioxidant activity toward lipid peroxides in vitro and displayed enhanced cellular uptake relative to a structurally related drug, probucol. This resulted in potent inhibition of cellular levels of reactive oxygen species in multiple cell types. AGIX-4207 selectively inhibited tumor necrosis factor (TNF)-α-inducible levels of the redox-sensitive genes, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1, with less inhibition of E-selectin, and no effect on intracellular adhesion molecule-1 expression in endothelial cells. In addition, AGIX-4207 inhibited cytokine-induced levels of monocyte chemoattractant protein-1, interleukin (IL)-6, and IL-8 from endothelial cells and human fibroblast-like synoviocytes as well as lipopolysaccharide-induced release of TNF-α, IL-1β, and IL-6 from human peripheral blood mononuclear cells. AGIX-4207 did not inhibit TNF-α-induced nuclear translocation of nuclear factor of the κ-enhancer in B cells (NF-κB), suggesting that the mechanism of action is independent of this redox-sensitive transcription factor. Taken together, these results provide a mechanistic framework for understanding the anti-inflammatory and antirheumatic activity of AGIX-4207 and provide further support for the view that inhibition of redox-sensitive inflammatory gene expression is an attractive approach for the treatment of chronic inflammatory diseases. The American Society for Pharmacology and Experimental Therapeutics