Received for publication November 17, 2004.
Revised February 1, 2005.
Accepted for publication February 1, 2005.

AGIX-4207, a novel antioxidant and anti-inflammatory compound: I. Cellular and biochemical characterization of antioxidant activity and inhibition of redox-sensitive inflammatory gene expression

Abstract

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 anti-rheumatic 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 towards 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 TNF--inducible levels of the redox-sensitive genes, VCAM-1 and MCP-1, with less inhibition of E-selectin, and no effect on ICAM-1 expression in endothelial cells. In addition, AGIX-4207 inhibited cytokine-induced levels of MCP-1, IL-6 and IL-8 from endothelial cells and human fibroblast-like synoviocytes as well as LPS-induced release of TNF-, IL-1 and IL-6 from human peripheral blood mononuclear cells. AGIX-4207 did not inhibit TNF--induced nuclear translocation of NF-B 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 anti-rheumatic 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.

Key words: anti-inflammatory, antioxidant, inflammation, redox, rheumatoid arthritis, vascular cell adhesion molecule-1

This article has been cited by other articles:

				J. P. Luyendyk, J. D. Piper, M. Tencati, K. V. Reddy, T. Holscher, R. Zhang, J. Luchoomun, X. Chen, W. Min, C. Kunsch, et al. A Novel Class of Antioxidants Inhibit LPS Induction of Tissue Factor by Selective Inhibition of the Activation of ASK1 and MAP Kinases Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1857 - 1863. [Abstract] [Full Text] [PDF]

				X.-L. Chen, G. Dodd, S. Thomas, X. Zhang, M. A. Wasserman, B. H. Rovin, and C. Kunsch Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1862 - H1870. [Abstract] [Full Text] [PDF]