Received for publication February 29, 2008.
Revised August 1, 2008.
Accepted for publication August 1, 2008.

Anti-inflammatory, antiproliferative, and cytoprotective activity of NO chimera nitrates of use in cancer chemoprevention

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) have shown promise in colorectal cancer (CRC), but are compromised by gastrotoxicity. NO-NSAIDs are hybrid nitrates conjugated to an NSAID designed to exploit the gastroprotective properties of NO bioactivity. The NO chimera, GT-094, a novel nitrate containing an NSAID and disulfide pharmacophores, is effective in vivo in rat models of CRC and is a lead compound for design of agents of use in CRC. Preferred chemopreventive agents possess: (1) antiproliferative and (2) anti-inflammatory actions; and (3), the ability to induce cytoprotective phase 2 enzymes. To determine the contribution of each pharmacophore to the biological activity of GT-094, these 3 biological activities were studied in vitro in compounds that deconstructed the structural elements of the lead, GT-094. The anti-inflammatory and antiproliferative actions of GT-094 in vivo were recapitulated in vitro; and, GT-094 was seen to induce phase 2 enzymes via the antioxidant response element (ARE). In the variety of colon, macrophage-like, and liver cell lines studied, the evidence from structure-activity relationships was that the disulfide structural element of GT-094 is the dominant contributor in vitro to the anti-inflammatory activity, antiproliferation, and enzyme induction. The results provide a direction for lead compound refinement. The evidence for a contribution from the NO mimetic activity of nitrates in vitro was equivocal and combinations of nitrates with ASA were inactive.

Key words: Nitric oxide, Nitric oxide synthases, MAP Kinase, Structure-activity relationships and modeling, Phase II enzymes, Quinone oxidoreductase, Structure/function/mechanism, Mechanisms of cell killing/apoptosis