US EPA

477445 

Journal Article 

Anti-Inflammatory, Antiproliferative, and Cytoprotective Activity of NO Chimera Nitrates of Use in Cancer Chemoprevention 

Hagos, GK; Abdul-Hay, SO; Sohn, J; Edirisinghe, PD; Chandrasena, REP; Wang, ZQ; Li, Q; Thatcher, GRJ 

2008 

1 

Molecular Pharmacology
ISSN: 0026-895X
EISSN: 1521-0111 

74 

5 

1381-1391 

English 

18676677 

10.1124/mol.108.046664 

WOS:000260197300021 

Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown promise in colorectal cancer (CRC), but they 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 ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl) benzoate (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 three 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 responsive element. 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 acetylsalicylic acid were inactive. 

oxide-donating aspirin; aberrant crypt foci; phase-ii enzymes; nitric-oxide; colon-cancer; in-vitro; organosulfur compounds; growth-inhibition; quinone reductase; oxidative stress