PT  - JOURNAL ARTICLE
AU  - Ghenet K. Hagos
AU  - Samer O. Abdul-Hay
AU  - Johann Sohn
AU  - Praneeth D. Edirisinghe
AU  - R. Esala P. Chandrasena
AU  - Zhiqiang Wang
AU  - Qian Li
AU  - Gregory R. J. Thatcher
TI  - Anti-Inflammatory, Antiproliferative, and Cytoprotective Activity of NO Chimera Nitrates of Use in Cancer Chemoprevention
AID  - 10.1124/mol.108.046664
DP  - 2008 Nov 01
TA  - Molecular Pharmacology
PG  - 1381--1391
VI  - 74
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/74/5/1381.short
4100  - http://molpharm.aspetjournals.org/content/74/5/1381.full
SO  - Mol Pharmacol2008 Nov 01; 74
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics