RT Journal Article
SR Electronic
T1 Anti-Inflammatory, Antiproliferative, and Cytoprotective Activity of NO Chimera Nitrates of Use in Cancer Chemoprevention
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1381
OP 1391
DO 10.1124/mol.108.046664
VO 74
IS 5
A1 Hagos, Ghenet K.
A1 Abdul-Hay, Samer O.
A1 Sohn, Johann
A1 Edirisinghe, Praneeth D.
A1 Chandrasena, R. Esala P.
A1 Wang, Zhiqiang
A1 Li, Qian
A1 Thatcher, Gregory R. J.
YR 2008
UL http://molpharm.aspetjournals.org/content/74/5/1381.abstract
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