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

Ghenet K. Hagos, Samer O. Abdul-Hay, Johann Sohn, Praneeth D. Edirisinghe, R. Esala P. Chandrasena, Zhiqiang Wang, Qian Li, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1381-1391
Number of pages11
JournalMolecular pharmacology
Volume74
Issue number5
DOIs
StatePublished - Nov 2008
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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