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.
Footnotes
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This research was funded in part by National Institutes of Health grants CA102590 and CA121107.
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ABBREVIATIONS: CRC, colorectal cancer; ACF, aberrant crypt foci; AOM, azoxymethane; iNOS, inducible nitric-oxide synthase; NSAID nonsteroidal anti-inflammatory drug; ASA, aspirin; GI, gastrointestinal; NO-NSAID, NO-donating nonsteroidal anti-inflammatory drug; BECS, 1,2-bis-(2-ethoxycarbonylphenyl)sulfane; FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; ARE, antioxidant responsive element; LPS, lipopolysaccharide; l-NAME, Nω-nitro-l-arginine methyl ester; CM, conditioned media; PBS, phosphate buffered saline; ERK, extracellular signal-regulated kinase; ERK, extracellular signal-regulated kinase; NQO1, NAD(P)H-dependent quinone oxidoreductase; CI, chemopreventive index; RT-PCR, reverse transcription-polymerase chain reaction; TNF, tumor necrosis factor; IL, interleukin; COX, cyclooxygenase; PG, prostaglandin; SPE/NO, spermine diazeniumdiolate salt; DETA/NO, diethyltriamine diazeniumdiolate; BF, 4′-bromoflavone; ISDN, isosorbide dinitrate; PTIO, 2-phenyl-4,4,5,5-tetramethylimidazoline-l-oxyl-3-oxide; CD, concentration required to double the specific activity of NAD(P)H-dependent quinone oxidoreductase; ODQ, 1H-[1,2,4]oxadiazolo[3,4-a]quinoxalin-1-one; MAPK, mitogen-activated protein kinase; PD 98059, 2′-amino-3′-methoxyflavone; GTN, nitroglycerin; DADS, dipropyl disulfide and diallyl disulfide; Keap1, protein Kelch-like ECH-associated protein 1; NCX 4016, 2-acetoxybenzoate-2-(1-nitroxymethyl)phenyl ester; GT-947, ethyl 2-(1,3-bis(nitrooxy)propan-2-ylthio)benzoate; GT-794, ethyl 2-(2,3-bis(nitrooxy)propylthio)benzoate; GT-103, 2-((2,3-bis(nitrooxy)propylthio)carbonyl)phenyl acetate; GT-094, ethyl 2-((2,3-bis(nitrooxy)propyl)-disulfanyl)benzoate; GT-015, 3,3′-disulfanediylbis(propane-3,2,1-triyl) tetranitrate.
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. - Received February 23, 2008.
- Accepted August 1, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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Anti-Inflammatory, Antiproliferative, and Cytoprotective Activity of NO Chimera Nitrates of Use in Cancer Chemoprevention
