Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo

• Published in: Molecular cancer therapeutics 2007-08, Vol.6 (8), p.2230-2239
• Main Authors: Hagos, Ghenet K, Carroll, Robert E, Kouznetsova, Tatiana, Li, Qian, Toader, Violeta, Fernandez, Patricia A, Swanson, Steven M, Thatcher, Gregory R J
• Format: Article
• Language: English
• Subjects: ACF; Animals; anti-inflammatory; antiproliferative; Apoptosis - drug effects; Azoxymethane; Cell Count; Cell Line, Tumor; Cell Proliferation - drug effects; Chemoprevention; colon cancer; Colonic Neoplasms - enzymology; Colonic Neoplasms - pathology; Colonic Neoplasms - prevention & control; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Disulfides - chemistry; Disulfides - pharmacology; Disulfides - therapeutic use; DNA Damage; Enzyme Induction - drug effects; Flow Cytometry; Humans; Inflammation; Male; Mice; nitrates; Nitrates - chemistry; Nitrates - pharmacology; Nitrates - therapeutic use; nitric oxide; Nitric Oxide - chemistry; Nitric Oxide - pharmacology; Nitric Oxide - therapeutic use; Nitric Oxide Synthase Type II - biosynthesis; Poly(ADP-ribose) Polymerases - metabolism; Precancerous Conditions - pathology; Rats; Rats, Inbred F344
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-07-0069

Chemopreventive agents in colorectal cancer possess either antiproliferative or anti-inflammatory actions. Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 inhibitors have shown promise, but are compromised by side effects. Nitric oxide donor NSAIDs are organic nitrates conjugated via a labile linker to an NSAID, originally designed for use in pain relief, that have shown efficacy in colorectal cancer chemoprevention. The NO chimera, GT-094, is a novel nitrate containing an NSAID and disulfide pharmacophores, a lead compound for the design of agents specifically for colorectal cancer. GT-094 is the first nitrate reported to reduce aberrant crypt foci (by 45%) when administered after carcinogen in the standard azoxymethane rat model of colorectal cancer. Analysis of proximal and distal colon tissue from 8- and 28-week rat/azoxymethane studies showed that GT-094 treatment reduced colon crypt proliferation by 30% to 69%, reduced inducible NO synthase (iNOS) levels by 33% to 67%, reduced poly(ADP-ribose)polymerase-1 expression and cleavage 2- to 4-fold, and elevated levels of p27 in the distal colon 3-fold. Studies in cancer cell cultures recapitulated actions of GT-094: antiproliferative activity and transient G 2 -M phase cell cycle block were measured in Caco-2 cells; apoptotic activity was examined but not observed; anti-inflammatory activity was seen in the inhibition of up-regulation of iNOS and endogenous NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. In summary, antiproliferative, anti-inflammatory, and cytoprotective activity observed in vivo and in vitro support GT-094 as a lead compound for the design of NO chimeras for colorectal cancer chemoprevention. [Mol Cancer Ther 2007;6(8):2230–9]