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

Abstract

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.

• Authors: Ghenet K Hagos, Robert E Carroll, Tatiana Kouznetsova, Qian Li, Violeta Toader, Patricia A Fernandez, Steven M Swanson, Gregory R J Thatcher
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 8 Pg. 2230-9 (Aug 2007) ISSN: 1535-7163 [Print] United States
• PMID: 17699720 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Disulfides
• GT 094
• Nitrates
• Cyclin-Dependent Kinase Inhibitor p27
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Poly(ADP-ribose) Polymerases
• Azoxymethane

Topics

• Animals
• Apoptosis (drug effects)
• Azoxymethane
• Cell Count
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chemoprevention
• Colonic Neoplasms (enzymology, pathology, prevention & control)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• DNA Damage
• Disulfides (chemistry, pharmacology, therapeutic use)
• Enzyme Induction (drug effects)
• Flow Cytometry
• Humans
• Inflammation
• Male
• Mice
• Nitrates (chemistry, pharmacology, therapeutic use)
• Nitric Oxide (chemistry, pharmacology, therapeutic use)
• Nitric Oxide Synthase Type II (biosynthesis)
• Poly(ADP-ribose) Polymerases (metabolism)
• Precancerous Conditions (pathology)
• Rats
• Rats, Inbred F344