Colon cancer chemoprevention by a novel NO chimera
that shows anti-inflammatory and antiproliferative
activity in vitro and in vivo
Ghenet K. Hagos,1 Robert E. Carroll,2
Tatiana Kouznetsova,2 Qian Li,1 Violeta Toader,1
Patricia A. Fernandez,1 Steven M. Swanson,1
and Gregory R.J. Thatcher1
1Department of Medicinal Chemistry and Pharmacognosy,
College of Pharmacy, University of Illinois at Chicago and
2Department of Medicine, University of Illinois at Chicago and
Chicago Veterans Administration Medical Center
(West Side Division), Chicago, Illinois
Abstract
Chemopreventive agents in colorectal cancer possess
either antiproliferative or anti-inflammatory actions. Non-
steroidal anti-inflammatory drugs (NSAID) and cyclooxy-
genase-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)polymer-
ase-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: antiprolifer-
ative activity and transient G2-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 iNOSand
endogenous NO production in lipopolysacchar