Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo.
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.
Hagos
Ghenet K
GK
Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S Wood Street, Chicago, IL 60612, USA.
Carroll
Robert E
RE
Kouznetsova
Tatiana
T
Li
Qian
Q
Toader
Violeta
V
Fernandez
Patricia A
PA
Swanson
Steven M
SM
Thatcher
Gregory R J
GR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004249:DNA Damage; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004790:Enzyme Induction / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D009566:Nitrates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011230:Precancerous Conditions / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344
D004220:Disulfides; C523454:GT 094; D009566:Nitrates; D050760:Cyclin-Dependent Kinase Inhibitor p27; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases; D001397:Azoxymethane