COX-2 and iNOS, good targets for chemoprevention of colon cancer.
Cyclooxygenase (COX)-2 has been suggested to play an important role in colon carcinogenesis. We found that the COX-2 selective inhibitor, nimesulide, reduces azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rats and colon carcinogenesis in mice, as well as formation of intestinal polyps in Min mice. Thus, selective inhibitors of COX-2, which catalyzes the synthesis of prostanoids, could be good candidates as chemopreventive agents against colon cancer. Examination of the effect of prostanoid receptor deficiency and a selective antagonist of prostanoid receptor on the development of AOM-induced ACF in mice revealed the involvement of the EP1 receptor. Moreover, a selective EP1 antagonist reduced the number of intestinal polyps in Min mice. These results suggest that PGE2 contributes to colon carcinogenesis through binding to the EP1 receptor. Nitric oxide synthase (NOS) is known to be overexpressed in colon cancers of humans and rats, and a NOS inhibitor, L-NG-nitroarginine methyl ester, was found to inhibit the development of AOM-induced ACF in rats. Thus, NOS including iNOS could also be a good target for chemoprevention of colon cancer, as in the COX-2 case.
Watanabe
K
K
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan.
Kawamori
T
T
Nakatsugi
S
S
Wakabayashi
K
K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001397:Azoxymethane; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000502:physiology; D013449:Sulfonamides / Q000627:therapeutic use
D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001397:Azoxymethane; C012655:nimesulide; D019331:NG-Nitroarginine Methyl Ester