Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression.
Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid to prostaglandin H2. The inducible isoform, COX-2, promotes colorectal tumorigenesis, and nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit this isoform are chemopreventive in murine models of intestinal tumorigenesis. To establish a mechanism for their chemopreventive properties, we examined the effect of a COX-2-selective inhibitor, NS-398, on two colorectal carcinoma cell lines: HT29, which was found to express COX-2 protein constitutively; and S/KS, which did not express detectable levels of COX-2 protein. NS-398 had a dose-dependent antiproliferative effect on each cell line (IC50, 82.0 +/- 10.1 microM for HT29 and 78.6 +/- 11.1 microM for S/KS), and this was due to the induction of apoptosis. Cell cycle parameters were unaffected by NS-398 treatment. The ability of NS-398 to induce apoptosis provides a potential mechanism by which COX-2-selective inhibitors are chemopreventive and also indicates their potential as chemotherapeutic agents for colorectal cancer. That this effect was independent of COX-2 protein expression suggests that COX-2-selective NSAIDs may, like nonselective NSAIDs, be antineoplastic in the absence of COX-2.
Elder
D J
DJ
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom.
Halton
D E
DE
Hague
A
A
Paraskeva
C
C
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D012004:Rectal Neoplasms / Q000201:enzymology / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases