The effect of non-steroidal anti-inflammatory drugs on human colorectal cancer cells: evidence of different mechanisms of action.
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit proliferation and induce apoptosis in human colorectal cancer cells in vitro. It remains unclear whether individual NSAIDs act by cyclooxygenase-2 (COX-2) inhibition and how NSAIDs exert their anti-proliferative effects. We investigated the effects of NS-398 (a selective COX-2 inhibitor), indomethacin (a non-selective COX inhibitor) and aspirin on four human colorectal cancer cell lines (HT29.Fu, HCA-7, SW480 and HCT116). NS-398 completely inhibited proliferation, induced G1 arrest and promoted apoptosis in COX-2-expressing cells (HT29.Fu and HCA-7). However, indomethacin had similar effects on all cells, regardless of COX-2 expression. NS-398 also had anti-proliferative activity on COX-2-negative cell lines (SW480 and HCT116). Aspirin inhibited proliferation of all cell lines but did not induce apoptosis. Indomethacin decreased beta-catenin protein expression in all cells (unlike NS-398 or aspirin). NSAIDs act on human colorectal cancer cells via different mechanisms. Decreased beta-catenin protein expression may mediate the anti-proliferative effects of indomethacin.
Smith
M L
ML
Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds, UK.
Hawcroft
G
G
Hull
M A
MA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D017209:Apoptosis; D001241:Aspirin / Q000627:therapeutic use*; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015151:Immunoblotting; D007213:Indomethacin / Q000627:therapeutic use*; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use*; D015534:Trans-Activators; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D015534:Trans-Activators; D051176:beta Catenin; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D007213:Indomethacin