Cyclooxygenase-2 level and culture conditions influence NS398-induced apoptosis and caspase activation in lung cancer cells.
Cyclooxygenases (COXs) catalyze the synthesis of prostaglandins (PGs) from arachidonic acid. Overexpression of COX-2 is frequently found in human cancers and is suggested to play an important role in tumorigenesis. Recent studies indicated that COX-2 inhibitors exert potent anti-cancer effects on a number of cancers. Interestingly, some COX-2 inhibitors potently induce apoptosis, while other COX-2 inhibitors primarily induce growth inhibition. Therefore, there is a variability in the effects that different COX-2 inhibitors have on cancer cells. In this study, we demonstrated that induction of apoptosis of high COX-2-expressing A549 lung cancer cells by a specific COX-2 inhibitor NS398 was observed in cells cultured under serum-free condition. However, this drug induced G1 growth arrest rather than apoptosis in A549 cells maintained in 10% serum medium. Conversely, low COX-2-expressing H226 lung cancer cells were resistant to NS398-induced apoptosis under both serum-free and serum-containing conditions. Moreover, our results showed that NS398-induced apoptosis is associated with activation of caspase-3, a cysteine protease that plays a crucial role in the execution phase of apoptosis. These results suggest that the cytotoxic effect of COX-2 inhibitors on cancer cells may be influenced by extracellular environments and the anti-cancer action of these inhibitors in vivo needs careful evaluation. Additionally, a correlation between the level of COX-2 expression and the extent of apoptosis induced by COX-2 inhibitors was found.
Chang
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HC
Department of Physiology, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC. m740127@cc.kmu.edu.tw
Weng
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CF
D017209:Apoptosis / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle; D016895:Culture Media, Serum-Free; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016895:Culture Media, Serum-Free; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases