Carcinogenesis Advance Access published online on May 20, 2004
Carcinogenesis, doi:10.1093/carcin/bgh184
© 2004 by Oxford University Press
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1 General Surgery Department, Norfolk and Norwich University Hospital, Colney, Norwich NR4 7UY, United Kingdom; Nutrition and Gastrointestinal Health Programme, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, United Kingdom
* To whom correspondence should be addressed. E-mail: Ian.Johnson{at}BBSRC.AC.UK.
Epidemiological studies suggest that use of NSAIDs and/or a high intake of fruit and vegetables reduce the risk of oesophageal adenocarcinoma. Since COX-2 is up-regulated in Barrett's oesophageal carcinogenesis, the protective effect of NSAIDs and natural food components might reflect COX-2 inhibition. We explored the effects of quercetin, a natural flavonoid with a potent COX-2 inhibitory activity, and two commercially available selective COX-2 inhibitors (NS-398 and nimesulide), on cell proliferation, apoptosis, PGE2 production and COX-2 mRNA expression in a human oesophageal adenocarcinoma cell line (OE33). Changes in the relative numbers of adherent and floating cells were quantified, and apoptotic cells were identified using ethidium bromide and acridine orange staining under fluorescence microscopy. Flow cytometric analysis of adherent and floating cells was used to quantify apoptosis, and to examine the effects of the agents on the cell cycle. After 48h exposure at concentrations of 1µM and above, both COX-2 inhibitors and quercetin suppressed cell proliferation (p<0.01), and increased the fraction of floating apoptotic cells. At higher concentrations (50 µM) and longer exposure (48h) the effects of quercetin were significantly greater than those of the selective COX-2 inhibitors (p<0.01). Cell-cycle analyses showed that quercetin blocked cells in S phase, while selective COX-2 inhibitors blocked cells in G1/S interphase. COX-2 mRNA expression was suppressed by quercetin and the synthetic COX-2 inhibitors in a time- and dose-dependent manner. Quercetin and the synthetic COX-2 inhibitors (10 µM) suppressed PGE2 production by approximately 70% after 24h exposure (P < 0.001). We conclude that OE33 is a useful model for the study of COX-2 expression and associated phenomena in human adenocarcinoma cells. Synthetic COX-2 inhibitors and the food-borne flavonoid quercetin suppress proliferation, induce apoptosis and cell cycle block in human oesophageal adenocarcinoma cells in vitro, and future studies should assess their effects in vivo. Key Words:
cyclooxygenase-2, COX-2 inhibitors, oesophageal adenocarcinoma, quercetin
Revised April 28, 2004
Accepted May 1, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Synthetic and naturally-occurring COX-2 inhibitors suppress proliferation in a human oesophageal adenocarcinoma cell line (OE33) by inducing apoptosis and cell cycle arrest
2 Nutrition and Gastrointestinal Health Programme, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, United Kingdom
3 General Surgery Department, Norfolk and Norwich University Hospital, Colney, Norwich NR4 7UY, United Kingdom
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