Abstract
Recent studies have suggested that apoptosis is a key phenomenon in the chemopreventive action of nonsteroidal antiinflammatory drugs (NSAIDs), which exhibit cancer‐preventive and tumor‐regressive effects in the human colon. The effect of NS‐398, N‐(2‐cyclohexyloxy‐4‐nitrophenyl)methanesul‐fonamide, which is a selective inhibitor of cyclooxygenase‐2 (COX‐2), on the induction of apoptosis in two human colorectal cancer cell lines (Colo320 and THRC) was determined. The apoptotic ratios (‐fold vs. control value) of Colo320 in the presence of 100 μM indomethacin and NS‐398 were 3.3 ± 1.5 and 9.0±0.94, and those of THRC were 2.3±0.46 and 7.4±0.87, respectively. The ability of NS‐398 to induce apoptosis is greater than that of indomethacin. Both indomethacin and NS‐398 reduced the cell proliferation in a concentration‐dependent manner. The IC50 values of NS‐398 (54.8+3.6 and 77.2±4.9μM) were significantly lower than those of indomethacin (206.3±43.0 and 180.3±22.6/μM) at P<0.01 in Colo320 and THRC cell lines, respectively. These findings suggest that NS‐398, a selective inhibitor of COX‐2, is a possible candidate for a chemopreventive agent with a potent apoptosis‐inducing effect and low nlcerogenic activity.
Keywords: Apoptosis, COX‐2 inhibitor, NS‐398, Colorectal cancer, DNA fragmentation
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REFERENCES
- 1. ) Thun , M. J. , Namboodiri , M. M. and Heath , C. W , Jr.Aspirin use and reduced risk of fatal colon cancer . N. Engl. J. Med. , 325 , 1593 – 1596 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Giardiello , F. M. , Hamilton , S. R. , Krush , A. J. , Piantadosi , S. , Hylind , L. M. , Celano , P. , Booker , S. V. , Robinson , C. R. and Offerhaus , G. J.Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis . N. Engl. J. Med. , 328 , 1313 – 1316 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Labyle , D. , Fischer , D. , Vielh , P. , Drouhin , P. , Pariente , A. , Bories , C. , Duhamel , O. , Trousset , M. and Attali , P.Sulindac causes regression of rectal polyps in familial adenomatous polyposis . Gastroenterology , 101 , 635 – 639 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 4. ) Reddy , B. S. , Rao , C. V. , Rivenson , A. and Kelloff , G.Inhibitory effects of aspirin 'on azoxymethane‐induced colon carcinogenesis in F344 rats . Carcinogenesis , 14 , 1493 – 1497 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 5. ) Rao , C. V. , Rivenson , A. , Simi , B. , Zang , E. , Kelloff , G. , Steele , V. and Reddy , B. S.Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti‐inflammatory agent . Cancer Res. , 55 , 1464 – 1472 ( 1995. ). [PubMed] [Google Scholar]
- 6. ) Arai , I. , Hamasaka , Y. , Futaki , N. , Takahashi , S. , Yoshikawa , K. , Higuchi , S. and Otomo , S.Effect of NS‐398, a new nonsteroidal anti‐inflammatory agent, on gastric ulceration and acid secretion in rats . Res. Commun, Chem. Pathol. Pharmacol. , 81 , 259 – 270 ( 1993. ). [PubMed] [Google Scholar]
- 7. ) Futaki , N. , Takahashi , S. , Yokoyama , M. , Arai , I. , Higuchi , S. and Otomo , S.NS‐398, a new anti‐inflammatory agent, selectively inhibits prostaglandin G/H syn‐thase/cyclooxygenase (COX‐2) activity in vitro . Prostaglandins , 47 , 55 – 59 ( 1994. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Alberts , D. S. , Hixson , L. , Ahnen , D. , Bogert , C. , Einspahr , J. , Paranka , N. , Brendel , K. , Gross , P. H. , Pamukcu , R. and Burt , R. W.Do NSAIDs exert their colon cancer chemoprevention activities through the inhibition of mucosal prostaglandin synthetase ? J. Cell. Biochem. , 22 , 18 – 23 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 9. ) Piazza , G. A. , Rahm , A. L. , Krutzsch , M. , Sperl , G. , Paranka , N. S. , Gross , P. H. , Brendel , K. , Burt , R. W. , Alberts , D. S. , Pamukcu , R. and Ahnen , D. J.Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis . Cancer Res. , 55 , 3110 – 3116 ( 1995. ). [PubMed] [Google Scholar]
- 10. ) Elder , D. J. , Hague , A. , Hicks , D. J. and Paraskeva , C.Differential growth inhibition by the aspirin metabolite salicylate in human colorectal tumor cell lines: enhanced apoptosis in carcinoma and in vitro‐transformed adenoma relative to adenoma cell lines . Cancer Res. , 56 , 2273 – 2276 ( 1996. ). [PubMed] [Google Scholar]
- 11. ) Shiff , S. L , Koutsos , M. I. , Qiao , L. and Rigas , B.Nonsteroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: effects on cell cycle and apoptosis . Exp. Cell Res. , 222 , 179 – 188 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Hague , A. , Manning , A. M. , Hanlon , K. A. , Huschtscha , L. I. , Hart , D. and Paraskeva , C.Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53‐independent pathway: implications for the possible role of dietary fibre in the prevention of large‐bowel cancer . Int. J. Cancer , 55 , 498 – 505 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Heerdt , B. G. , Houston , M. A. and Augenlicht , L. H.Potentiation by specific short‐chain fatty acids of differentiation and apoptosis in human colonic carcinoma cell lines . Cancer Res. , 54 , 3288 – 3294 ( 1994. ). [PubMed] [Google Scholar]
- 14. ) Sellins , K. S. and Cohen , J. J.Gene induction by γ‐irradiation leads to DNA fragmentation in lymphocytes. J . Immunol , 139 , 3199 – 3206 ( 1987. ). [PubMed] [Google Scholar]
- 15. ) Bennett , A. , Civier , A. , Hensby , C. N. , Melhuish , P. B. and Stamford , I. F.Measurement of arachidonate and its metabolites extracted from human normal and malignant gastro‐intestinal tissues . Gut , 28 , 315 – 318 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. ) Reddy , B. S. , Rao , C. V. , Rivenson , A. and Kelloff , G.Inhibitory effect of aspirin on azoxymethane‐induced colon carcinogenesis in F344 rats . Carcinogenesis , 14 , 1493 – 1497 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Maxwell , W. J. , Kelleher , D. , Keating , J. J. , Hogan , F. P. , Bloomfleld , F. J. , Macdonald , G. S. and Keeling , P. W. N.Enhanced secretion of prostaglandin E2 by tissue‐fixed macrophages in colonic carcinoma . Digestion , 47 , 160 – 166 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 18. ) De Mello , M. C. , Bayer , B. M. and Beaven , M. A.Evidence that prostaglandins do not have a role in the cytostatic action of antiinflammatory drugs . Biochem. Pharmacol , 29 , 311 – 318 ( 1980. ). [DOI] [PubMed] [Google Scholar]
- 19. ) Knapp , D. W. , Chan , T. C. , Kuczek , T. , Reagan , W. J. and Park , B.Evaluation of in vitro cytotoxicity of nonsteroidal anti‐inflammatory drugs against canine tumor cells . Am. J. Vet. Res. , 56 , 801 – 805 ( 1995. ). [PubMed] [Google Scholar]
- 20. ) Langman , M. J. S.Epidemiologic evidence on the association between peptic ulceration and antiinflammatory drug use . Gastroenterology , 96 , 640 – 646 ( 1989. ). [DOI] [PubMed] [Google Scholar]