Journal of Gastrointestinal Cancer

, Volume 38, Issue 2–4, pp 78–82

Cyclooxygenase-2 (COX-2) in Carcinogenesis and Selective COX-2 Inhibitors for Chemoprevention in Gastrointestinal Cancers

  • Takashi Fujimura
  • Tetsuo Ohta
  • Katsunobu Oyama
  • Tomoharu Miyashita
  • Kochi Miwa
Article

Abstract

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to have a property to inhibit tumor development in some cancers while it shows various side effects such as gastrointestinal bleeding and renal disorder. Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were originally developed as one of anti-inflammatory drugs to avoid side effect of NSAIDs. Fortunately, the coxibs was also proved to have an inhibiting effect on tumorigenesis by many experimental studies using cell lines and animal models like NSAIDs.

Discussion

Since a randomized study for polyp chemoprevention by celecoxib in familial adenomatous polyposis (FAP) patients demonstrated a significant reduction in the number of colorectal polyps, the clinical use of celecoxib was approved for FAP patients. Three large trials using celecoxib (the Adenoma Prevention with Celebrex and the Prevention of Spontaneous Adenomatopus Polyps) or refecoxib (the Adenomatous Polyp Prevention on Vioxx) for the recurrence of colorectal polyps in patients with a history of colorectal adenoma polypectomized confirmed chemopreventive effects on colorectal adenoma but two of three trails alerted us a hazard of cardiovascular (CV) events. Thereafter, some coxibs were withdrawn from the market because they showed to increase risk of serious CV events including heart attacks and strokes. But recent reports concluded that a merit of the reduction in gastrointestinal events by coxibs exceeded a demerit of the increase in serious CV events. In this review, a role of COX-2 in carcinogenesis of gastrointestinal tract and a future of coxibs for chemoprevention are discussed

Keywords

Cyclooxygenase-2 (COX-2) selective COX-2 inhibitors (Coxibs) esophageal cancer gastric cancer colorectal cancer 

References

  1. 1.
    Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med. 2002;8:289–93.PubMedCrossRefGoogle Scholar
  2. 2.
    Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995;83:493–501.PubMedCrossRefGoogle Scholar
  3. 3.
    Sharma S, Stolina M, Yang SC, Baratelli F, Lin JF, Atianzar K, Luo J, Zhu L, Lin Y, Huang M, Dohadwala M, Batra RK, Dubinett SM. Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. Clin Cancer Res. 2003;9:961–68.PubMedGoogle Scholar
  4. 4.
    Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 1998;93:705–16.PubMedCrossRefGoogle Scholar
  5. 5.
    Li G, Yang T, Yan J. Cyclooxygenase-2 increased the angiogenic and metastatic potential of tumor cells. Biochem Biophys Res Commun. 2002;299:886–90.PubMedCrossRefGoogle Scholar
  6. 6.
    Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci U S A. 1997;94:3336–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Morris CD, Armstrong GR, Bigley G, Green H, Attwood SE. Cyclooxygenase-2 expression in the Barrett's metaplasia–dysplasia–adenocarcinoma sequence. Am J Gastroenterol. 2001;96:990–96.PubMedGoogle Scholar
  8. 8.
    Kauer WK, Peters JH, DeMeester TR, Ireland AP, Bremner CG, Hagen JA. Mixed reflux of gastric and duodenal juice is more harmful to the esophagus than gastric juice alone. The need for surgical therapy re-emphasized. Ann Surg. 1995;222:525–33.PubMedGoogle Scholar
  9. 9.
    Stein HJ, Barlow AP, DeMeester TR, Hinder RA. Complications of gastroesophageal reflux disease: role of the lower esophageal sphincter, esophageal acid acid/alkaline exposure and duodenogastric reflux. Ann Surg. 1992;216:35–43.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang F, Altorki NK, Wu YC, Soslow RA, Subbaramaiah K, Dannenberg AJ. Duodenal reflux induces cyclooxygenase-2 in the esophageal mucosa of rats: evidence for involvement of bile acids. Gastroenterology. 2001;121:1391–99.PubMedCrossRefGoogle Scholar
  11. 11.
    Song S, Guha S, Liu K, Buttar NS, Bresalier R. COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signaling pathways in Barrett’s oesophagus and oesophageal adenocarcinoma. Gut. 2007;56:1512–21.PubMedCrossRefGoogle Scholar
  12. 12.
    Buttar NS, Kenneth KW, Leontovich O, Westcott JY, Pacifico RJ, Anderson MA, Krishnadath KK, Lutzke LS, Burgart LJ. Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett’s esophagus. Gastroenterology. 2002;122:1101–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Oyama K, Fujimura T, Ninomiya I, Miyashita T, Kinami S, Fushida S, Ohta T, Miwa K. A COX-2 inhibitor prevents the esophageal inflammation–metaplasia–adenocarcinoma sequence in rats. Carcinogenesis. 2005;26:565–70.PubMedCrossRefGoogle Scholar
  14. 14.
    Kaur BS, Khamnehei N, Iravani M, Namburu SS, Lin O, Tradafilopoulos G. Rofecoxib inhibits cyclooxygenase 2 expression and activity and reduce cell proliferation in Barrett’s esophagus. Gastroenterology. 2002;123:60–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Heath EI, Canto MI, Wu TT, Piantadosi S, Hawk E, Unalp A, Gordon G, Forastiere AA, CBET Research Group. Chemoprevention for Barrett's esophagus trial. Design and outcome measures. Dis Esophagus. 2003;16:177–86.PubMedCrossRefGoogle Scholar
  16. 16.
    Heath EI, Canto MI, Piantadosi S, Montgomery E, Weinstein WM, Herman JG, Dannenberg AJ, Yang VW, Shar AO, Hawk E, Forastiere AA, Chemoprevention for Barrett's Esophagus Trial Research Group. Secondary chemoprevention of Barrett's esophagus with celecoxib: results of a randomized trial. J Natl Cancer Inst. 2007;99:545–57.PubMedCrossRefGoogle Scholar
  17. 17.
    Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—first American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52:6735–40.PubMedGoogle Scholar
  18. 18.
    Romano M, Ricci V, Memoli A, Tuccillo C, Di Popolo A, Sommi P, Acquaviva AM, Del Vecchio Blanco C, Bruni CB, Zarrilli R. Helicobacter pylori up-regulates cyclooxygenase-2 mRNA expression and prostaglandin E2 synthesis in MKN 28 gastric mucosal cells in vitro. J Biol Chem. 1998;273:28560–563.PubMedCrossRefGoogle Scholar
  19. 19.
    Sung JJ, Leung WK, Go MY, To KF, Cheng AS, Ng EK, Chan FK. Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. Am J Pathol. 2000;157:729–35.PubMedGoogle Scholar
  20. 20.
    Sun WH, Yu Q, Shen H, Ou XL, Cao DZ, Yu T, Qian C, Zhu F, Sun YL, Fu XL, Su H. Roles of Helicobactor pylori infection and cyclooxygenase-2 expression in gastric carcinogenesis. World J Gastroenterol. 2004;10:2809–13.PubMedGoogle Scholar
  21. 21.
    Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res. 1997;57:1276–80.PubMedGoogle Scholar
  22. 22.
    Saukkonen K, Rintahaka J, Sivula A, Buskens CJ, Van Rees BP, Rio MC, Haglund C, Van Lanschot JJ, Offerhaus GJ, Ristimaki A. Cyclooxygenase-2 and gastric carcinogenesis. APMIS. 2003;111:915–25.PubMedCrossRefGoogle Scholar
  23. 23.
    Oshima H, Oshima M, Inaba K, Taketo MM. Hyperplastic gastric tumors induced by activated macrophage in COX-2/mPGES-1 transgenic mice. EMBO J. 2004;23:1669–78.PubMedCrossRefGoogle Scholar
  24. 24.
    Oshima H, Matsunaga A, Fujimura T, Tsukamoto T, Taketo MM, Oshima M. Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E3 pathway. Gastroenterology. 2006;131:1086–95.PubMedCrossRefGoogle Scholar
  25. 25.
    Miwa K, Hasegawa H, Fujimura T, Matsumoto H, Miyata R, Kosaka T, Miyazaki I, Hattori T. Duodenal reflux through the pylorus induces gastric adenocarcinoma in the rat. Carcinogenesis. 1992;13:2313–16.PubMedCrossRefGoogle Scholar
  26. 26.
    Oshima M, Taketo MM. COX selectivity and animal models for colon cancer. Curr Pharm Des. 2002;8:1021–34.PubMedCrossRefGoogle Scholar
  27. 27.
    Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Trzaskos JM, Evans JF, Taketo MM. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell. 1996;87:803–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res. 2000;60:5040–44.PubMedGoogle Scholar
  29. 29.
    Oshima M, Murai N, Kargman S, Arguello M, Luk P, Kwong E, Taketo MM, Evans JF. Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res. 2001;61:1733–40.PubMedGoogle Scholar
  30. 30.
    Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, Wakabayashi N, Saunders B, Shen Y, Fujimura T, Su LK, Levin B. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342:1946–52.PubMedCrossRefGoogle Scholar
  31. 31.
    Baron JA, Sandler RS, Bresalier RS, Quan H, Riddell R, Lanas A, Bolognese JA, Oxenius B, Horgan K, Loftus S, Morton DG, APPROVe Trial Investigators. A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology. 2006;131:1674–82.PubMedCrossRefGoogle Scholar
  32. 32.
    Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, Tang J, Rosenstein RB, Wittes J, Corle D, Hess TM, Woloj GM, Boisserie F, Anderson WF, Viner JL, Bagheri D, Burn J, Chung DC, Dewar T, Foley TR, Hoffman N, Macrae F, Pruitt RE, Saltzman JR, Salzberg B, Sylwestrowicz T, Gordon GB, Hawk ET, APC Study Investigators. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355:873–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Arber N, Eagle CJ, Spicak J, Racz I, Dite P, Hajer J, Zavoral M, Lechuga MJ, Gerletti P, Tang J, Rosenstein RB, Macdonald K, Bhadra P, Fowler R, Wittes J, Zauber AG, Solomon SD, Levin B. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355:885–95.PubMedCrossRefGoogle Scholar
  34. 34.
    Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520–8.PubMedCrossRefGoogle Scholar
  35. 35.
    White WB, West CR, Borer JS, Gorelick PB, Lavange L, Pan SX, Weiner E, Verburg KM. Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. Am J Cardiol. 2007;99:91–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Moore RA, Derry S, McQuary HJ. Cyclo-oxygenase-2 selective inhibitors and nonsteroidal anti-inflammatory drugs: balancing gastrointestinal and cardiovascular risk. BMC Musculoskelet Disord. 2007;8:73–83.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • Takashi Fujimura
    • 1
  • Tetsuo Ohta
    • 1
  • Katsunobu Oyama
    • 1
  • Tomoharu Miyashita
    • 1
  • Kochi Miwa
    • 2
  1. 1.Kanazawa University HospitalKanazawaJapan
  2. 2.Toyama Rosai HospitalUozuJapan

Personalised recommendations