Archives of Gynecology and Obstetrics

, Volume 284, Issue 6, pp 1515–1521 | Cite as

Effects of a selective COX-2 inhibitor in patients with uterine endometrial cancers

  • Kiyoshi Hasegawa
  • Yutaka Torii
  • Risa Ishii
  • Shuko Oe
  • Rina Kato
  • Yasuhiro Udagawa
Gynecologic Oncology



COX-2 is highly expressed in endometrial cancers, suggesting that a selective COX-2 inhibitor could be valuable for treating endometrial cancers that overexpress COX-2. In this study, we investigated the anti-tumor effects of the selective COX-2 inhibitor etodolac on endometrial cancer patients.


Etodolac (400 mg, bid, for 2 weeks) was administered preoperatively to 21 endometrial cancer patients who had provided informed consent. Using pre-treatment biopsies and post-treatment surgical specimens, the expression levels of COX-2, Ki-67, p53, p21, p27, and cyclin D1 were evaluated by immunohistochemistry and the apoptotic index (AI) was determined by TUNEL staining. Preoperative biopsies and surgical specimens from 32 patients with endometrial cancer not treated with etodolac served as controls.


Surgical specimens from COX-2 positive endometrial cancer patients treated with etodolac had significantly reduced expression levels of COX-2, Ki-67, p53, p21, p27, and cyclin D1 as determined by immunohistochemistry, while AI was not affected. These markers were unchanged for COX-2 negative endometrial cancer patients treated with etodolac and the control group.


The selective COX-2 inhibitor etodolac showed anti-proliferative effects by suppressing COX-2 and cell-cycle regulator protein expression in patients with endometrial cancer positive for COX-2 expression. This study demonstrates that a selective COX-2 inhibitor is a potentially beneficial treatment for COX-2 positive endometrial cancers.


Endometrial cancer COX-2 COX-2 inhibitor Immunohistochemistry Cell-cycle regulator proteins 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Uefuji K, Ichikura T, Shinomiya N, Mochizuki H (2000) Induction of apoptosis by JTE-522, a specific cyclooxygenase-2 inhibitor, in human gastric cancer cell lines. Anticancer Res 20:4279–4284PubMedGoogle Scholar
  2. 2.
    Souza RF, Shewmake K, Beer DG, Cryer B, Spechler SJ (2000) Selective inhibition of cyclooxygenase-2 suppresses growth and induced apoptosis in human esophageal adenocarcinoma cells. Cancer Res 60:5767–5772PubMedGoogle Scholar
  3. 3.
    Li M, Lotan R, Levin B, Tahara E, Lippman SM, Xu XC (2000) Aspirin induction of apoptosis in esophageal cancer: a potential for chemoprevention. Cancer Epidemiol Biomarkers Prev 9:545–549PubMedGoogle Scholar
  4. 4.
    Sumitani K, Kamijo R, Toyoshima T, Nakanishi Y, Takizawa K, Hatori M et al (2001) Specific inhibition of cyclooxygenase-2 results in inhibition of proliferation of oral cancer cell lines via suppression of prostaglandin E2 production. J Oral Pathol Med 30:41–47PubMedCrossRefGoogle Scholar
  5. 5.
    Joki T, Heese O, Nikas DC, Bello L, Zhang J, Kraeff SK et al (2000) Expression of cyclooxygenase-2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitors, NS-398. Cancer Res 60:4926–4931PubMedGoogle Scholar
  6. 6.
    Tsubouchi Y, Mukai S, Kawahito Y, Yamada R, Kohno M, Inoue K et al (2000) Meloxicam inhibits the growth of non-small cell lung cancer. Anticancer Res 20:2867–2872PubMedGoogle Scholar
  7. 7.
    Molina MA, Sitja-Arnau M, Lemoine MG, Frazier ML, Sinicrope FA (1999) Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res 59:4356–4362PubMedGoogle Scholar
  8. 8.
    Hasegawa K, Ohashi Y, Ishikawa K, Yasue A, Kato R, Achiwa Y et al (2005) Expression of cyclooxygenase-2 (COX-2) in uterine endometrial cancer and anti-tumor effects of a selective COX-2 inhibitor. Int J Oncol 26:1419–1428PubMedGoogle Scholar
  9. 9.
    Uotila PJ, Erkkola RU, Klemi PJ (2002) The expression of cyclooxygenase-1 and -2 in proliferative endometrium and endometrial adenocarcinoma. Ann Med 34:428–433PubMedCrossRefGoogle Scholar
  10. 10.
    Fujiwaki R, Iida K, Kanasaki H, Ozaki T, Hata K, Miyazaki K (2002) Cyclooxygenase-2 expression in endometrial cancer: correlation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase. Hum Pathol 33:213–219PubMedCrossRefGoogle Scholar
  11. 11.
    Tong BJ, Tan J, Tajeda L, Das SK, Chapman JA, Dubois RN et al (2000) Heightened expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-delta in human endometrial adenocarcinoma. Neoplasia 2:483–490PubMedCrossRefGoogle Scholar
  12. 12.
    Farrandina G, Legge F, Ranelletti FO, Zannoni GF, Maggiano N, Evangelisti A et al (2002) Cyclooxygenase-2 expression in endometrial carcinoma—correlation with clinicopathological parameter and clinical outcome. Cancer 95:801–807CrossRefGoogle Scholar
  13. 13.
    Jeon YT, Kang S, Kang DH, Yoo KY, Park IA, Bang YJ et al (2004) Cyclooxygenase-2 and p53 expressions in endometrial cancer. Cancer Epidemiol Biomarkers Prev 13:1538–1542PubMedGoogle Scholar
  14. 14.
    Genç S, Attar E, Gürdöl F, Kendigelen S, Bilir A, Serdaroğlu H (2007) The effect of COX-2 inhibitor, nimesulide, on angiogenetic factors in primary endometrial carcinoma cell culture. Clin Exp Med 7:6–10PubMedCrossRefGoogle Scholar
  15. 15.
    Wood NJ, Quinton NA, Burdall S, Sheridan E, Duffy SR (2007) Exploring the potential chemopreventative effect of aspirin and rofecoxib on hereditary nonpolyposis colorectal cancer-like endometrial cancer cells in vitro through mechanisms involving apoptosis, the cell cycle, and mismatch repair gene expression. Int J Gynecol Cancer 17:447–454PubMedCrossRefGoogle Scholar
  16. 16.
    Detre S, Saclani Jotti G, Dowsett M (1995) A “quickscore” method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. J Clin Pathol 48:876–878PubMedCrossRefGoogle Scholar
  17. 17.
    Buttar NS, Wang KK, Leontovich O, Westcott JY, Pacifico RJ, Anderson MA et al (2002) Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitor in an animal model of Barrett’s esophagus. Gastroenterology 122:1101–1112PubMedCrossRefGoogle Scholar
  18. 18.
    Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA (2000) The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res 60:5040–5044PubMedGoogle Scholar
  19. 19.
    Oshima M, Murai (Hara) N, Kargman S, Arguello M, Luk P, Kwong P et al (2001) Chemoprevention of intestinal polyposis in the ApcΔ716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res 61:1733–1740PubMedGoogle Scholar
  20. 20.
    Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB et al (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946–1952PubMedCrossRefGoogle Scholar
  21. 21.
    Phillips RK, Wallace MH, Lynch PM, Hawk E, Gordon GB, Saunders BP et al (2002) A randomized, double blinded, placebo controlled study of celecoxib, a selective cyclooxygenase-2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 50:857–860PubMedCrossRefGoogle Scholar
  22. 22.
    Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K et al (2005) Cardiovascular events associated with refecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352:1092–1102PubMedCrossRefGoogle Scholar
  23. 23.
    Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P et al (2005) Cardiovascular risk with celecoxib in a clinical trial for colorectal adenoma prevention. N Eng J Med 352:1071–1080CrossRefGoogle Scholar
  24. 24.
    McGettigan P, Henny D (2006) Cardiovascular risk and inhibitor of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 296:1633–1644PubMedCrossRefGoogle Scholar
  25. 25.
    Roumie CL, Choma NN, Kaltenbach L, Mitcher EF, Arbogast PG, Griffin MR (2009) Non-aspirin NSAIDs, cyclooxygenase-2 inhibitors and risk for cardiovascular events- stroke, acute myocardial infarction, and death from coronary heart disease. Pharmacoepidemiol Drug Saf 18:1053–1063PubMedCrossRefGoogle Scholar
  26. 26.
    Motsko SP, Rascati KL, Busti AJ, Wilson JP, Barner JC, Lawson KA et al (2006) Temporal relationship between use of NSAIDs, including selective COX-2 inhibitors, and cardiovascular risk. Drug Saf 29:621–632PubMedCrossRefGoogle Scholar
  27. 27.
    Warner JJ, Weideman RA, Kelly KC, Brilakis ES, Banerjee S, Cunningham F et al (2008) The risk of acute myocardial infarction with etodolac is not increased compared to naproxen: a historical cohort analysis of a genetic COX-2 selective inhibitor. J Cardiovasc Pharmacol Ther 13:252–260PubMedCrossRefGoogle Scholar
  28. 28.
    Yanaoka K, Oka M, Yoshimura N, Deguchi H, Mukoubayashi C, Enomoto S et al (2010) Preventive effects of etodolac, a selective cyclooxygenase-2 inhibitor, on cancer development in extensive metaplastic gastritis, a Helicobacter pylori-negative precancerous lesion. Int J Cancer 126:1467–1473PubMedGoogle Scholar
  29. 29.
    Altorki NK, Keresztes JL, Port JL, Libby DM, Korst RJ, Flieder DB et al (2003) Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer. J Clin Oncol 21:2645–2650PubMedCrossRefGoogle Scholar
  30. 30.
    Shinohara N, Kumagai A, Kanagawa K, Maruyama S, Abe T, Sazawa A, Nonomura K (2009) Multicenter phase II trial of combination therapy with meloxicam, a COX-2 inhibitor, and natural interferon-α for metastatic renal cell carcinoma. Jpn J Clin Oncol 39:720–729PubMedCrossRefGoogle Scholar
  31. 31.
    Lipton A, Campbell-Baird C, Witters L, Harvey H, Ali S (2010) Phase II trial of gemcitabine, irinotecan, and celecoxib in patients with advanced pancreatic cancer. J Clin Gastroenterol 44:286–288PubMedCrossRefGoogle Scholar
  32. 32.
    Aruajo AM, Mendez JC, Coelho AL, Sousa B, Barata F, Figueiredo A et al (2009) Phase II study of celecoxib with cisplatin plus etoposide in extensive-stage small cell lung cancer. Cancer Invasion 27:391–396CrossRefGoogle Scholar
  33. 33.
    Debucquoy A, Roels S, Goethals L, Libbrecht L, Culsem EV, Geboes K et al (2009) Double blind randomized phase II study with radiation + 5-fluorouracil ± celecoxib for resectable rectal cancer. Radiother Oncol 93:273–278PubMedCrossRefGoogle Scholar
  34. 34.
    Sooriakumaran P, Coley HM, Fox SB, Macanas-Pirard P, Lovell DP, Henderson A et al (2009) A randomized controlled trial investigating the effects of celecoxib in patients with localized prostate cancer. Anticancer Res 29:1483–1488PubMedGoogle Scholar
  35. 35.
    Watanabe J, Sato H, Kanai T, Kamata Y, Jobo T, Hata H et al (2002) Paradoxical expression of cell cycle inhibitory p27 in endometrial adenocarcinoma of the uterine corpus-correlation with proliferative and clinicopathological parameters. Br J Cancer 87:81–85PubMedCrossRefGoogle Scholar
  36. 36.
    Shih HC, Shiozawa T, Kato K, Imai T, Miyamoto T, Uchikawa J et al (2003) Immunohistochemical expression of cyclins, cyclin-dependent kinases, tumor-suppressor gene products, Ki-67, and sex steroid receptors in endometrial carcinoma: positive staining for cyclin A as a poor prognostic indicator. Hum Pathol 34:471–478PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Kiyoshi Hasegawa
    • 1
  • Yutaka Torii
    • 1
  • Risa Ishii
    • 1
  • Shuko Oe
    • 1
  • Rina Kato
    • 1
  • Yasuhiro Udagawa
    • 1
  1. 1.Department of Obstetrics and GynecologyFujita Health University School of MedicineToyoakeJapan

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