Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1999 Oct;90(10):1152–1162. doi: 10.1111/j.1349-7006.1999.tb00690.x

A Selective Cyclooxygenase‐2 Inhibitor Suppresses Tumor Growth in Nude Mouse Xenografted with Human Head and Neck Squamous Carcinoma Cells

Goshi Nishimura 1,, Syunsuke Yanoma 2, Hiromi Mizuno 1, Koji Kawakami 1, Mamoru Tsukuda 1
PMCID: PMC5925997  PMID: 10595745

Abstract

The anti‐tumor effect of a selective cyclooxygenase (COX)‐2 inhibitor, JTE‐522, was examined with the human head and neck squamous cell carcinoma cell line KB. KB cells do not produce prostaglandin (PG)‐E2. In vitro, JTE‐522 induced an increase of G1 phase‐arrested cells, suppression of platelet‐derived growth factor (PDGF) production and inhibition of telomerase activity. No cytotoxic effect was detected. In vivo, the growth of the tumor xenografted into nude mice was significantly suppressed by JTE‐522. Suppression of angiogenesis at the periphery of the tumor, increase of G1‐arrested cells and suppression of telomerase activity were observed, together with an increase of apoptotic cell death in the tumor. Immunological enhancement did not play a role. We concluded that the anti‐tumor effect of JTE‐522 was caused by anti‐angiogenesis action, cell cycle arrest and inhibition of telomerase activity of the tumor cells. These combined effects might induce apoptosis.

Keywords: Head and neck squamous carcinoma cells, Selective cyclooxgenase‐2 inhibitor, Cell cycle arrest, Anti‐angiogenesis, Telomerase activity inhibition

Full Text

The Full Text of this article is available as a PDF (447.3 KB).

REFERENCES

  • 1.Kelloff , G. J. , Boone , C. W. , Crowell , J. A. , Steele , V. E. , Lubet , R. and Sigman , C. C.Chemopreventive drug development: perspectives and progress. Cancer Epidemiol . Biomarkers Prev. , 59 , 85 , 98 ( 1994. ). [PubMed] [Google Scholar]
  • 2.Giardiello , F. M. , Offerhaus , G. J. A. and DuBois , R. N.The role of nonsteroidal anti‐inflammatory drugs in colorectal cancer prevention . Eur. J. Cancer , 31A, 1071 , 1076 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 3.Moon , R. C. , Detrisac , C. J. , Thomas , C. F. and Kelloff , G. J.Chemoprevention of experimental bladder cancer . J. Cell. Biochem. , 161 ( Suppl. ), 134 – 138 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 4.Denda , A. , Endoh , T. , Kitajima , W. , Tang , Q. , Noguchi , O. , Kobayashi , Y. , Akai , H. , Okajima , E. , Tsujiuchi , T. , Tsutsumi , M. , Nakae , D. and Konishi , Y.Inhibition by piroxicam of oxidative DNA damage, liver cirrhosis and development of enzyme‐altered nodules caused by a cholinedeficient, L‐amino acid‐defined diet in rats . Carcinogenesis , 18 , 1921 – 1930 ( 1997. ) [DOI] [PubMed] [Google Scholar]
  • 5.Marnett , L. J.Aspirin and the potential role of prostaglandins in colon cancer . Cancer Res. , 59 , 5575 , 5589 ( 1992. ). [PubMed] [Google Scholar]
  • 6.Lupulescu , A.Prostaglandins, their inhibitors and cancer. Prostaglandins Leukotrienes Essent . Fatty Acids , 59 , 83 , 94 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 7.Eberhart , C. E. and DuBois , R. N.Eicosanoids and the gastrointestinal tract . Gastroenterology , 109 , 285 – 301 ( 1995. ) [DOI] [PubMed] [Google Scholar]
  • 8.Vane , J.Towards a better aspirin . Nature , 367 , 215 – 216 ( 1994. ) [DOI] [PubMed] [Google Scholar]
  • 9.Williams , C. S. , Smalley , W. and DuBois , R. N.Aspirin use and potential mechanisms for colorectal cancer prevention . J. Clin. Invest. , 59 , 1325 , 1329 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Kargman , S. L. , O'Neill , G. P. , Vickers , P. J. , Evans , J. F. , Mancini , J. A. and Jothy , S.Expression of prostaglandin G/H synthase‐1 and ‐2 protein in human colon cancer . Cancer Res. , 59 , 2556 , 2559 ( 1995. ). [PubMed] [Google Scholar]
  • 11.DuBois , R. N. , Radhika , A. , Reddy , B. S. and Entingh , A. J.Increased cyclooxygenase‐2 levels in carcinogen‐induced rat colonic tumors . Gastroenterology , 59 , 1259 , 1262 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 12.Restimäki , A. , Honkanen , N. , Jänkälä , H. , Sipponen , P. and Härkönen , M.Expression of cyclooxygenase‐2 in human gastric carcinoma . Cancer Res. , 59 , 1276 , 1280 ( 1997. ). [PubMed] [Google Scholar]
  • 13.Müller‐Decker , K. , Scholz , K. , Marks , F. and Fürstenberger , G.Differential expression of prostaglandin H synthase isozymes during multistage carcinogenesis in mouse epidermis . Mol. Carcinog. , 59 , 31 , 41 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 14.Liu , X.‐H. and Rose , D. P.Differential expression and regulation of cyclooxygenase‐1 and ‐2 in two human breast cancer cell lines . Cancer Res. , 59 , 5125 , 5127 ( 1996. ). [PubMed] [Google Scholar]
  • 15.Tsujii , M. and DuBois , R. N.Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2 . Cell , 59 , 493 , 501 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 16.Oshima , M. , Dinchuk , J. E. , Kargman , S. L. , Oshima , H. , Hancock , B. , Kwong , E. , Trzaskos , J. M. , Evans , J. F. and Taketo , M. M.Suppression of intestinal polyposis in ApcD716 knockout mice by inhibition of cyclooxygenase 2 (COX‐2) . Cell , 59 , 803 , 809 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 17.Shiff , S. J. , Qiao , L. , Tsai , L. L. and Rigas , B.Sulindac sulfide, an aspirin‐like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT‐ 29 colon adenocarcinoma cells . J. Clin. Invest. , 59 , 491 , 503 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Duggan , D. E. , Hare , L. E. , Ditzler , C. A. , Lei , B. W. and Kwan , K. C.The disposition of sulindac . Clin. Pharmacol. Ther. , 59 , 326 , 335 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 19.Sheng , H. M. , Shao , J. Y. , Morrow , J. D. , Beauchamp , R. D. and DuBois , R. N.Modulation of apoptosis and bcl‐2 expression by prostaglandin E2 in human colon cancer cells . Cancer Res. , 59 , 362 , 366 ( 1998. ). [PubMed] [Google Scholar]
  • 20.Liu , X.‐H. , Yao , S. , Kirschenbaum , A. and Levine , A. C.NS398, a selective cyclooxygenase‐2 inhibitor, induces apoptosis and downregulates bcl‐2 expression in LNCaP cells . Cancer Res. , 59 , 4245 , 4249 ( 1998. ). [PubMed] [Google Scholar]
  • 21.Thompson , H. J. , Briggs , S. , Paranka , N. S. , Piazza , G. A. , Brendel , K. , Gross , P. H. , Sperl , G. J. , Pamukcu , R. and Ahnen , D. J.Inhibition of mammary carcinogenesis in rats by sulfone metabolite of sulindac . J. Natl. Cancer Inst. , 59 , 1259 , 1260 ( 1995. ). [PubMed] [Google Scholar]
  • 22.Tsujii , M. , Kawano , S. , Tsuji , S. , Sawaoka , H. , Hori , M. and DuBois , R. N.Cyclooxygenase regulates angiogenesis induced by colon cancer cell . Cell , 59 , 705 , 716 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 23.Eagle , H.Propagation in a fluid medium of a human epidermoid carcinoma, strain KB . Proc. Soc. Exp. Biol. Med. , 59 , 362 , 364 ( 1955. ). [DOI] [PubMed] [Google Scholar]
  • 24.Matsushita , M. , Masaki , Y. , Yagi , Y. , Tanaka , T. and Wakitani , K.Pharmacological profile of JTE‐522, a novel prostaglandin H synthase‐2 inhibitor, in rats . Inflamm. Res. , 59 , 461 , 466 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 25.Mosmann , T.Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays . J. Immunol. Methods , 59 , 55 , 63 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 26.Kim , N. W. , Piatyszek , M. A. , Prowse , K. R. , Harley , C. B. , West , M. D. , Ho , P. L. C. , Coviello , G. M. , Wright , W. E. , Weinrich , S. L. and Shay , J. W.Specific association of human telomerase activity with immortal cells and cancer . Science , 59 , 2011 , 2014 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 27.Zhou , L.X. Biological behavior of hypopharyngeal carcinoma . J. Otolaryngol. Jpn. , 100 , 59 – 67 ( 1997. ) [DOI] [PubMed] [Google Scholar]
  • 28.Metzger , U. , Meier , J. , Uhlschmidt , G. and Weihe , H.Influence of various prostaglandin synthesis inhibitors on DNH‐induced rat colon cancer . Dis. Colon Rectum , 59 , 366 , 369 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 29.Narisawa , T. , Sato , M. , Tani , M. , Kudo , T. , Takahashi , T. and Goto , A.Inhibition of development of methylnitrosourea‐ induced rat colon tumors by indomethacin treatment . Cancer Res. , 59 , 1954 , 1957 ( 1981. ). [PubMed] [Google Scholar]
  • 30.Polland , M. and Luckert , P. H.Indomethacin treatment of rats with dimethylhydrazine‐induced intestinal tumors . Cancer Treat. Rev. , 59 , 1323 , 1327 ( 1980. ). [PubMed] [Google Scholar]
  • 31.Reddy , B. S. , Murayama , H. and Kelloff , G.Dose‐related inhibition of colon carcinogenesis by dietary piroxicam, a nonsteroidal anti‐inflammatory drug, during different stages of rat colon tumor development . Cancer Res. , 59 , 5340 , 5346 ( 1987. ). [PubMed] [Google Scholar]
  • 32.Rosenberg , L. , Palmer , J. R. , Zauber , A. G. , Warshauer , M. E. , Stolley , P. D. and Shapiro , S.A hypothesis: nonsteroidal anti‐inflammatory drugs reduce the incidence of largebowel cancer . J. Natl. Cancer Inst. , 59 , 355 , 358 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 33.Thun , M. J. , Namboodiri , M. M. and Heath , C. W. J.Aspirin use and reduced risk of fatal colon cancer . N. Engl. J. Med. , 59 , 1593 , 1596 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 34.Nugent , K. P. , Farmer , K. C. , Spiegelman , A. D. , Williams , C. B. and Phillips , R. K.Randomized double blind placebo controlled clinical trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in familial adenomatous polyposis . Br. J. Surg. , 59 , 1618 , 1619 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 35.Sheng , H. , Shao , J. , Kirkland , S. C. , Isakson , P. , Coffey , R. , Morrow , J. , Beauchamp , R. D. and DuBois , R. N.Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase‐2 . J. Clin. Invest. , 59 , 2254 , 2259 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Kawamori , T. , Rao , C. V. , Seibert , K. and Reddy , B. S.Chemopreventive activity of celecoxib, a specific cyclooxygenase‐ 2 inhibitor, against colon carcinogenesis . Cancer Res. , 58 , 409 – 412 ( 1998. ) [PubMed] [Google Scholar]
  • 37.Simmons , D. L. , Levy , D. B. , Yannoni , Y. and Erikson , R. L.Identification of a phorbol ester‐repressible v‐srcinducible gene . Proc. Natl. Acad. Sci. USA , 59 , 1178 , 1182 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Hughes‐Fulford , M. , Appel , R. , Kumegawa , M. and Schmidt , J.Effect of dexamethasone on proliferating osteoblasts: inhibition of prostaglandin E2 synthesis, DNA synthesis, and alterations in actin cytoskeleton . Exp. Cell Res. , 59 , 150 , 156 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 39.Tjandrawinata , R. R. , Dahiya , R. and Hughes‐Fulford , M.Induction of cyclooxygenase‐2 mRNA by prostaglandin E2 in human prostatic carcinoma cells . Br. J. Cancer , 75 , 1111 , 1118 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Levy , G. N.Prostaglandin H synthases, nonsteroidal antiinflammatory drugs, and colon cancer . FASEB J. , 11 , 234 , 247 ( 1997. ). [PubMed] [Google Scholar]
  • 41.Chinery , R. , Coffey , R. J. , Graves‐Deal , R. , Kirkland , S. C. , Sanchez , S. C. , Zackert , W. E. , Oates , J. A. and Morrow , J. D.Prostaglandin J2 and 15‐deoxy‐ Δ12,14‐prostaglandin J2 induce proliferation of cyclooxygenase‐dependent colorectal cancer cells . Cancer Res. , 59 , 2739 , 2746 ( 1999. ). [PubMed] [Google Scholar]
  • 42.Zimmermann , K. C. , Sarbia , M. , Weber , A.‐A. , Borchard , F. , Gabbert , H. E. and Schror , K.Cyclooxygenase‐2 expression in human esophageal carcinoma . Cancer Res. , 59 , 198 , 204 ( 1999. ). [PubMed] [Google Scholar]
  • 43.Kido , A. , Tsujiuchi , T. , Morishita , T. , Tsutsumi , M. , Takahama , M. , Miyauchi , Y. , Mii , Y. , Tamai , S. and Konishi , Telomerase Y.activity correlates with growth of transplantable osteosarcomas in rats treated with cis‐diammine dichloroplatinum or the angiogenesis inhibitor AGM‐ 1470 . Jpn. J. Cancer Res. , 59 , 1074 , 1081 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES