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Anti-cancer effects of celecoxib in head and neck carcinoma

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Molecules and Cells

Abstract

Although many studies highlighted cyclooxygenase2 (COX2) inhibition as a promising therapeutic strategy for cancer, more evidence is needed for clinical application. The purpose of this study was to investigate the feasibility of COX2 inhibition as a strategic treatment modality for head and neck carcinoma (HNC). We tested COX2 inhibitor, celecoxib in six types of HNC cells and analyzed the expression changes in proteins related to angiogenesis and apoptosis in vitro. We also evaluated proliferation, gelatinolysis and in vitro invasion. We used a hamster carcinogenesis model and a mouse tumorigenesis model for the in vivo evaluation of COX2 inhibition. We performed immunohistochemistry to assess changes in the expression of COX2, survivin and angiogenesis. Celecoxib administration caused decreases in the expressions of COX2, VEGF and survivin in vitro. Proliferation, in vitro invasion and gelatinolytic activity were reduced in HNC cell lines, but the effect was inconsistent across lines. COX2 inhibition retarded oral carcinogenesis from an early carcinogenic stage with increased apoptosis and decreased survivin expression. COX2 inhibition did not inhibit tumor growth, even with the COX2 downregulation and decrease in neovascularization. We conclude that COX2 inhibition has a chemopreventive effect, but its application as a treatment of HNC in a clinical setting still requires further research to overcome its limited anti-cancer effects.

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References

  • Attiga, F.A., Fernandez, P.M., Weeraratna, A.T., Manyak, M.J., and Patierno, S.R. (2000). Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Res. 60, 4629–4637.

    CAS  PubMed  Google Scholar 

  • Barnes, N., Haywood, P., Flint, P., Knox, W.F., and Bundred, N.J. (2006). Survivin expression in in situ and invasive breast cancer relates to COX-2 expression and DCIS recurrence. Brit. J. Cancer 94, 253–258.

    Article  CAS  PubMed  Google Scholar 

  • Bartsch, H. (2000). Studies on biomarkers in cancer etiology and prevention: a summary and challenge of 20 years of interdisciplinary research. Mutat. Res. 462, 255–279.

    Article  CAS  PubMed  Google Scholar 

  • Bartsch, H., and Nair, J. (2000). Ultrasensitive and specific detection methods for exocylic DNA adducts: markers for lipid peroxidation and oxidative stress. Toxicology 153, 105–114.

    Article  CAS  PubMed  Google Scholar 

  • Bernardo, M.M., and Fridman, R. (2003). TIMP-2 (tissue inhibitor of metalloproteinase-2) regulates MMP-2 (matrix metalloproteinase-2) activity in the extracellular environment after pro-MMP-2 activation by MT1 (membrane type 1)-MMP. Biochem. J. 374, 739–745.

    Article  CAS  PubMed  Google Scholar 

  • Bosari, S. (1992). Microvessel quantitation and prognosis in invasive breast carcinoma, Hum. Pathol. 23, 755–761.

    Article  CAS  PubMed  Google Scholar 

  • Chan, T.A. (2002). Nonsteroidal anti-inflammatory drugs, apoptosis, and colon-cancer chemoprevention. Lancet. Oncol. 3, 166–174.

    Article  CAS  PubMed  Google Scholar 

  • Chan, G., Boyle, J.O., Yang, E.K., Zhang, F., Sacks, P.G., Shah, J.P., Edelstein, D., Soslow, R.A., Koki, A.T., Woerner, B.M., et al. (1999). Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res. 59, 991–994.

    CAS  PubMed  Google Scholar 

  • Crowell, P.L., Schmidt, C.M., Yip-Schneider, M.T., Savage, J.J., Hertzler, II D.A., and Cummings, W.O. (2006). Cyclooxygenase-2 expression in hamster and human pancreatic neoplasia. Neoplasia 8, 437–445.

    Article  CAS  PubMed  Google Scholar 

  • Dannenberg, A.J., Altorki, N.K., Boyle, J.O., Dang, C., Howe, L.R., Weksler, B.B., and Subbaramaiah, K. (2001). Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. Lancet Oncol. 2, 544–551.

    Article  CAS  PubMed  Google Scholar 

  • Duffy, M.J., O’Donovan, N., Brennan, D.J., Gallagher, W.M., and Ryan, B.M. (2007). Survivin: a promising tumor biomarker. Cancer Lett. 249, 49–60.

    Article  CAS  PubMed  Google Scholar 

  • Dvory-Sobol, H., Cohen-Noyman, E., Kazanov, D., Figer, A., Birkenfeld, S., Madar-Shapiro, L., Benamouzig, R., and Arber, N. (2006). Celecoxib leads to G2/M arrest by induction of p21 and down-regulation of cyclin B1 expression in a p53-independent manner. Eur. J. Cancer. 42, 422–426.

    Article  CAS  PubMed  Google Scholar 

  • Edwards, J., Mukherjee, R., Munro, A.F., Wells, A.C., Almushatat, A., and Bartlett, J.M. (2004). HER2 and COX2 expression in human prostate cancer. Eur. J. Cancer 40, 50–55.

    Article  CAS  PubMed  Google Scholar 

  • Erkanli, S., Bolat, F., Kayaselcuk, F., Demirhan, B., and Kuscu, E. (2007). COX-2 and survivin are overexpressed and positively correlated in endometrial carcinoma. Gynecol. Oncol. 104, 320–325.

    Article  CAS  PubMed  Google Scholar 

  • Feng, L., and Wang, Z. (2006). Chemopreventive effect of celecoxib in oral precancers and cancers. Laryngoscope 116, 1842–1845.

    Article  CAS  PubMed  Google Scholar 

  • Folkman, J. (1990). What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer Inst. 82, 4–6.

    Article  CAS  PubMed  Google Scholar 

  • Folkman, J., and Shing, Y., (1992). Angiogenesis. J. Biol. Chem. 267, 10931–10934.

    CAS  PubMed  Google Scholar 

  • Gleich, L.L., Zimmerman, N., Wang, Y.O., and Gluckman, J.L. (1998). Angiogenic inhibition for the treatment of head and neck cancer. Anticancer Res. 18, 2607–2609.

    CAS  PubMed  Google Scholar 

  • Goodin, S., and Shiff, S.J. (2004). NSAIDs for the chemoprevention of oral cancer: promise or pessimism? Commentary re J.L. Mulshine et al., randomized, double-blind, placebocontrolled, phase IIB trial of the cyclooxygenase inhibitor Ketorolac as an oral rinse in oropharyngeal leukoplakia. Clin. Cancer Res. 10, 1565–1573.

    Article  Google Scholar 

  • Hao, Y., Xie, T., Korotcov, A., Zhou, Y., Pang, X., Shan, L., Ji, H., Sridhar, R., Wang, P., Califano, J., et al. (2009). Salvianolic acid B inhibits growth of head and neck squamous cell carcinoma in vitro and in vivo via cyclooxygenase-2 and apoptotic pathways. Int. J. Cancer 124, 2200–2209.

    Article  CAS  PubMed  Google Scholar 

  • Harris, R.E. (2007). Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. Subcell. Biochem. 42, 93–126.

    Article  PubMed  Google Scholar 

  • Haupt, S., Kleinstern, J., Haupt, Y., and Rubinstein, A. (2006). Celecoxib can induce cell death independently of cyclooxygenase-2, p53, Mdm2, c-Abl and reactive oxygen species. Anti-Cancer Drugs 17, 609–619.

    Article  CAS  PubMed  Google Scholar 

  • Hsue, S.S., Chen, Y.K., and Lin, L.M. (2008). Expression of survivin and XIAP for DMBA-induced hamster buccal pouch squamous cell carcinogenesis is associated with p53 accumulation. Oral Oncol. 44, 43–49.

    Article  CAS  PubMed  Google Scholar 

  • Inoue, H., Yokoyama, C., Hara, S., Tone, Y., and Tanabe, T. (1995). Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element. J. Biol. Chem. 270, 24965–24971.

    Article  CAS  PubMed  Google Scholar 

  • Johnstone, S., and Logan, R.M. (2006). The role of vascular endothelial growth factor (VEGF) in oral dysplasia and oral squamous cell carcinoma. Oral Oncol. 42, 337–342.

    Article  CAS  PubMed  Google Scholar 

  • Kennedy, S.M., O’Driscoll, L., Purcell, R., Fitz-Simons, N., Mc-Dermott, E.W., and Hill, A.D. (2003). Prognostic importance of survivin in breast cancer. Br. J. Cancer 88, 1077–1083.

    Article  CAS  PubMed  Google Scholar 

  • Kinugasa, Y., Hatori, M., Ito, H., Kurihara, Y., Ito, D., and Nagumo, M. (2004). Inhibition of cyclooxygenase-2 suppresses invasiveness of oral squamous cell carcinoma cell lines via downregulation of matrix metalloproteinase-2 and CD44. Clin. Exp. Metastasis 21, 737–745.

    Article  CAS  PubMed  Google Scholar 

  • Kulp, S.K., Yang, Y.T., Hung, C.C., Chen, K.F., Lai, J.P., Tseng, P.H., Fowble, J.W., Ward, P.J., and Chen, C.S. (2004). 3-phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells. Cancer Res. 64, 1444–1451.

    Article  CAS  PubMed  Google Scholar 

  • Lai, G.H., Zhang, Z., and Sirica, A.E. (2003). Celecoxib acts in a cyclooxygenase-2-independent manner and in synergy with emodin to suppress rat cholangiocarcinoma growth in vitro through a mechanism involving enhanced Akt inactivation and increased activation of caspases-9 and -3. Mol. Cancer Ther. 2, 265–271.

    CAS  PubMed  Google Scholar 

  • Le Bitoux, M.A., and Stamenkovic, I. (2008). Tumor-host interactions: the role of inflammation. Histochem. Cell Biol. 130, 1079–1090.

    Article  PubMed  Google Scholar 

  • Lerebours, F., Vacher, S., Andrieu, C., Espie, M., Marty, M., Lidereau, R., and Bieche, I. (2008). NF-kappa B genes have a major role in inflammatory breast cancer. BMC Cancer 4, 8–41.

    Google Scholar 

  • Liu, C.H., Chang, S.H., Narko, K., Trifan, O.C., Wu, M.T., Smith, E., Haudenschild, C., Lane, T.F., and Hla, T. (2001). Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J. Biol. Chem. 276, 18563–18569.

    Article  CAS  PubMed  Google Scholar 

  • Maeda, S., and Omata, M. (2008). Inflammation and cancer: role of nuclear factor-kappaB activation. Cancer Sci. 99, 836–842.

    Article  CAS  PubMed  Google Scholar 

  • Maier, T.J., Schilling, K., Schmidt, R., Geisslinger, G., and Grösch, S. (2004). Cyclooxygenase-2 (COX-2)-dependent and -independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. Biochem. Pharmacol. 67, 1469–1478.

    Article  CAS  PubMed  Google Scholar 

  • Mann, J.R., Backlund, M.G., and DuBois, R.N. (2005). Mechanisms of Disease: inflammatory mediators and cancer prevention. Nat. Clin. Pract. Oncol. 2, 202–210.

    Article  CAS  PubMed  Google Scholar 

  • Mohan, S., and Epsteina, J.B. (2003). Carcinogenesis and cyclooxygenase: the potential role of COX-2 inhibition in upper aerodigestive tract cancer. Oral Oncol. 39, 537–546.

    Article  CAS  PubMed  Google Scholar 

  • Mori, F., Piro, F.R., Rocca, C.D., Mesiti, G., Giampaoli, S., Silvestre, G., and Lazzaro, D. (2007). Survivin and Cyclooxygenase-2 are co-expressed in human and mouse colon carcinoma and in terminally differentiated colonocytes. Histol. Histopathol. 22, 61–77.

    CAS  PubMed  Google Scholar 

  • Ouhtit, A., Matrougui, K., Bengrine, A., Koochekpour, S., Zerfaoui, M., and Yousief, Z. (2007). Survivin is not only a death encounter but also a survival protein for invading tumor cells. Front. Biosci. 12, 1260–1270.

    Article  CAS  PubMed  Google Scholar 

  • Park, M.K., Hwang, S.Y., Kim, J.O., Kwack, M.H., Kim, J.C., Kim, M.K., and Sung, Y.K. (2004). NS398 inhibits the growth of Hep3B human hepatocellular carcinoma cells via caspaseindependent apoptosis. Mol. Cells 17, 45–50.

    CAS  PubMed  Google Scholar 

  • Parkin, D.M., Bray, F., Ferlay, J., and Pisani, P. (2005). Global cancer statistics 2002. CA Cancer J. Clin. 55, 74–108.

    Article  PubMed  Google Scholar 

  • Pyrko, P., Soriano, N., Kardosh, A., Liu, Y.T., Uddin, J., Petasis, N.I., Hofman, F.M., Chen, C.S., Chen, T.C., and Schönthal, A.H. (2006). Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo. Mol. Cancer 18, 5.19.

    Google Scholar 

  • Ristimaki, A., Honkanen, N., Jankala, H., Sipponen, P., and Harkonen, M. (1997). Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res. 57, 1276–1280.

    CAS  PubMed  Google Scholar 

  • Ristimaki, A., Nieminen, O., Saukkonen, K., Hotakainen, K., Nordling, S., and Haglund, C. (2001). Expression of cyclooxygenase-2 in human transitional cell carcinoma of the urinary bladder. Am. J. Pathol. 158, 849–853.

    CAS  PubMed  Google Scholar 

  • Sheng, H., Shao, J., Dixon, D.A., Williams, C.S., Prescott, S.M., DuBois, R.N., and Beauchamp, R.D. (2000). Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J. Biol. Chem. 275, 6628–6635.

    Article  CAS  PubMed  Google Scholar 

  • Shin, S., Sung, B.J., Cho, Y.S., Kim, H.J., Ha, N.C., Hwang, J.I., Chung, C.W., Jung, Y.K., and Oh, B.H. (2001). An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry 40, 1117–1123.

    Article  CAS  PubMed  Google Scholar 

  • Steinbach, G., Lynch, P.M., Phillips, R.K., Wallace, M.H., Hawk, E., Gordon, G.B., Wakabayashi, N., Saunders, B., Shen, Y., Fujimura, T., et al. (2000). The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 342, 1946–1952.

    Article  CAS  PubMed  Google Scholar 

  • Tang, D.W., Lin, S.C., Chang, K.W., Chi, C.W., Chang, C.S., and Liu, T.Y. (2003). Elevated expression of cyclooxygenase (COX)-2 in oral squamous cell carcinoma—evidence for COX-2 induction by areca quid ingredients in oral keratinocytes. J. Oral Pathol. Med. 32, 522–529.

    Article  CAS  PubMed  Google Scholar 

  • Ulrich, C.M., Bigler, J., and Potter, J.D. (2006). Non-steroidal antiinflammatory drugs for cancer prevention, promise, perils, and pharmacogenetics. Nat. Rev. Cancer 6, 130–140.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Z., Fuentes, C.F., and Shapshay, S.M. (2002). Antiangiogenic and chemopreventive activities of celecoxib in oral carcinoma cell. Laryngoscope 112, 839–843.

    Article  CAS  PubMed  Google Scholar 

  • Wilson, K.T., Fu, S., Ramanujam, K.S., and Meltzer, S.J. (1998). Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett’s esophagus and associated adenocarcinomas. Cancer Res. 58, 2929–2934.

    CAS  PubMed  Google Scholar 

  • Woolgar, J.A., Rogers, S.N., Lowe, D., Brown, J.S., and Vaughan, E.D. (2003). Cervical lymph node metastasis in oral cancer: the importance of even microscopic extracapsular spread. Oral Oncol. 39, 130–137.

    Article  CAS  PubMed  Google Scholar 

  • Yamazaki, R., Kusunoki, N., Matsuzaki, T., Hashimoto, S., and Kawai, S. (2002). Selective cyclooxygenase-2 inhibitors show a differential ability to inhibit proliferation and induce apoptosis of colon adenocarcinoma cells. FEBS Lett. 531, 278–284.

    Article  CAS  PubMed  Google Scholar 

  • Yang, C., Zeisberg, M., Lively, J.C., Nyberg, P., Afdhal, N., and Kalluri, R. (2003). Integrin alpha1beta1 and alpha2beta1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. Cancer Res. 63, 8312–8317.

    CAS  PubMed  Google Scholar 

  • Yang, W.T., Lewis, M.T., and Hess, K. (2010). Decreased TGF beta signaling and increased COX2 expression in high risk women with increased mammographic breast density. Breast Cancer Res. Treat. 119, 305–314.

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann, K.C., Sarbia, M., Weber, A.A., Borchard, F., Gabbert, H.E., and Schrör, K. (1999). Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res. 59, 198–204.

    CAS  PubMed  Google Scholar 

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Correspondence to Hoon Myoung.

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Kim, YY., Lee, EJ., Kim, YK. et al. Anti-cancer effects of celecoxib in head and neck carcinoma. Mol Cells 29, 185–194 (2010). https://doi.org/10.1007/s10059-010-0026-y

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