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Medical Oncology
Published in: Medical Oncology 2/2008

01-06-2008 | Original Paper

Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study

Authors: Likun Chen, Youjian He, He Huang, Hai Liao, Weidong Wei

Published in: Medical Oncology | Issue 2/2008

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Abstract

Constitutive expression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) occurs frequently in non-small cell lung cancer (NSCLC). Anticancer research targeting EGFR has got an extensive attention especially in NSCLC and COX-2 inhibitor also shown a certain anticancer activity in recent years. Simultaneously targeting COX-2 and EGFR may be a promising therapeutic way. We carried out the in vitro study using selective COX-2 inhibitor celecoxib combined with EGFR-tyrosine kinase inhibitor (EGFR-TKI) ZD1839 on NSCLC cell lines to investigate the anti proliferation effect and the cell molecular mechanism. MTT growth assay showed the synergistic therapeutic effect of certain concentration of celecoxib combined with ZD1839 and synergistic apoptosis effect was detected by Hoechest33258 fluorescence staining and flow cytometric analysis. In western blot analysis, ZD1839 single agent inhibited the activation of EGFR and downstream cell signal transduction AKT and extrocellular signal-regulated kinase (ERK) pathways, the transcription activity of nuclear factor-kappa B (NF-κB), and the expression of COX-2. Celecoxib single agent could also inhibit AKT and ERK pathway in NSCLC, even the EGFR expression under high concentration treatment. Celecoxib combined with ZD1839 led to stronger inhibition of related cell signal transduction pathways in NSCLC.
Literature
1.
Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J cancer 2001;37(8):S4–S66.PubMedCrossRef
2.
Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular and molecular biology. Annu Rev Biochem 2000;69:145–82.PubMedCrossRef
3.
Koki AT, Jaime L. Celecoxib. A specific COX-2 inhibitor with anticancer properties. Cancer Control March/April 2002;9(2):Supplement: 28–35.
4.
Dannenberg AJ, Altorki NK, Boyle JO, et al. Cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol 2003;4:605–15.CrossRef
5.
Tsuji M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endo-peroxide synthase 2. Cell 1995;83:493–501.CrossRef
6.
Cao Y, Pearman AT, Zimmerman GA, et al. Intracellular unesterified arachidonic acid signals apoptosis. Proc Natl Acad Sci USA 2000;97:11280–5.PubMedCrossRef
7.
Chan TA, Morin PJ, Vogelstein B, et al. Mechanisms underlying nonsteroidal anti-inflammatory drug-mediated apoptosis. Proc Natl Acad Sci USA 1998;95:681–6.PubMedCrossRef
8.
Tsujii M, Kawano S, Tsuji S, et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998; 93:705–16.PubMedCrossRef
9.
O Byrne KJ, Koukourakis MI, Giatromanolaki A, et al. Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer. Br J Cancer 2000;82:1427–32.CrossRef
10.
Tsujji M, Kawano S, Dubois RN. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997;94:3330–40.CrossRef
11.
Stolina M, Sharma S, Lin Y, et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 2000;164:361–70.PubMed
12.
O Byrne KJ, Dalgleish AG. Evolution, immune response and cancer. Lancet 2000;356:1033–4.
13.
Sawaoka H, Kawano S, Tsuji S, et al. Effects of NSAIDs on proliferation of gastric cancer cells in vitro. J Clin Gastroenterol 1998;27:S47–52.PubMedCrossRef
14.
Tomozawa S, Nagawa H, Tsuno N, et al. Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522. Br J Cancer 1999;81:1274–9.PubMedCrossRef
15.
Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition. Cell 1996;87:803–9.PubMedCrossRef
16.
Giardiello FM, Hamilton SR, Krush AJ, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous. N Engl J Med 1993;328:1313–6.PubMedCrossRef
17.
Harris RE, Alshafie GA, Abou-Issa H, et al. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 2000;60(8):2101–3.PubMed
18.
Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous. N Engl J Med 2000;342:1946–52.PubMedCrossRef
19.
Harris RE, Beebe-Donk J, Schuller HM. Chemoprevention of lung cancer by non-steroidal anti-inflammatory drugs among cigarette smokers. Oncol Rep 2002;9:693–5.PubMed
20.
Akhmedkhanov A, Toniolo P, Zeleniuch-Jacquotte A, et al. Aspirin and lung cancer in women. Br J Cancer 2002;87:49–53.PubMedCrossRef
21.
Hida T, Kozaki K, Muramatsu H, et al. Cyclooxygenase-2 inhibitor induces apoptosis and enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell lines. Clin Cancer Res 2000;6:2006–11.PubMed
22.
Diperna CA, Bart RD, Sievers EM, et al. Cyclooxygenase-2 inhibition decreases primary and metastatic tumor burden in a murine model of orthotopic lung adenocarcinoma. J Thorac Cardiovasc Surg 2003;126(4):1129–33.PubMedCrossRef
23.
Tanaka T, Delong PA, Amin K, et al. Treatment of lung cancer using clinically relevant oral doses of the cyclooxygenase-2 inhibitor rofecoxib: potential value as adjuvant therapy after surgery. Ann Surg 2005;241(1):168–78.PubMed
24.
Altorki N, Keresztes R, Port J, et al. Celecoxib(Celebrex), a selective COX-2 inhibitor, enhances the response to preoperative paclitaxel/carboplatin in early stage non-small cell lung cancer. Am Soc Clin Oncol Proc 2002;21:A101.
25.
Csiki I, Morrow JD, Sandler A, et al. Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase II trial of celecoxib and docetaxel. Clin Cancer Res 2005;11(18):6634–40.PubMedCrossRef
26.
Wells A. The epidermal growth factor receptor (EGFR)-a new target in cancer therapy. Signal 2000;1:4–11.CrossRef
27.
Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999;82:241–50.PubMedCrossRef
28.
Fukuodk M, Yano S, Gaccone G, et al. Final results from a Phase II trial of ZD1839(‘Iressa’) for patients with advanced non-small-cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol, 2002;21:298a (A1188).
29.
Kris MG, Natale RB, Herbst RS, et al. A Phase II trial of ZD1839 (‘Iressa’) in advanced non-small-cell lung cancer (NSCLC) patients who had failed platinum-and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol, 2002;21:292a(A1166).
30.
Tortora G, Caputo R, Damiano V, et al. Combination of a selective cyclooxygenase-2 inhibitor with epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 and protein kinase A antisense causes cooperative antitumor and antiangiogenic effect. Clin Cancer Res 2003;9:1566–72.PubMed
31.
Torrance CJ, Jackson PE, Montgomery E, et al. Combinatorial chemoprevention of intestinal neoplasia. Nat Med 2000;6:1024–8.PubMedCrossRef
32.
Chen Z, Zhang X, Li M, et al. Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck. Clin Cancer Res 2004;10:5930–9.PubMedCrossRef
33.
Jin Z. The addictiveness of combined drug treatment. Trans Pharmacol Chin Tradit med 1991;2:70–2.
34.
Hida T, Yatabe Y, Achiwa H, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998;58:3761–4.PubMed
35.
Ermert L, Dierkes C, Ermert M. Immumohistochemical expression of cyclooxygenase isoenzymes and downstream enzymes in human lung tumors. Clin Cancer Res 2003;9:1604–10.PubMed
36.
Petkova DK, Clelland C, Ronan J, et al. Overexpression of cyclooxygenade-2 in non-small cell lung cancer. Respir Med 2004;98(2):164–72.PubMedCrossRef
37.
Richardson CM, Richardson D, Swinson DE, et al. Cyclooxygenase-2 protein levels are independent of epidermal growth factor receptor expression or activation in operable non-small cell lung cancer. Lung Cancer 2005;48(1):47–57.PubMedCrossRef
38.
Lu C, Soria LC, Tang X, et al. Prognostic factors in resected stage I non-small-cell lung cancer: a multivariate analysis of six molecular markers. J Clin Oncol 2004;22(22):4575–83.PubMedCrossRef
39.
Chang HC, Weng CF. Cyclooxygenase-2 level and culture conditions influence NS398-induced apoptosis and caspase activation in lung cancer cells. Oncol Rep 2001;8(6):1321–5.PubMed
40.
Sánchez Alcázar JA, Bradbury DA, Pang L, et al. Cyclooxygenase (COX) inhibitors induce apoptosis in non-small cell lung cancer through cyclooxygenase in-dependent pathways. Lung Cancer 2003;40:33–44.PubMedCrossRef
41.
Sun SY, Schroeder CP, Yue P, et al. Enhanced growth inhibition and apoptosis induction in NSCLC cell lines by combination of celecoxib and 4HPR at clinically relevant concentrations. Cancer Biol Ther 2005;4(4):407–13.PubMedCrossRef
42.
Liu X, Yue P, Zhou Z, et al. Death receptor regulation and celecoxib-induced apoptosis in human lung cancer cells. J Natl Cancer Inst 2004;96(23):1769–80.PubMed
43.
Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366(9496):1527–37.PubMedCrossRef
44.
Dannenberg AJ, Lippman SM, Mann JR, et al. Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 2005;23(2):254–67.PubMedCrossRef
45.
Richardson CM, Sharma RA, Cox G, et al. Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer: potential targets for chemoprevention and systemic therapy. Lung Cancer 2003;39:1–13.PubMedCrossRef
46.
Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990;31:637–43.
47.
Sako Y, Minoghchi S, Yanagida T. Single-molecule imaging of EGFR signalling on the surface of living cells. Nat Cell Biol 2000;2:168–72.PubMedCrossRef
48.
Riese DJ 2nd, Stern DF. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays 1998;20:41–8.PubMedCrossRef
49.
Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol -3-OH kinase signal transduction. Nature 1995;376:599–602.PubMedCrossRef
50.
Muthuswamy SK, Gilman M, Brugge JS. Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol 1999;19:6845–57.PubMed
51.
Xie W, Herschman HR. V-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. J Biol Chem 1995;270:27622–8.PubMedCrossRef
52.
Coffey RJ, Hawkey CJ, Damstrup L, et al. Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells. Proc Natl Acad Sci USA 1997;94(2):657–62.PubMedCrossRef
53.
Mestre JR, Subbaramaiah K, Sacks PG, et al. Retinoids suppress epidermal growth factor-induced transcription of cyclooxygenase-2 in human oral squamous carcinoma cells. Cancer Res 1997;57(14):2890–5.PubMed
54.
Yucel-Lindberg T, Ahola H, Carlstedt-Duke J, et al. Involvement of tyrosine kinases on cyclooxygenase expression and prostaglandin E2 production in human gingival fibroblasts stimulated with interleukin-1beta and epidermal growth factor. Biochem Biophys Res Commun 1999;257(2):528–32.PubMedCrossRef
55.
Sheng H, Shao J, Washington MK, et al. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J Biol Chem 2001;276:18075–81.PubMedCrossRef
56.
Tsujii M, DuBois RN. Alterations in cellular adehesion and apoptosis in epithelial cells over-expressing prostaglandin endoperoxide synthase-2. Cell 1995;83:493–501.PubMedCrossRef
57.
Shao J, Lee SB, Guo H, et al. Prostaglandin E2 stimulates the growth of colon cancer cells via induction of amphiregulin. Cancer Res 2003;63:5218–23.PubMed
58.
Buchanan FG, Wang D, Bargiacchi F, et al. Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003;278:35451–7.PubMedCrossRef
59.
Fujino H, West KA, Regan JW. Phosphorylation of glycogen synthase kinase-3 and stimulation of T-cell factor signaling following activation of EP2 and EP4 prostanoid receptors by prostaglandin E2. J Biol Chem 2002;277:2614–9.PubMedCrossRef
60.
Krysan K, Reckamp KL, Dalwadi H, et al. Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signaling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner. Cancer Res 2005;65(14):6275–81.PubMedCrossRef
61.
62.
Gingery A, Bradley E, Shaw A, et al. Phosphatidylinositol 3-kinase coordinately activates the MEK/ERK and AKT/NF Kb pathways to maintain osteoclast survival. J Cell Biochem 2003;89:165–179.PubMedCrossRef
Metadata
Title
Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study
Authors
Likun Chen
Youjian He
He Huang
Hai Liao
Weidong Wei
Publication date
01-06-2008
Publisher
Humana Press Inc
Published in
Medical Oncology / Issue 2/2008
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-007-9015-1

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