Regulation of endothelial cell integrin function and angiogenesis by COX-2, cAMP and Protein Kinase A

Olivier Dormond; Curzio Rüegg

doi:10.1160/TH03-03-0196

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(04): 577-585
DOI: 10.1160/TH03-03-0196

Review Article

Schattauer GmbH

Regulation of endothelial cell integrin function and angiogenesis by COX-2, cAMP and Protein Kinase A

Olivier Dormond

¹Centre Pluridisciplinaire d’Oncologie (CePO), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

³Current address: Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

,

Curzio Rüegg

¹Centre Pluridisciplinaire d’Oncologie (CePO), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

²Swiss Institute for Experimental Cancer Research (ISREC), NCCR Molecular Oncology, Epalinges, Switzerland

› Author Affiliations

Abstract

Summary

Angiogenesis, the development of new blood vessels from preexisting vessels, is a key step in tumor growth, invasion and metastasis formation. Inhibition of tumor angiogenesis is considered as an attractive approach to suppress cancer progression and spreading. Adhesion receptors of the integrin family promote tumor angiogenesis by mediating cell migration, proliferation and survival of angiogenic endothelial cells. Integrins up regulated and highly expressed on neovascular endothelial cells, such as αVβ3 and α5β1, have been considered as relevant targets for anti-angiogenic therapies. Small molecular integrin antagonists or blocking antibodies suppress angiogenesis and tumor progression in many animal models, and some of them are currently being tested in cancer clinical trials as anti-angiogenic agents. COX-2 inhibitors exert anti-cancer effects, at least in part, by inhibiting tumor angiogenesis. We have recently shown that COX-2 inhibitors suppress endothelial cell migration and angiogenesis by preventing αVβ3-mediated and cAMP/PKA-dependent activation of the small GTPases Rac and Cdc42. Here we will review the evidence for the involvement of vascular integrins in mediating angiogenesis and the role of COX-2 metabolites in modulating the cAMP/Protein Kinase A pathway and αVβ3-dependent Rac activation in endothelial cells.

The pulication was partially financed by Serono Foundation for the Advancement of Medical Sience.

Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6–9, 2003 in Geneva, Switzerland.

Keywords

Adhesion receptors - integrins - cell-matrix interactions - endothelial cells - prostaglandins

Full Text

References

References
1 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
2 Cavallaro U, Christofori G. Molecular mechanisms of tumor angiogenesis and tumor progression. J Neurooncol 2000; 50: 63-70.
3 Risau W. Mechanisms of angiogenesis. Nature 1997; 386: 671-4.
4 Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000; 6: 389-95.
5 Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2002; 2: 727-39.
6 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249-57.
7 Holash J, Wiegand SJ, Yancopoulos GD. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 1999; 18: 5356-62.
8 Yancopoulos GD, Davis S, Gale NW. et al. Vascular-specific growth factors and blood vessel formation. Nature 2000; 407: 242-8.
9 Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69: 11-25.
10 Hynes RO. Cell adhesion: old and new questions. Trends Cell Biol 1999; 9: M33-7.
11 Plow EF, Haas TA, Zhang L. et al. Ligand binding to integrins. Journal of Biological Chemistry. 2000; 275: 21785-8.
12 Woodside DG, Liu S, Ginsberg MH. Integrin activation. Thromb Haemost 2001; 86: 316-23.
13 Sastry SK, Burridge K. Focal adhesions: a nexus for intracellular signaling and cytoskeletal dynamics. Exp Cell Res 2000; 261: 25-36.
14 Giancotti FG, Ruoslahti E. Integrin signaling. Science 1999; 285: 1028-32.
15 Miranti CK, Brugge JS. Sensing the environment: a historical perspective on integrin signal transduction. Nat Cell Biol 2002; 4: E83-90.
16 Smyth SS, Patterson C. Tiny dancers: the inte-grin-growth factor nexus in angiogenic signaling. J Cell Biol 2002; 158: 17-21.
17 Rüegg C, Dormond O, Foletti A. Suppression of tumor angiogenesis through the inhibition of integrin function and signaling in endothelial cells: which side to target?. Endothelium 2002; 9: 151-60.
18 Eliceiri B P. Integrin and growth factor receptor crosstalk. Circ Res 2001; 89: 1104-10.
19 Rüegg C, Mariotti A. Vascular integrins: pleio-tropic adhesion and signaling molecules in vascular homeostasis and angiogenesis. Cell Mol Life Sci 2003; 60: 1135-57.
20 Hynes RO, Bader BL. Targeted mutations in integrins and their ligands: their implications for vascular biology. Thromb Haemost 1997; 78: 83-7.
21 Hynes RO, Bader BL, Hodivala-Dilke K. Integrins in vascular development. Braz J Med Biol Res 1999; 32: 501-10.
22 Sheppard D. In vivo functions of integrins: lessons from null mutations in mice. Matrix Biol 2000; 19: 203-9.
23 Rupp PA, Little CD. Integrins in vascular development. Circ Res 2001; 89: 566-72.
24 Bouvard D. et al. Functional consequences of integrin gene mutations in mice. Circ Res 2001; 89: 211-23.
25 Yang JT, Rayburn H, Hynes RO. Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development 1993; 119: 1093-105.
26 Francis SE, Goh KL, Hodivala-Dilke K. et al. Central roles of alpha5beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol 2002; 22: 927-33.
27 Yang JT, Rayburn H, Hynes RO. Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development 1995; 121: 549-60.
28 Bader BL, Rayburn H, Crowley D. et al. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 1998; 95: 507-19.
29 McCarty JH, Monahan-Earley RA, Brown LF. et al. Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alphav integrins. Mol Cell Biol 2002; 22: 7667-77.
30 McHugh KP, Hodivala-Dilke K, Zheng MH. et al. Mice lacking beta3 integrins are osteo-sclerotic because of dysfunctional osteoclasts. J Clin Invest 2000; 105: 433-40.
31 Huang X, Griffiths M, Wu J. et al. Normal development, wound healing, and adenovirus susceptibility in beta5-deficient mice. Mol Cell Biol 2000; 20: 755-9.
32 Reynolds LE, Wyder L, Lively JC. et al. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 inte-grins. Nat Med 2002; 8: 27-34.
33 Tomiyama Y. Glanzmann thrombasthenia: integrin alpha IIb beta 3 deficiency. Int J Hematol 2000; 72: 448-54.
34 Hynes RO, Hodivala-Dilke KM. Insights and questions arising from studies of a mouse model of Glanzmann thrombasthenia. Thromb Haemost 1999; 82: 481-5.
35 Huang XZ, Wu JF, Ferrando R. et al. Fatal bilateral chylothorax in mice lacking the inte-grin alpha9beta1. Mol Cell Biol 2000; 20: 5208-15.
36 Petrova TV, Makinen T, Makela TP. et al. Lymphatic endothelial reprogramming of vascular endothelial cells by the Pro-1 homeo-box transcription factor. Embo J 2002; 21: 4593-9.
37 Varner JA, Cheresh DA. Tumor angiogenesis and the role of vascular cell integrin alphavbeta3. Important Adv Oncol 1996; 69-87.
38 Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 1994; 264: 569-71.
39 Max R, Gerritsen RR, Nooijen PT. et al. Immunohistochemical analysis of integrin alpha vbeta3 expression on tumor-associated vessels of human carcinomas. Int J Cancer 1997; 71: 320-4.
40 Sipkins DA, Cheresh DA, Kazemi MR. et al. Detection of tumor angiogenesis in vivo by alpha V beta 3 - targeted magnetic resonance imaging. Nat Med 1998; 4: 623-6.
41 Cheresh DA. Human endothelial cells synthe-size and express an Arg-Gly-Asp-directed adhesion receptor involved in attachment to fibrinogen and von Willebrand factor. Proc Natl Acad Sci U S A 1987; 84: 6471-5.
42 Dechantsreiter MA, Planker E, Matha B. et al. N-Methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists. J Med Chem 1999; 42: 3033-40.
43 Friedlander M, Brooks PC, Shaffer RW. et al. Definition of two angiogenic pathways by distinct alpha v integrins. Science 1995; 270: 1500-2.
44 Hammes HP, Brownlee M, Jonczyk A. et al. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type inte-grins inhibits retinal neovascularization. Nat Med 1996; 2: 529-33.
45 Brooks PC, Montgomery AM, Rosenfeld M. et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994; 79: 1157-64.
46 Brooks PC, Stromblad S, Klemke R. et al. Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 1995; 96: 1815-22.
47 Soldi R, Mitola S, Strasly M. et al. Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. Embo J 1999; 18: 882-92.
48 Eliceiri BP. et al. Integrin alphavbeta3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis. J. Cell Biol 1998; 140: 1255-63.
49 Brooks PC. et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 1996; 85: 683-93.
50 Byzova TV, Goldman CK, Pampori N. et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell 2000; 6: 851-60.
51 Scatena M, Almeida M, Chaisson ML. et al. NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. J Cell Biol 1998; 141: 1083-93.
52 Stromblad S, Becker JC, Yebra M. et al. Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin alphaVbeta3 during angiogenesis. J Clin Invest 1996; 98: 426-33.
53 Stupack DG, Puente XS, Boutsaboualoy S. et al. Apoptosis of adherent cells by of caspase-8 to unligated integrins. J Cell Biol 2001; 155: 459-70.
54 Hynes RO. A reevaluation of integrins as regulators of angiogenesis. Nat Med 2002; 8: 918-21.
55 Collo G, Pepper MS. Endothelial cell integrin alpha5beta1 expression is modulated by cyto-kines and during migration in vitro. Journal of Cell Science 1999; 112: 569-78.
56 Taverna D, Hynes RO. Reduced blood vessel formation and tumor growth in alpha5-inte-grin-negative teratocarcinomas and embryoid bodies. Cancer Res 2001; 61: 5255-61.
57 Kim S, Bakre M, Yin H, Varner JA. Inhibition of endothelial cell survival and angiogenesis by protein kinase A. J Clin Invest 2002; 110: 933-41.
58 Kim S, Harris M, Varner JA. Regulation of integrin alpha vbeta 3-mediated endothelial cell migration and angiogenesis by integrin alpha 5beta 1 and protein kinase A [In Process Citation]. J Biol Chem 2000; 275: 33920-8.
59 Pasqualini R, Koivunen E, Ruoslahti E. A peptide isolated from phage display libraries is a structural and functional mimic of an RGD-binding site on integrins. J Cell Biol 1995; 130: 1189-96.
60 Stoeltzing O, Liu W, Reinmuth N. et al. Inhibition of integrin alpha5beta1 function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice. Int J Cancer 2003; 104: 496-503.
61 Senger DR, Claffey KP, Benes JE. et al. Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. Proceedings of the National Academy of Sciences of the United States of America 1997; 94: 13612-7.
62 Senger DR, Perruzzi CA, Streit M. et al. The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol 2002; 160: 195-204.
63 Funahashi Y, Sugi NH, Semba T. et al. Sulfonamide derivative, E7820, is a unique angiogenesis inhibitor suppressing an expression of integrin alpha2 subunit on endothelium. Cancer Res 2002; 62: 6116-23.
64 Pozzi A, Moberg PE, Miles LA. et al. Elevated matrix metalloprotease and angiosta-tin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. Proc Natl Acad Sci USA 2000; 97: 2202-7.
65 Pozzi A, Wary KK, Giancotti FG. et al. Integrin alpha1beta1 mediates a unique collagen-dependent proliferation pathway in vivo. J Cell Biol 1998; 142: 587-94.
66 Gardner H, Broberg A, Pozzi A. et al. Absence of integrin alpha1beta1 in the mouse causes loss of feedback regulation of collagen synthesis in normal and wounded dermis. J Cell Sci 1999; 112: 263-72.
67 Holtkotter O, Nieswandt B, Smyth N. et al. Integrin alpha 2-deficient mice develop normally, are fertile, but display partially defective platelet interaction with collagen. J Biol Chem 2002; 277: 10789-94.
68 Chen J, Diacovo TG, Grenache DG. et al. The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 2002; 161: 337-44.
69 Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 1999; 18: 7908-16.
70 Giardiello FM, Hamilton SR, Krush AJ. et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993; 328: 1313-6.
71 Willoughby DA, Moore AR, Colville-Nash PR. CO-1, CO-2, and CO-3 and the future treatment of chronic inflammatory disease. Lancet 2000; 355: 646-8.
72 Chandrasekharan NV, Dai H, Roos KL. et al. CO-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA 2002; 99: 13926-31.
73 Dubois RN, Abramson SB, Crofford L. et al. Cyclooxygenase in biology and disease. Faseb J 1998; 12: 1063-73.
74 Coyne DW, Nickols M, Bertrand W. et al. Regulation of mesangial cell cyclooxygenase synthesis by cytokines and glucocorticoids. Am J Physiol 1992; 263: F97-102.
75 Simmons DL, Levy DB, Yannoni Y. et al. Identification of a phorbol ester-repressible v-src-inducible gene. Proc Natl Acad Sci U S A 1989; 86: 1178-82.
76 Eberhart CE, Coffey RJ, Radhika A. et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 1994; 107: 1183-8.
77 Oshima M, Dinchuk JE, Kargman SL. et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (CO-2). Cell 1996; 87: 803-9.
78 Muller-Decker K, Neufang G, Berger I. et al. Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis. Proc Natl Acad Sci U S A 2002; 99: 12483-8.
79 Liu CH, Chang SH, Narko K. et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 2001; 276: 18563-9.
80 Williams CS, Tsujii M, Reese J. et al. Host cyclooxygenase-2 modulates carcinoma growth. J Clin Invest 2000; 105: 1589-94.
81 Steinbach G, Lynch PM, Phillips RK. et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946-52.
82 Masferrer JL, Leahy KM, Koki AT. et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306-11.
83 Leahy KM, Ornberg RL, Wang Y. et al. Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 2002; 62: 625-31.
84 Tsujii M, Kawano S, Tsuji S. et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998; 93: 705-16.
85 Jones MK, Wang H, Peskar BM. et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 1999; 5: 1418-23.
86 Dormond O, Foletti A, Paroz C. et al. NSAIDs inhibit alphaVbeta3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis. Nat Med 2001; 7: 1041-7.
87 Dormond O, Bezzi M, Mariotti A. et al. Prostaglandin E2 promotes integrin aVb3-dependent endothelial cell adhesion, Rac-activation and spreading through cAMP/PKA signaling. J Biol Chem 2002; 277: 45838-46.
88 Soga N, Connolly JO, Chellaiah M. et al. Rac regulates vascular endothelial growth factor stimulated motility. Cell Comm Adhes 2001; 8: 1-13.
89 Kiosses WB, Hood J, Yang S. et al. A dominant-negative p65 PAK peptide inhibits angio-genesis. Circ Res 2002; 90: 697-702.
90 Shimizu Y, van Seventer GA, Ennis E. et al. Crosslinking of the T cell-specific accessory molecules CD7 and CD28 modulates T cell adhesion. J Exp Med 1992; 175: 577-82.
91 van Willigen G, Akkerman JW. Protein kinase C and cyclic AMP regulate reversible exposure of binding sites for fibrinogen on the glycoprotein IIB-IIIA complex of human platelets. Biochem J 1991; 273: 115-20.
92 Haverstick DM, Gray LS. Lymphocyte adhesion mediated by lymphocyte function-associated antigen-1. II. Interaction between phorbol ester- and cAMP-sensitive pathways. J Immunol 1992; 149: 397-402.
93 Halvorson MJ, Coligan JE. Enhancement of VLA integrin receptor function on thymocytes by cAMP is dependent on the maturation stage of the thymocytes. J Immunol 1995; 155: 4567-74.
94 Lampugnani MG, Giorgi M, Gaboli M. et al. Endothelial cell motility, integrin receptor clustering, and microfilament organization are inhibited by agents that increase intracellular cAMP. Lab Invest 1990; 63: 521-31.
95 Lang P, Gesbert F, Delespine-Carmagnat M. et al. Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. Embo J 1996; 15: 510-9.
96 Bakre MM, Zhu Y, Yin H. et al. Parathyroid hormone-related peptide is a naturally occurring, protein kinase A-dependent angiogenesis inhibitor. Nat Med 2002; 8: 995-1003.
97 Ydrenius L, Molony L, Ng-Sikorski J. et al. Dual action of cAMP-dependent protein kinase on granulocyte movement. Biochem Biophys Res Commun 1997; 235: 445-50.
98 Goldman AP, Williams CS, Sheng H. et al. Meloxicam inhibits the growth of colorectal cancer cells. Carcinogenesis 1998; 19: 2195-9.
99 Fukutake M, Nakatsugi S, Isoi T. et al. Suppressive effects of nimesulide, a selective inhibitor of cyclooxygenase-2, on azoxyme-thane-induced colon carcinogenesis in mice. Carcinogenesis 1998; 19: 1939-42.
100 Daniel TO, Liu H, Morrow JD. et al. Thromboxane A2 is a mediator of cyclooxygenase-2-dependent endothelial migration and angiogenesis. Cancer Res 59 1999; 4574-7.
101 Kishi K, Petersen S, Petersen C. et al. Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitor. Cancer Res 2000; 60: 1326-31.
102 Majima M, Hayashi I, Muramatsu M. et al. Cyclo-oxygenase-2 enhances basic fibroblast growth factor-induced angiogenesis through induction of vascular endothelial growth factor in rat sponge implants. Br J Pharmacol 2000; 130: 641-9.
103 Zhang X, Morham SG, Langenbach R. et al. Malignant transformation and antineoplastic actions of nonsteroidal antiinflammatory drugs (NSAIDs) on cyclooxygenase-null embryo fibroblasts. J Exp Med 1999; 190: 451-59.
104 Grosch S, Tegeder I, Niederberger E. et al. CO-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective CO-2 inhibitor celecoxib. FASEB J 2001; 15: 2742-4.
105 Wang Z, Fuentes CF, Shapshay SM. Antiangiogenic and chemopreventive activities of celecoxib in oral carcinoma cell. Laryngoscope 2002; 112: 839-43.
106 Kundu N, Fulton AM. Selective cyclooxygenase (COX)-1 or CO-2 inhibitors control metastatic disease in a murine model of breast cancer. Cancer Res 2002; 62: 2343-6.
107 Kundu N, Smyth MJ, Samsel L. et al. Cyclooxygenase inhibitors block cell growth, increase ceramide and inhibit cell cycle. Breast Cancer Res Tr 2002; 76: 57-64.
108 Zweifel BS, Davis TW, Ornberg RL. et al. Direct evidence for a role of cyclooxygenase 2-derived prostaglandin E2 in human head and neck xenograft tumors. Cancer Res 2002; 62: 6706-11.
109 Hanif R, Pittas A, Feng Y. et al. Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin- independent pathway. Biochem Pharmacol 1996; 52: 237-45.
110 Ding XZ, Tong WG, Adrian TE. Blockade of cyclooxygenase-2 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Anticancer Res 2000; 20: 2625-31.
111 Marrogi A, Pass HI, Khan M. et al. Human mesothelioma samples overexpress both cyclooxygenase-2 (CO-2) and inducible nitric oxide synthase (NOS2): in vitro antiproliferative effects of a CO-2 inhibitor. Cancer Res 2000; 60: 3696-700.
112 Sheng H, Shao J, Kirkland SC. et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 1997; 99: 2254-9.
113 Hsu AL, Ching TT, Wang DS. et al. The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J Biol Chem 2000; 275: 11397-403.
114 Li M, Wu X, Xu XC. Induction of apoptosis by cyclo-oxygenase-2 inhibitor NS398 through a cytochrome C-dependent pathway in esophageal cancer cells. Int J Cancer 2001; 93: 218-23.
115 Jacoby RF, Seibert K, Cole CE. et al. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res 2000; 60: 5040-4.
116 Oshima M, Murai N, Kargman S. et al. Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res 2001; 61: 1733-40.
117 Kawamori T, Rao CV, Seibert K. et al. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res 1998; 58: 409-12.
118 Reddy BS, Hirose Y, Lubet R. et al. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res 2000; 60: 293-7.
119 Howe LR, Subbaramaiah K, Patel J. et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res 2002; 62: 5405-7.
120 Abou-Issa HM, Alshafie GA, Seibert K. et al. Dose-response effects of the CO-2 inhibitor, celecoxib, on the chemoprevention of mammary carcinogenesis. Anticancer Res 2001; 21: 3425-32.
121 Alshafie GA, Abou-Issa HM, Seibert K. et al. Chemotherapeutic evaluation of Celecoxib, a cyclooxygenase-2 inhibitor, in a rat mammary tumor model. Oncol Rep 2000; 7: 1377-81.
122 Grubbs CJ, Lubet RA, Koki AT. et al. Celecoxib inhibits N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancers in male B6D2F1 mice and female Fischer-344 rats. Cancer Res 2000; 60: 5599-602.
123 Yoshimi N, Shimizu M, Matsunaga K. et al. Chemopreventive effect of N-(2-cyclohexyloxy-4-nitrophenyl)methane sulfonamide (NS-398), a selective cyclooxygenase-2 inhibitor, in rat colon carcinogenesis induced by azoxymethane. Jpn J Cancer Res 1999; 90: 406-12.
124 Rioux N, Castonguay A. Prevention of NNK-induced lung tumorigenesis in A/J mice by acetylsalicylic acid and NS-398. Cancer Res 1998; 58: 5354-60.
125 Williams CS, Watson AJ, Sheng H. et al. Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res 2000; 60: 6045-51.
126 Yao M, Kargman S, Lam EC. et al. Inhibition of cyclooxygenase-2 by rofecoxib attenuates the growth and metastatic potential of colorectal carcinoma in mice. Cancer Res 2003; 63: 586-92.
127 Tseng WW, Deganutti A, Chen MN. et al. Selective cyclooxygenase-2 inhibitor rofecoxib (Vioxx) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer. J Gastroint Surg 2002; 6: 838-43. discussion 844
128 Sawaoka H, Tsuji S, Tsujii M. et al. Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab Invest 1999; 79: 1469-77.
129 Kishimoto Y, Yashima K, Morisawa T. et al. Effects of cyclooxygenase-2 inhibitor NS-398 on APC and c-myc expression in rat colon carcinogenesis induced by azoxymethane. J Gastroenterol 2002; 37: 186-93.
130 Liu X H, Kirschenbaum A, Yao S. et al. Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo. J Urol 2000; 164: 820-5.
131 Sawaoka H, Kawano S, Tsuji S. et al. Cyclooxygenase-2 inhibitors suppress the growth of gastric cancer xenografts via induction of apoptosis in nude mice. Am J Physiol 1998; 274: G1061-7.
132 Rozic JG, Chakraborty C, Lala PK. Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angio-genesis. Int J Cancer 2001; 93: 497-506.
133 Williams CS, Sheng H, Brockman JA. et al. A cyclooxygenase-2 inhibitor (SC-58125) blocks growth of established human colon cancer xenografts. Neoplasia 2001; 3: 428-36.
134 Trifan OC, Durham WF, Salazar VS. et al. Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diar-rhea side effect of CPT-11. Cancer Res 2002; 62: 5778-84.