Celecoxib - A Selective Cyclooxygenase-2 Inhibitor Exhibits Dose - Dependent Chemopreventive Activity on an Animal Model of Colorectal Cancer*
Colorectal cancer (CRC) is still one of the unresolved issues in medicine. Despite constant improvements in diagnosis and treatment, the prognosis for CRC is unsatisfactory. In recent years, much attention has been paid to experiments concerning chemoprevention of CRC.
The aim of the study was evaluation of the effectiveness of celecoxib, a selective Cyclooxygenase-2 (COX-2) inhibitor of chemically-induced CRC carcinogenesis in Fisher F344 rats.
Material and methods. Forty-five four-week old male F344 rats were randomized into four groups. In Groups 1, 2, and 3, we induced the CRC carcinogenesis through two subcutaneous injections of Azoxymethane in doses of 20 mg/kg. Rats from groups 1 and 2 were treated with celecoxib in doses of 10 and 30 mg/kg from the start of the experiment. Group 4 was a negative control. The experiment ended in the 26th week. We assessed the following parameters: the number of Aberrant Crypt Foci (premalignant lesions in colons) and the immunoexpression indexes: COX-2, Vascular Endothelial Growth Factor (VEGF), and c-myc.
Results. Celecoxib reduced the ACF number. The ACF reduction was dose-dependent. The median ACF number per field of vision was as follows for each of the groups: 1.7, 0.75, 3.2, and 0.2. Celecoxib, irrespective of the dose, reduced the VEGF immunoexpression index. We did not observe a reduction of COX-2 or c-myc immunoexpression in the celecoxib groups.
Conclusions. In this experiment, we proved that celecoxib possessed chemopreventive activity. Carcinogenesis inhibition by selective COX-2 inhibitor was dose-dependent. We demonstrated that celecoxib hidners angiogenesis, expressed as VEGF immunoexpression. We indirectly confirmed the hypothesis of a celecoxib COX-2 independent pathway mechanism of action.
Landis S, Murray T, Bolden S et al.: Cancer Statistics. CA Cancer J Clin 1998; 48: 6-29.
Montoya RG, Wargovich MJ: Chemoprevention of gastrointestinal cancer. Cancer Metastasis Rev 1997; 16(3-4): 405-19.
Tomeo CA, Colditz GA, Willett WC et al.: Harvard report on cancer prevention. Cancer causes and control 1999; 10: 167-80.
Arbman G, Axelson O, Ericsson-Begodzkim AB et al.: Cereal fiber, calcium, and colorectal cancer. Cancer 1992; 69: 2042-48.
Willett WC, Stampfer MJ, Colditz GA et al.: Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 1990; 323: 1664-72.
Buecher B, Thouminot C, Menanteau J et al.: Fructooligosaccharide associated with celecoxib reduces the number of aberrant crypt foci in the colon of rats. Reprod Nutr Dev 2003; 43(4): 347-56.
Wei M, Morimura K, Wanibuchi H et al.: Chemopreventive effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on 1, 2-dimethylhydrazine-induced rat colon carcinogenesis. Cancer Lett 2003; 202(1): 11-16.
Brown WA, Skinner SA, Malcontenti-Wilson C et al.: Non-steroidal anti-inflammatory drugs with different cyclooxygenase inhibitory profiles that prevent aberrant crypt foci formation but vary in acute gastrotoxicity in a rat model. J Gastroenterol Hepatol 2000; 15(12): 1386-92.
Bird RP: Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 1987; 37: 147-51.
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.
Juni P, Nartey L, Reichenback S et al.: Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364: 2021-29.
Kobaek-Larsen M, Fenger C, Hansen K et al.: Comparative study of histopathologic characterization of azoxymethane-induced colon tumors in three inbred rat strains. Comp Med 2002; 52(1): 50-57.
Arber N, Eagle CJ, Spicak J et al.: Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355(9): 885-95.
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(18): 5040-44.
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.
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(2): 293-97.
Yamada Y, Yoshimi N, Hirose Y et al.: Suppression of occurrence and advancement of beta-catenin-accumulated crypts, possible premalignant lesions of colon cancer, by selective cyclooxygenase-2 inhibitor, celecoxib. Jpn J Cancer Res 2001; 92(6): 617-23.
Grosch S, Tegeder I, Niederberger E et al.: Cox-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by selective COX-2 inhibitor, celecoxib. FASEB J 2001; 15(14): 2742-44.
Bing RJ, Miyataka M, Rich KA et al.: Nitric oxide, prostanoids, cyclooxygenase and angiogenesis in colon and breast cancer. Clin Cancer Res 2001; 7: 3385-92.
Amano H, Ando K, Minamida S et al.: Adenylate cyclase/protein kinase A signaling pathway enhances angiogenesis through induction of vascular endothelial growth factor in vivo. Jpn J Pharmacol 2001; 87: 181-88.
Shoji Y, Takahashi M, Kitamura T et al.: Downregulation of prostaglandin E receptor subtype EP3 during colon cancer development. Gut 2004; 53(8): 1151-58.
Tegeder I, Pfeilschifter J, Geisslinger G: Cyclooxygenase- independent actions of cyclooxigenase inhibitors. FASEB J 2001; 15(12): 2057-72.
Kawamori T, Uchiya N, Sugimura T et al.: Enhancement of colon carcinogenesis by prostaglandin E2 administration. Carcinogenesis 2003; 24(5): 985-89.
Bos JL, Fearon ER, Hamilton SR et al.: Prevalence of ras gene mutations in human colorectal cancers. Nature 1987; 327(6120): 293-97.
Barré B, Perkins ND: A cell cycle regulatory network controlling NF-kappa B subunit activity and function. EMBO J 2007; 26(23): 4841-55. Epub 2007 Oct 25.
Shishodia S, Koul D, Aggarwal BB: Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-kappa B activation through inhibition of activation of I kappa B alpha kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis. J Immunol 2004; 173(3): 2011-22.
Takada Y, Khuri F, Aggawal BB: Protein farnesyltransferase inhibitor (SCH 66336) abolishes NF-kappa B activation induced by various carcinogens and inflammatory stimuli leading to suppression of NF-kappa B-regulated gene expression and up-regulation of apoptosis. J Biol Chem 2004; 18; 279(25): 26287-99.