罗格列酮对实验性大鼠结肠癌的化学预防作用

摘要/Abstract

摘要： 目的: 观察罗格列酮对实验性结肠癌的化学预防作用及其与环氧化酶-2(COX-2)表达的关系。方法: 以二甲肼(1-2 dimethylhydrazine,DMH) 40 mg/kg 皮下注射+1%葡聚糖硫酸钠(dextran sodium sulfate,DSS)水溶液饮用诱导形成大鼠结肠癌模型,观察罗格列酮(0.75 mg·kg^-1·d^-1,1周 5 d)和美洛昔康(1.35 mg·kg^-1·d^-1,1周 5 d)灌服、连续16周对大鼠体重、异常隐窝灶(ACF)和结肠癌发生率的影响。采用四甲基谷氮蓝法(MTT)研究罗格列酮和美洛昔康抑制培养的人结肠癌Lovo细胞增殖的量-效和时-效关系;用Western Blot法检测罗格列酮组细胞COX-2蛋白表达水平。结果: 与模型组相比,罗格列酮明显改善DMH+DSS诱癌过程中大鼠的恶液质状态并阻遏体重减轻,显著减少实验第10周大鼠结肠ACF数和明显降低结肠癌的发生率;其作用与美洛昔康组相似。罗格列酮呈浓度和时间依赖性明显抑制Lovo细胞增殖,其作用 6 h、12 h 和 24 h 的IC₅₀均显著小于美洛昔康。罗格列酮呈浓度依赖性降低Lovo细胞中COX-2蛋白表达。结论: 罗格列酮能抑制DMH和DSS联合使用诱导大鼠早期ACF的形成和结肠癌发生,其作用途径可能与抑制COX-2表达有关。

关键词: 罗格列酮, 结肠癌, 环氧化酶-2, 化学预防

Abstract: AIM: To investigate the anti-colon cancer effects of rosiglitazone and possible relationship with COX-2. METHODS: Wistar rat colon cancer model was induced by 1-2 dimethylhydrazine (DMH)(40 mg/kg s.c.)+1% dextran sodium sulfate solution (DSS)(freely drinking). All rats were randomly divided into 3 groups:control(DMH + DSS + solvant), rosiglitazone(Ros) (DMH+DSS+Ros 0.75 mg·kg^-1·d^-1) , meloxicam(Mel):(DMH+DSS+Mel 1.35 mg·kg^-1·d^-1). The drugs were given orally once a day for 5 day per week. The body weight, the number of colon ACFs, the incidence and number of colon cancer in rats, as well as the morphological changes of rat colon tissues were evaluated. Human colon cancer Lovo cell line was treated by either Ros or Mel in various concentrations (10^-6,10^-5,10^-4,10^-3 mol/ L) for 6 h,12 h and 24 h,respectively, and the cell growth was assayed by MTT method. Western blot were used to evaluate the protein expressions of COX-2 from Lovo cells treated with Ros.RESULTS: Ros significantly improved the dyscrasia induced by DMH+DSS, the both of body weight and general condition were better than those of control group. Ros also significantly inhibited ACF and colon cancer incidence in the rats treated by DMH+DSS for 10 weeks or 20 weeks,which was similar to that of Mel. Ros inhibited the proliferation of Lovo cells in concentration- and time-dependent manners, and the IC₅₀ values were significantly smaller than that of Mel at 6 h,12 h, and 24 h after Lovo cells were treated by either Ros or Mel. Ros also concentration-dependently decreased expressions of COX-2 protein.CONCLUSION: Ros can inhibit ACF and tumor formation induced by DMH+DSS,and decrease the Lovo cell proliferation index. The anti-tumor effects of Ros may involve in an unknown pathway through which the expressions of COX-2 were inhibited.

Key words: Rosiglitazone, Colon cancer, COX-2, Chemoprevention

中图分类号:

R965.2

吴柯, 何百成, 周岐新. 罗格列酮对实验性大鼠结肠癌的化学预防作用[J]. 中国临床药理学与治疗学, 2012, 17(10): 1124-1129.

WU Ke, HE Bai-cheng, ZHOU Qi-xin. Chemoprevention effect of Rosiglitazone on the experimental colon cancer in rat[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(10): 1124-1129.

参考文献

[1] Tencer L, Burgermeister E, Ebert MP, et al.Rosiglitazone induces caveolin-1 by PPARgamma-dependent and PPRE-independent mechanisms: the role of EGF receptor signaling and its effect on cancer cell drug resistance[J]. Anticancer Res, 2008,28(2A):895-906.
[2] Toaldo C, Pizzimenti S, Cerbone A, et al.PPARgamma ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network, in colon cancer cells[J]. J Cell Mol Med,2009,13(14):1347-1357.
[3] Rageul J,Mottier S,Jarry A, et al.KLF4-dependent, PPARgamma-induced expression of GPA33 in colon cancer cell lines[J].Int J Cancer,2009,125(12):2802-2809.
[4] Wu WK,Sung JJ, Lee CW, et al.Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms[J]. Cancer Lett,2010,295(1):7-16.
[5] Onose J, Imai T, Hasumnra M, et al.A new medium-term rat colon bioassay applying neoplastic lesions as endpoints for detection of carcinogenesis modifiers-validation with known modifiers[J]. Cancer Lett,2006,232(2):272-278.
[6] Latham P, Lund EK, Johnson IT.Dietary n-3 PUFA increases the apoptotic response to 1,2-dimethylhydrazine, reduces mitosis and supresses the induction of carcinogenesis in the rat colon[J]. Cracinogenesis,1999,20(4):645-650.
[7] 周昕, 董立,黄波,等.黄连、吴茱萸及其药对对大鼠结肠异变腺窝的影响[J]. 中国临床药理学与治疗学,2011,16(2): 143-147.
[8] Che TC, François S, Bouchet S,et al.Early lesions induced in rat colon epithelium by N-methyl-N'-nitro-N-nitrosoguanidine[J]. Tissue Cell,2010,42(3):190-194.
[9] Mutch MG, Schoen RE, Fleshman JW, et al.A multicenter study of prevalence and risk factors for aberrant crypt foci[J]. Clin Gastroenterol Hepatol,2009,7(5):568-574.
[10] Santarelli RL, Vendeuvre JL, Naud N et al. Meat processing and colon carcinogenesis: cooked, nitrite-treated, and oxidized high-heme cured meat promotes mucin-depleted foci in rats[J]. Cancer Prev Res,2010 ,3(7):852-864.
[11] Sangeetha N, Felix AJ, Nalini N.Silibinin modulates biotransforming microbial enzymes and prevents 1,2-dimethylhydrazine-induced preneoplastic changes in experimental colon cancer[J]. Eur J Cancer Prev,2009,18(5):385-394.
[12] Eberhart CE, Coffey RJ, Radhika A, et al.Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas[J]. Gastroenterol,1994,107(4):1183-1188.
[13] Saini MK, Vaiphei K, Sanyal SN.Chemoprevention of DMH-induced rat colon carcinoma initiation by combination administration of piroxicam and C-phycocyanin[J]. Mol Cell Biochem,2012,361(1/2):217-228.
[14] Chen S, Cao W, Yue P, et al.Celecoxib promotes c-FLIP degradation through Akt-independent inhibition of GSK3[J].Cancer Res,2011,71(19):6270-6281.
[15] Sarraf P, Mueller E, Jones D,et al.Differentiation and reversal of malignant changes in colon cancer through PPARgamma[J]. Nat Med,1998 ,4(9):1004-1005.
[16] Osawa E, Nakajima A, Wada K,et al.Peroxisome proliferator-activated receptor gamma ligands suppress colon carcinogenesis induced by azoxymethane in mice[J]. Gastroenterol,2003,124(2):361-367.
[17] Galli A,Ceni E, Mello T,et al.Thiazolidinediones inhibit hepatocarcinogenesis in hepatitis B virus-transgenic mice by peroxisome proliferator-activated receptor gamma-independent regulation of nucleophosmin[J]. Hepatology,2010,52(2):493-505.