Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model
Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model
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DOI：
10.1002/ijc.24593
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发表时间：
2009-11-01
影响因子：
6.4
通讯作者：
Aggarwal, Bharat B.
中科院分区：
文献类型：
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作者：
Kunnumakkara, Ajaikumar B.;Diagaradjane, Parmeswaran;Aggarwal, Bharat B.
由于晚期转移性结直肠癌预后差，且对化疗药物产生耐药，目前的治疗方法效果不佳。研究姜黄素是否能增强卡培他滨对结直肠癌生长和转移的抑制作用。线粒体染色法检测姜黄素对大肠癌细胞增殖的影响，酯酶染色检测细胞凋亡率，凝胶迁移率改变法检测核因子-kappaB的表达，Western印迹法检测细胞基因表达。采用裸鼠原位移植瘤模型，观察姜黄素对结直肠癌生长和转移的影响。在体外，姜黄素抑制人结直肠癌细胞的增殖，增强卡培他滨诱导的细胞凋亡，抑制核因子-kappaB的激活，抑制核因子-kappaB调节的基因产物。在裸鼠体内，姜黄素和卡培他滨的联合使用被发现在缩小肿瘤体积(p=0.001比对照组；p=0.031比单用卡培他滨)、Ki-67增殖指数(p=0.001比对照组)和微血管密度标记CD31方面比单独用药更有效。联合治疗在抑制腹水和肝、肠、肺、直肠和脾的远处转移方面也非常有效。同时抑制活化的核因子-kappaB和核因子-kappaB调节的基因产物细胞周期蛋白1c-myc、bcl2、bclxl、CIAP-1、COX-2、ICAM-1、MMP9、CXCR4和VEGF的表达。总体而言，我们的结果表明，姜黄素通过抑制核因子-kappaB细胞信号通路，使结直肠癌对卡培他滨的抗肿瘤和抗转移作用变得敏感。(C)2009年UICC
Because of the poor prognosis and the development of resistance against chemotherapeutic drugs, the current treatment for advanced metastatic colorectal cancer (CRC) is ineffective. Whether curcumin (a component of turmeric) can potentiate the effect of capecitabine against growth and metastasis of CRC was investigated. The effect of curcumin on proliferation of CRC cell lines was examined by mitochondrial dye-uptake assay, apoptosis by esterase staining, nuclear factor-kappaB (NF-kappa B) by electrophoretic mobility shift assay and gene expression by Western blot analysis. The effect of curcumin on the growth and metastasis of CRC was also examined in orthotopically implanted tumors in nude mice. In vitro, curcumin inhibited the proliferation of human CRC cell lines, potentiated capecitabine-induced apoptosis, inhibited NF-kappa B activation and suppressed NF-kappa B-regulated gene products. In nude mice, the combination of curcumin and capecitabine was found to be more effective than either agent alone in reducing tumor volume (p = 0.001 vs. control; p = 0.031 vs. capecitabine alone), Ki-67 proliferation index (p = 0.001 vs. control) and microvessel density marker CD31. The combination treatment was also highly effective in suppressing ascites and distant metastasis to the liver, intestines, lungs, rectum and spleen. This effect was accompanied by suppressed expression of activated NF-kappa B and NF-kappa B-regulated gene products cyclin I c-myc, bcl-2, bcl-xL, cIAP-1, COX-2, ICAM-1, MMP-9, CXCR4 and VEGF). Overall, our results suggest that curcumin sensitizes CRC to the antitumor and antimetastatic effects of capecitabine by suppressing NF-kappa B cell signaling pathway. (C) 2009 UICC