Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products
Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products
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DOI：
10.1007/s00109-013-1095-0
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发表时间：
2014-03-01
影响因子：
4.7
通讯作者：
Sethi, Gautam
中科院分区：
文献类型：
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作者：
Manu, Kanjoormana A.;Shanmugam, Muthu K.;Sethi, Gautam
化疗耐药仍然是胃癌患者治疗中的一个主要问题。因此，迫切需要能够克服耐药性的新型药物。研究辛伐他汀是否能使胃癌对卡培他滨体外和体内抗肿瘤作用增敏。采用线粒体染色3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑法观察辛伐他汀对胃癌细胞增殖的影响，采用酯酶染色法观察细胞凋亡。DNA结合检测B活化，western blot检测蛋白表达。同时观察辛伐他汀对人胃癌异种移植小鼠模型肿瘤生长的影响。辛伐他汀抑制胃癌细胞的增殖，增强卡培他滨的凋亡作用，抑制NF-的组成性活化。B，并消除环氧化酶-2 （COX-2）、cyclin D1、Bcl-2、survivin、CXC motif受体4和MMP-9蛋白的表达。在异种移植小鼠模型中，我们观察到辛伐他汀单独给药（5mg / kg体重，腹腔注射3次/周）显著抑制肿瘤的生长，卡培他滨治疗进一步增强了这种作用。与对照相比，辛伐他汀抑制了NF-的表达。肿瘤组织中b调控的基因产物如cyclin D1、COX2、ICAM-1、MMP-9、survivin、Bcl-xL和XIAP。总之，我们的研究结果表明辛伐他汀可以通过抑制NF-kappa b调节的增殖、侵袭、血管生成和转移标志物来增强卡培他滨的作用。
Chemoresistance remains a major problem in the treatment of gastric cancer patients. Hence, novel pharmacological agents that can overcome drug resistance are urgently required. Whether simvastatin can sensitize the gastric cancer to the antitumor effects of capecitabine in vitro and in vivo was investigated. The effect of simvastatin on the proliferation of gastric cancer cells was examined by mitochondrial dyeuptake 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, apoptosis by esterase staining, NF-.B activation by DNA binding assay, and protein expression by western blot analysis. The effect of simvastatin on the tumor growth in xenograft mouse model of human gastric cancer was also examined. Simvastatin suppressed the proliferation of gastric cancer cells, enhanced the apoptotic effects of capecitabine, suppressed the constitutive activation of NF-.B, and abrogated the expression of cyclooxygenase-2 (COX-2), cyclin D1, Bcl-2, survivin, CXC motif receptor 4, and MMP-9 proteins. In a xenograft mouse model, we observed that the administration of simvastatin alone (5 mg/ kg body weight, intraperitoneal thrice/ week) significantly suppressed the growth of the tumor and this effect was further potentiated by capecitabine treatment. As compared to the vehicle control, simvastatin also suppressed the expression of NF-.B-regulated gene products such as cyclin D1, COX2, ICAM-1, MMP-9, survivin, Bcl-xL, and XIAP in tumor tissues. Overall, our results demonstrate that simvastatin can enhance the effects of capecitabine through suppression of NF-kappa B-regulated markers of proliferation, invasion, angiogenesis, and metastasis.