Combined inhibition of Dnmt and mTOR signaling inhibits formation and growth of colorectal cancer
Combined inhibition of Dnmt and mTOR signaling inhibits formation and growth of colorectal cancer
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DOI：
10.1007/s00384-009-0664-8
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发表时间：
2009-02
影响因子：
2.8
通讯作者：
Yan-jie Zhang;Shuliang Zhao;Xiao-qing Tian;Dan‐feng Sun;H. Xiong;Q. Dai;Xiao-Qiang Li;J. Fang
中科院分区：
文献类型：
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作者：
Yan-jie Zhang;Shuliang Zhao;Xiao-qing Tian;Dan‐feng Sun;H. Xiong;Q. Dai;Xiao-Qiang Li;J. Fang
背景与目的虽然雷帕霉素（RPM）和5- AZA -脱氧胞苷（AZA）的抗癌作用已被广泛研究，但这两种药物在结直肠癌（CRC）中的联合作用尚不清楚。本研究旨在探讨AZA和RPM联合治疗CRC的作用及其对哺乳动物雷帕霉素靶蛋白（mTOR）及其信号转导途径的影响。研究对象和方法人类结直肠癌细胞系HCT116分别接受AZA单独、RPM单独或两种药物联合治疗。分析细胞活力、凋亡和细胞周期分布。在S-ICR小鼠中启动结直肠癌，然后用上述药物治疗，并测量肿瘤发生率和体积。Western blot和免疫组化检测mTOR信号转导通路的活性。结果AZA与RPM联合治疗可抑制小鼠HCT116细胞生长，诱导凋亡，延缓细胞周期，降低CRC发生率和肿瘤体积，抑制mTOR信号转导通路组分磷酸化。这些效果比单一药物治疗更显著。结论AZA和RPM联合治疗可抑制结直肠癌的形成和生长。这些发现可能为结直肠癌的治疗提供一种新的策略。
Background and aimsAlthough the anticancer effects of rapamycin (RPM) and 5-aza-deoxycytidine (AZA) have been studied extensively, the combined effect of these two drugs on colorectal cancer (CRC) is still unknown. This study addresses the effect of AZA and RPM combination therapy on CRC and its influence on the mammalian target of rapamycin (mTOR) and its signal transduction pathway.Subjects and methodsHuman CRC cell line HCT116 was treated with AZA alone, RPM alone, or concurrently with a combination of both drugs. Cell viability, apoptosis, and cell cycle distribution were analyzed. CRC was initiated in S-ICR mice, which were then treated with the drugs mentioned above, and tumor incidence and volume were measured. The activity of the mTOR signal transduction pathway was detected by Western blot analysis or immunohistochemistry.ResultsCombination treatment with AZA and RPM inhibited the growth of HCT116 cells, induced apoptosis, arrested the cell cycle, and reduced the incidence and tumor volume of CRC in mice, as well as inhibited the phosphorylation of components of the mTOR signal transduction pathway. These effects were more significant than those of single-drug treatments.ConclusionCombination treatment with AZA and RPM inhibits the formation and growth of CRC. These findings may provide a novel strategy for CRC treatment.