| 内质网相关降解通路小分子抑制剂与传统抗癌药物联合运用对肿瘤细胞的抑制作用 |
| 投稿时间：2015-10-21 修订日期：2015-11-10 点此下载全文 |
| 引用本文：樊倩倩,李闯,王林.内质网相关降解通路小分子抑制剂与传统抗癌药物联合运用对肿瘤细胞的抑制作用[J].医学研究杂志,2016,45(5):24-30 |
| DOI：
10.11969/j.issn.1673-548X.2016.05.007 |
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| 基金项目:国家自然科学基金资助项目(81372201) |
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| 中文摘要:目的 探究内质网相关降解通路(endoplasmic reticulum-associated degradation,ERAD)小分子抑制剂EeyarestatinⅠ(EerⅠ)与传统抗癌药物联合运用对肿瘤细胞的抑制作用。方法 不同剂量的EerⅠ处理结肠癌SW480和胰腺癌PANC-1细胞,MTS法检测细胞增殖,流式细胞仪检测细胞凋亡率;EerⅠ单独或与抗癌药物顺铂(cisplatin,CDDP)和硼替佐米(bortezomib,BTZ)联用处理SW480和PANC-1细胞,Western blot法检测细胞中Poly ADP-ribose polymerase(PARP)及其剪切体和糖调节蛋白(GRP78/BiP)的蛋白表达。结果 EerⅠ抑制SW480和PANC-1细胞增殖,促进细胞凋亡(P<0.01),且呈剂量-效应关系;联合用药的实验结果显示EerⅠ提高了SW480和PANC-1细胞对CDDP和BTZ的敏感度(P<0.01);Western blot法检测结果表明,联合用药促进了PARP在SW480和PANC-1细胞中的剪切,同时BTZ处理可提高BiP蛋白的表达,提示激活内质网应激(endoplasmic reticulum stress,ERS)反应。结论 ERAD通路抑制剂EerⅠ可明显增强传统抗癌药物CDDP和BTZ的抗癌活性,这为抗癌新药研发及肿瘤耐药性逆转剂的研究提供了新的线索。 |
| 中文关键词:内质网相关蛋白降解通路 ERS反应 p97 化疗治疗 |
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| Inhibitor of the Endoplasmic Reticulum-associated Degradation Pathway Combined with Conventional Chemotherapeutic Drugs Synergistically Prohibits Cancer Growth |
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| Abstract:Objective To characterise the inhibitory effect of Eer Ⅰ, a small molecule targeting the key protein of the ERAD pathway, p97, alone or in combination with the traditional anticancer drugs on tumor cells. Methods The effect of Eer Ⅰ singularly and combined with cisplatin (CDDP) or bortezomib (BTZ) on tumor cell proliferation and apoptosis was measured through MTS assay and flow cytometry. Western blot was used to detect the cleavge of PARP and GRP78 in SW480 and PANC-1 cells after treatments. Results Eer Ⅰ significantly inhibited cell proliferation and induced apoptosis of SW480 and PANC-1 in a dose-dependent manner compared with the control group (P<0.01). MTS assay and flow cytometry assay showed that the combination treatment remarkably enhanced the cytotoxic effects of CDDP and BTZ (P<0.01). Western blot results demonstrated the combination treatment further enhanced the PARP cleavage, which was a marker of cell apoptosis. Interestingly, the expression of BiP, a marker for the unfolded protein response, was elevated after treatment of BTZ. Conclusion Eer Ⅰ combined with other chemotherapeutic drugs significantly inhibits the growth of SW480 and PANC-1, thus establishes p97 as a novel target in the treatment of colon and pancreatic cancer. |
| keywords:Endoplasmic reticulum-associated degradation Endoplasmic reticulum stress response p97 Chemotherapy |
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