3-叠氮-3-脱氧胸腺核苷通过Egr-1信号通路协同As2O3抗肝癌的分子机制研究

项目名称： 3-叠氮-3-脱氧胸腺核苷通过Egr-1信号通路协同As2O3抗肝癌的分子机制研究

项目编号： No.81460456

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈彻

作者单位： 甘肃中医药大学

项目金额： 47万元

中文摘要： As2O3是很有潜力的抗肝癌药物，但所需剂量偏大，具有明显的毒副作用。项目组前期系列研究表明3-叠氮-3-脱氧胸腺核苷（AZT）是突出的抗癌协同剂，在联合As2O3抗肝癌中具有更为明显的协同效果（协同指数CI<1），有效降低了As2O3的使用剂量。进一步研究发现，Egr-1可能是AZT起到协同作用的关键，而且两药联用可明显促进Caspase-3活性。 因此本研究拟应用RNA干扰、基因芯片、实时定量PCR及蛋白印迹等技术，重点阐明1. Egr-1是否是AZT起到协同作用的关键？其上调影响了下游那些效应分子？是如何影响到As2O3的抗肿瘤效应？2. Egr-1信号通路与Caspase-3凋亡途径是否有关联？如果存在关联，其通路是如何影响到Caspase-3途径？ 研究结果不仅为临床抗肝癌化疗联合方案的选择提供有价值的资料，也为降低肝癌化疗药物毒性及开发针对分子靶点的抗肿瘤新药提供重要的线索。

中文关键词： 肝癌；3-叠氮-3-脱氧胸腺核苷；三氧化二砷；Egr-1；协同机制

英文摘要： The studies have showed that As2O3 is a promising anti-hepatoma drug. However, the effective dose used lonely for treating hepatoma is too high, and has distinct toxic actions and side effects. Our previous results showed that AZT was a prominent anticancer synergist, and significantly enhanced the inhibitory effect of As2O3 on hepatocellular carcinoma, which offered the advantages of reduced toxic side effects and improved therapeutic efficacy (synergy index CI <1). Our further results suggested that Egr-1 promoted by AZT could be related to the synergic effect of As2O3 combined with AZT on human hepatoma. In addition, the combination of As2O3 and AZT significantly promoted the activity of Caspase-3. But the precise mechanism is still unclear. Thus, this project will apply RNA interference, microarray, PCR and Western blot techniques to explore the following question: 1. Is Egr-1 key target gene of AZT? What effector molecules will be affected by Egr-1 upregultion? How does the Egr-1 affect the effect of As2O3 against hepatoma? 2. Is Egr-1 signaling pathway linked to Caspase-3 apoptotic pathway? If there is a correlation between them, how does the Egr-1 signaling pathway affect Caspase-3 apoptotic pathway? The results of the project can not only provide theoretical basis to how to choose effective combination therapy program of anti-hepatoma, but also provide some important clues and information to reduce liver cancer chemotherapy drug toxicity and develop new anti-tumor drugs against molecular target.

英文关键词： Hepatocellular carcinoma;AZT;As2O3;Egr-1;Synergetic mechanism