基于MEK1/2为靶点的茅术醇抑制作用、定量构效关系及抗非小细胞肺癌生物活性研究

项目名称： 基于MEK1/2为靶点的茅术醇抑制作用、定量构效关系及抗非小细胞肺癌生物活性研究

项目编号： No.81502958

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 郭伟强

作者单位： 苏州科技大学

项目金额： 17.9万元

中文摘要： 肺癌是十大恶性肿瘤之首，约85%为非小细胞肺癌。天然产物作为抗肺癌肿瘤药物开发的重点和捷径，备受关注。茅术醇作为苍术、白术等的挥发油成分，具有结构简单，利于后续化学合成及修饰等特点。前期研究中，我们发现茅术醇是MEK1/2的潜在抑制剂；在体内外实验显示：其可通过下调ERK/RSK2/NF-κB通路实现强效抑制非小细胞肺癌增殖、诱导凋亡等活性，但抑制、构效和调控机理不明。本课题拟将天然产物、分子、细胞生物学、有机化学等相结合，分析茅术醇对MEK1/2的抑制机制及定量构效关系；以不同非小细胞肺癌细胞为研究对象，检测茅术醇对增殖、细胞周期和凋亡的影响，检测对ERK/RSK2/NF-κB通路相关因子的影响，全面分析茅术醇的抗非小细胞肺癌的生物活性，并在荷瘤小鼠中评价其体内药效的同时，验证其活性。本项目将为以茅术醇为先导物开发新型MEK1/2抑制剂打下基础，也为其进一步在临床应用方面提供实验依据。

中文关键词： 茅术醇；MEK1/2；非小细胞肺癌；ERK/RSK2/NF-κB通路

英文摘要： Lung cancer is the most common cancer and ranking NO. 1 in the world. More than 85% lung cancer patients are non small cell lung cancer. Research and development of the anti-lung cancer drug from plants and herbs has been become an important research field. In recent, many researches have shown that Atractylodes Lancea, Atractylodes Macrocephala and those components (including hinesol) exhibit anti-cancer acitivity. Hinesol is one ingredient of essential oil constituents of Atractylodes Lancea and Atractylodes Macrocephala, which has the advantages of simple structure, convenience for chemical subsequents synthesis and modification. In the previous research, we found that hinesol is the potential inhibitors of MEK1/2, the results of anti non small cell lung cancer activity of hinesol in vivo and vitro showed that hinesol can inhibits proliferation and induces apoptosis via ERK/RSK2/NF-κB pathway. However, Inhibition，QSAR and anti non-small lung cancer activity of hinesol on MEK1/2 are not well understood. . In this project, we will use technologies of natural products chemistry, molecular and cell biology, organic chemistry to analyze the inhibition and QSAR of hinesol on MEK1/2; the effect of hinesol on proliferation, apoptosis and ERK/RSK2/NF-κB pathway will be measured in different non small cell lung cancer cell lines. Then, its efficacy and activity in vivo will be evaluation in tumor bearing mice. This project will became the foundation for development of novel MEK1/2 inhibitors, also provide experiments basis for its further clinical application. . In conclusion, this research will be a great development in anti-tumor activity of hinesol, Atractylodes Lancea and Atractylodes Macrocephala, also provide the foundation for development of novel MEK1/2 inhibitors and experiments basis for clinical application in cancer realm.

英文关键词： Hinesol;MEK1/2;Non-small cell lung cancer;ERK/RSK2/NF-κB pathway