天然化合物调节白血病干细胞微环境诱导的异常信号途径分子作用机制研究

Guizhou ethnic medicine has been used efficiency for thousands of years to treat leukemia. This grant application is mainly focused on the discovery of the bioactive substances of Guizhou ethnic medicine to clear leukemic stem cells in the patients and investigate the molecular mechanism of their action. To achieve this goal, we use the chemical compounds laboratory generated by our chemical research group from Guizhou ethnic medicine to screen for inhibitors of the abnormal signal pathway induced by stromal cytokines in the microenvironment of leukemia stem cells. Previously, through investigating the relationship between B lymphocytic leukemia stem cells and their microenvironment, we found that stromal cytokines in leukemic stem cells can over-activate miRNAs regulate the Wnt, Notch and mTOR signaling pathways in leukemic stem cells. Indeed, large number of studies have previously shown a strong relationship between over-activation of these signaling pathways and abnormal renewal, differentiation and survival of leukemia stem cells. These studies revealed that these abnormal signaling pathways are ideal targets for removing leukemic stem cells. The objective of this application is isolate inhibitors of these abnormal signaling pathways from the library of compounds derived from Guizhou ethnic medicine and investigate their molecular mechanism. The outcome of these studies should provide a new strategy for treatment of leukemia.

贵州民族药在民间用于治疗白血病已有数千年历史。申请者课题组着眼于从贵州民族药中发现清除白血病干细胞的活性物质，并探讨其分子作用机制。为实现这一目标，申请者建立了筛选调节白血病干细胞微环境基质细胞因子诱导的异常信号途径的天然化合物的体系。利用这一体系，申请者发现白血病干细胞微环境中的基质细胞因子能过度激活白血病干细胞miRNAs调节的Wnt，Notch和mTOR信号途径。大量研究表明这些信号途径的过度激活是导致白血病干细胞异常更新、分化和存活的关键因素。以上研究也揭示了被过度激活的这些信号途径是清除白血病干细胞的理想靶标。本项目的目标是利用以上筛选体系，从源于贵州民族药的天然化合物库中，发现调节这些异常信号途径的化合物，并利用这些活性化合物作探针探讨白血病干细胞中异常信号途径的新基因，同时为开发贵州民族药的新功效和使其走向世界药品市场提供科学理论依据。

贵州民族药在民间用于治疗白血病已有数千年历史。申请者课题组着眼于从贵州民族药中发现清除白血病干细胞的活性物质，并探讨其分子作用机制。我们利用筛选调节白血病干细胞微环境基质细胞因子诱导的异常信号途径的贵州民族药的体系，对列入中国药典的154种贵州民族药配方制剂及源于其的500个天然小分子化合物进行系统的筛选，发现 化风丹，肺力咳胶囊，芪胶升白胶囊等11种贵州民族药配方制剂和15种天然小分子化合物有显著的抗白血病活性，这些活性物质通过调节具有白血病干细特性的细胞凋亡、增殖及分化途径而抑制白血病细胞的生长，促进白血病细胞的分化，并初步阐明了其分子作用机制。研究成果已在高质量学术杂志发表文章16篇，其中SCI收录7篇，提交发明专利14件，其中1项已获得授权。研究成果为治疗白血病，乳腺癌等疾病提供了物质基础和科学理论依据，为开拓贵州省民族药世界药品市场提供了科学理论依据。