唐松草中环菠萝蜜烷型三萜皂苷选择性增敏唐松草碱的作用机制研究

Signaling transduction pathway activated by tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) not only possesses antitumor activity, but also sensitizes and reverses tumorous drug tolerance throught combining with many drugs. It is fully meaningful for develepment a new antitumor drugs mediated by TRAIL. In the previous study，we found that cycloartane glycosides from Thalictrum foetunei could induce apoptosis in tumor cells, and sensitize thalicarpine in tumors. Further study indicated that these compounds could inhibit the expression of nuclear factor kappa B (NF-κB), downregulation of FADD-likeinterleukin-1βconverting enzyme inhibitory protein (c-FLIP), and reduce the content of phosphribosomal protein S6 kinase (p-P70S6K) through inhibiting the activity of mammalian target of rapamycin (mTOR). All above suggested that these compounds may play an important role in TRAIL pathway. .The scientific project based on previus study was undertaken to rapidly separate and identify of cycloartane glycosides from T. foetunei with the aid of LC-MS-MS and NMR, and further find more analogous compounds from other plants of Thalictrum L. under the guidance of pharmacophylogenetic investigation and pharmacological activity. In addtion, the mechanism behind sensitization and structure-activity relationship of these compounds on antitumor activity will be concluded, especially how these compounds regulte the NF-κB , c-FLIP protein expression and influence the biological function of TRAIL family, which will provide a powerful evidence for the research and development of novel antitumor sensitizer based on signaling transduction pathway activated by TRAIL.

肿瘤坏死因子相关凋亡诱导配体(TRAIL)通路激活不仅具有抗肿瘤活性，而且与多种药物协同并逆转肿瘤耐药，对于开发肿瘤增敏和肿瘤逆转药物具有重要的研究意义。课题组首次发现华东唐松草中环菠萝蜜烷型三萜皂苷不仅可以诱导肿瘤细胞凋亡，而且对唐松草碱的抗肿瘤活性有增敏作用；进一步研究表明该类成分可以抑制NF-κB的表达，下调c-FLIP蛋白，并通过抑制mTOR的活性，下调p-P70S6K含量，暗示该类化合物可能具有TRAIL通路激活作用。.本项目拟在前期研究基础上，在LC-MS-MS和NMR的监测下，快速分离和鉴定环菠萝蜜烷型化合物，结合药理活性采用药用植物亲缘学的方法寻找更多结构类似物。研究其选择性增敏抗癌药物的作用机理和构效关系，重点研究该类化合物怎样改变NF-κB、c-FLIP蛋白的表达进而影响TRAIL家族的生物学功能，为发展基于TRAIL家族通路激活的新型抗肿瘤增敏剂提供科学依据。

肿瘤坏死因子相关凋亡诱导配体（TRAIL）通路激活不仅具有独立的抗肿瘤活性，逆转部分肿瘤细胞对化疗的耐药，而且与多种药物之间存在协同作用，因此，寻找和开发具有TRAIL通路激活作用的药物具有重要的临床意义。课题组首次发现华东唐松草中部分环菠萝蜜烷型皂苷可以抑制NF-κB的表达，下调c-FLIP蛋白，并通过抑制mTOR的活性，下调p-P70S6K含量，提示这些化合物的抗肿瘤增敏作用机制可能是对TRAIL家族多通路激活实现的。. 课题组运用各种现代色谱技术对华东唐松草(T. fortunei ) 提取物的化学成分进行快速追踪和分离，得到更多结构类型的环菠萝蜜烷型三萜皂苷，通过光谱技术对分离得到的这些化合物进行结构鉴定；利用药用植物亲缘学的研究方法在同属或者同科亲缘植物中得到可能产生增敏作用更强的同类化合物，为科学开发利用本属植物的药用价值提供依据。. 通过对不同产地的华东唐松草和同属的其他唐松草的粗提物的抗肿瘤研究，发现庐山地区的华东唐松草和青城山地区的多枝唐松草具有较好的活性。关于新的环菠萝蜜烷型三萜皂苷的抗肿瘤活性的筛选工作正在进行中。