基于靶标Akt研究岭南山竹子中双xanthone类化合物抗非小细胞肺癌活性的构效关系及作用机制

Akt is a serine/threonine-specific protein kinase which plays a key role in cancer cell proliferation, apoptosis, transcription and cell migration. Drug development aimed at targetable genetic aberrations in the Akt pathway has been of great concern. Our group found for the first time that dimeric xanthones isolated from Garcinia oblongifolia Champ were dose- and time-dependent toxic to different cancer cell lines, especially to the lung cancer cells. Dimeric xanthones induced non small cell lung cancer cells (NSCLC) apoptosis through inhibition of Akt protein expression and phosphorylation. We also found that the growth inhibitary effect of dimeric xanthones is closely related to the type of substituents and their locations. The aims of the project were to isolate and identifie more dimeric xanthones from Garcinia oblongifolia Champ and investigate the anti-proliferation effect and the inhibition of Akt activity of these dimeric xanthones on the basis of preliminary studies. We will focus on not only the interactions (binding sites, modes and the binding effects) but also the structure-activity relationships between these dimeric xanthones and Akt enzyme. In addtion, anti-NSCLC mechanisms of dimeric xanthones in vitro and in vivo will be elucidated. In conclusion, this project will provide experimental basis for the development of new anti-NSCLC drugs.

作为肿瘤细胞生存信号通路中的关键分子，Akt是国际上高度关注的抗癌药物新靶标，寻找并深入研究基于Akt靶标的抗肺癌药物先导化合物具有重要意义。本课题组首次发现从岭南道地药材岭南山竹子中分离得到的双xanthone类成分具有显著的体外抗非小细胞肺癌活性，并发现此类成分可通过抑制Akt蛋白表达和磷酸化诱导非小细胞肺癌细胞凋亡。研究中还发现此类双xanthone类成分的生物活性强弱与其取代基类型和连接位点密切相关。 本项目拟在前期研究工作基础上，进一步分离鉴定岭南山竹子中双xanthone类成分，评价其抑制Akt酶活性和体内外抗非小细胞肺癌作用，并重点研究此类成分与Akt酶的相互作用（结合位点、结合模式和结合效果）及构效关系，深入阐明其对Akt相关凋亡信号通路的调控机制，为寻找结构新颖、靶点清楚的抗非小细胞肺癌先导化合物提供科学依据，为开发机制明确、效果显著的新型抗肺癌药物奠定科学基础。

本项目在前期研究工作基础上，开展了岭南山竹子抗肿瘤活性成分和作用机制研究。从岭南山竹子中分离鉴定了18个化合物，在生物活性筛选中发现部分双口山酮具有较好的抗肿瘤活性和Akt酶抑制活性，并对其构效关系进行了初步研究。选择活性最强的Griffipavixanthone作为代表化合物进行了深入系统的抗肿瘤作用机制研究，发现Griffipavixanthone可抑制Akt的磷酸化，并通过调控自噬与凋亡的相互作用诱导肿瘤细胞死亡。本项目的研究发现了靶点清楚、机制明确的抗肿瘤药物先导化合物Griffipavixanthone，同时为揭示岭南山竹子抗肿瘤活性的药效物质基础提供了科学依据。本项目研究成果发表SCI研究论文1篇，其它研究论文2篇，待发表SCI论文2篇，培养硕士研究生1名，出站博士后1名。