毛黄堇内生真菌抗肝癌活性代谢产物及其分子作用机制研究

Development of novel anticancer agents from endophytic fungi from medicinal plant has attracted a great deal of attention. Our preliminary study indicate that methanol extracts of 3 endophytic fungi from Cordalis tomentella Franch exhibited the inhibitory effect on cell proliferation and induced mitochondrial apoptosis in human hepatic carcinoma cells and ROCK1/PTEN/Akt signaling pathway may play an important role in these events. However，the effective constituents of these endophytic fungi which exhibits anti-hepatic carcinoma activity and molecular mechanism are still unclear. In this study，we will isolate and identify the bioactive constituents of the endophytic fungi through bioactivity-guided separation using chromatographic and spectral approaches. We will also investigate the effects of these active compounds on apoptosis and explore the molecular mechanism. Furthermore, we will investigate the inhibitory effects of these compounds on tumor growth in hepatic carcinoma cell xenograft mouse model. This study will reveal the material basis for the anti-cancer efficacy of the endophytic fungi, clarify the molecular mechanism, and explore the possible therapeutic targets. Our study will provide new antihepatoma drug candidates or lead compounds and expand the utilization of C. tomentella based on endophytic fungi.

目前从药用植物内生真菌中寻找新的抗肿瘤药物已成为抗肿瘤新药研发新的热点。前期研究筛选得到3株毛黄堇内生真菌甲醇提取物可通过线粒体损伤诱导肝癌细胞发生凋亡，从而显著抑制肝癌细胞生长；信号通路ROCK1/PTEN/Akt可能在其诱导细胞凋亡中发挥重要作用。但这些内生真菌具体的抗肝癌细胞活性成分及其分子机制目前还不清楚。为此，本项目拟通过色谱分离技术和光谱鉴定手段对3种毛黄堇内生真菌的甲醇提取物进行以抗肝癌活性为导向的化学成分分离鉴定，明确抗肝癌作用的活性成分，并进行整体动物抗肝癌的活性验证，同时筛选出抗肝癌活性最好的化合物进一步采用分子生物学手段从细胞水平和动物水平探讨活性成分抗肝癌作用的分子机制，揭示可能的作用靶点。本研究将揭示毛黄堇内生真菌抗肿瘤的药效物质基础，阐明其作用机制和作用靶点，期望为研发高效低毒的抗肿瘤新药提供先导化合物或候选药物，同时扩大毛黄堇内生真菌资源的开发利用。