防己诺林碱通过阻滞自噬流增效肺癌化疗的作用及其分子机制

自噬抑制剂在临床肿瘤治疗中有较好的应用前景。我们前期研究发现防己诺林碱能够有效的抑制肺癌细胞自噬，并能增效化疗对肺癌的杀伤，然而，其抑制自噬的具体分子机制并不清楚。预实验结果发现防己诺林碱能够阻断自噬小体和溶酶体的融合并抑制溶酶体酸化，这会导致线粒体自噬体的降解被阻滞而释放ROS，触发细胞凋亡。本项目拟在上述工作基础上，阐明防己诺林碱抑制晚期自噬流的详细的分子机制，并通过体内实验检测防己诺林碱联合顺铂抗肺癌的效果。该研究工作将系统地认识防己诺林碱抑制自噬的新功能及其分子机制，为评估防己诺林碱是否可以联合化疗药物协同抗肿瘤的新策略提供实验依据。

Autophagy inhibitors are promising in clinical tumor therapy. Recently, we discovered that fangchinoline could effectively inhibit the autophagy of lung cancer cells and synergized with chemotherapy to kill lung cancer. However, the molecular mechanisms of its action remain unclear. Our preliminary data suggested that fangchinoline could interfere with the fusion between autophagosomes and lysosomes, and inhibit lysosomal acidification, which in turn led to the block of the degradation of mitophagosomes with the release of ROS, triggering cell apoptosis. In this context, this project aims to unravel the molecular mechanisms by which fangchinoline inhibit late autophagic flux, and also to further evaluate the anti-tumor effect of fangchinoline combined with cisplatin in a xenografted tumor model. This work will provide evidence that the autophagy inhibitor fangchinoline combined with chemotherapy may be a novel therapeutic strategy in clinical tumor treatment.