Daurisoline通过调控自噬和G-四联体对胶质瘤发展及替莫唑胺敏感性的作用机制研究

胶质瘤是中枢神经系统最常见的肿瘤，患者预后十分不理想。替莫唑胺（TMZ）是治疗胶质瘤的首选药物，其敏感性对患者预后影响重大。课题组前期成果提示自噬在胶质瘤发展和TMZ化疗敏感性中发挥重要调控作用。本项目前期研究结果与文献调研发现：daurisoline（DAS）可以抑制胶质瘤细胞生长并促进其凋亡，潜在的分子机制可能和抑制细胞自噬活性及促进G-4联体形成有关。本研究拟通过细胞实验，查明DAS是否通过阻碍Ca2+内流下调细胞自噬活性，进而发挥抗胶质瘤作用；通过DAS和TMZ联合给药，查明DAS对TMZ化疗敏感性的影响及机制；分子水平探究DAS是否通过G-4联体介导独立发挥抗胶质瘤活性及作用靶点；最后，研究在动物水平初步验证DAS安全性、血脑屏障穿透性、抗胶质瘤活性和对TMZ化疗敏感性的影响。本项目旨在探讨DAS对胶质瘤发展和TMZ化疗敏感性的作用机制，为胶质瘤化疗药物的开发提供新的思路。

Glioma is the most common tumor of the central nervous system, the prognosis of glioma patients is gloomy. Temozolomide (TMZ) is the first-line chemotherapy drug for glioma, which significantly improves the prognosis of glioma patients. Our previous research suggested that autophagy played an important role in the progression of glioma and sensitivity of TMZ. According to the previous research and our results, we found that the daurisoline (DAS) could inhibit the growth of glioma and increase apoptosis by inhibiting autophagy. In addition, studies have shown that DAS could induce cell cycle arrest by promoting G-quadruplex. This study is designed to investigate the effect of DAS on glioma progression and the chemosensitivity of TMZ is related to the calcium associated autophagy inhibition and the G-quadruplex forming, respecting the important role of G-quadruplex and autophagy in cancer therapy and the potent anti-glioma activity of DAS.