基于内质网应激-自噬信号通路和代谢组学相结合的人参皂苷Rb1和Rh2抗非小细胞肺癌机制研究

Ginseng has definite anti-tumor effect, and its active ingredients are many kinds of ginsenosides. However, the anti-NSCLC mechanism of ginsenosides is not clear, and the existing researches have certain limitations, lacking of the combination of molecular signaling pathway and cell material metabolism. Previous studies of our group showed that total ginsenosides could significantly regulate the material metabolism of cancer cells and induce autophagic death of NSCLC cells through endoplasmic reticulum stress response, and they are closely related. Ginsenoside Rb1 and Rh2 could significantly up-regulate cell autophagy flux like total ginsenosides and have good anti-tumor effects. It was speculated that ginsenoside Rb1 and Rh2 might exert their anti-NSCLC effect by regulating the endoplasmic reticulum stress-autophagy signaling pathway and cell material metabolism. In summary, this project is to explore the anti-NSCLC mechanism of ginsenoside Rb1 and Rh2 regulating endoplasmic reticulum stress-autophagy pathway and cell metabonomics in cultured cancer cell lines and nude mice xenograft mode.This project will not only provide new directions and ideas for exploring the active ingredients and mechanism of anti-tumor effect of traditional Chinese medicine，but also provides scientific basis for rational clinical use of ginseng and its preparations.

人参具有确切的抗肿瘤药效，其活性成分是多种人参皂苷，然而，人参皂苷的抗非小细胞肺癌机制还不明确，现有研究很少将人参皂苷对细胞分子信号通路和细胞代谢组学的调控作用相结合，具有一定的局限性。本课题组前期研究结果显示：人参总皂苷显著调控肿瘤细胞的代谢组,并可通过内质网应激-自噬信号通路诱导非小细胞肺癌细胞死亡,二者关联密切；人参皂苷Rb1和Rh2表现出与人参总皂苷相同的细胞自噬流诱导作用，且抗肿瘤药效显著。据此推测，人参皂苷Rb1和Rh2很可能通过调控细胞物质代谢和内质网应激-自噬信号通路发挥抗非小细胞肺癌药效。综上，本课题拟将人参皂苷Rb1和Rh2对细胞内质网应激-自噬信号通路和细胞代谢组学的调控作用相结合，在体外培养肿瘤细胞株和裸鼠移植瘤模型上，探索其抗非小细胞肺癌的药效机制。课题不仅能为中药抗肿瘤药效物质基础及机制研究提供新方向和新思路，同时可以为人参及其制剂的临床合理用药提供科学依据。

本课题前期研究发现人参总皂苷显著调控肿瘤细胞的代谢组，并可通过内质网应激-自噬信号通路诱导非小细胞肺癌细胞自噬性死亡，两者关联密切；部分人参皂苷单体表现出与人参总皂苷相似的细胞自噬诱导作用，且抗肿瘤药效显著。人参及其制剂的辅助抗非小细胞肺癌机制还不十分明确，现有研究很少将人参皂苷对细胞分子信号通路和细胞代谢组学的调控作用相结合，具有一定的局限性。本课题拟从上述两方面出发，探讨人参皂苷抗非小细胞肺癌的药效及机制。课题研究结果显示，人参皂苷Rh2和Rg3可通过内质网-自噬信号通路诱导非小细胞肺癌细胞自噬性死亡，同时对细胞物质代谢有显著调控作用，对磷脂酰胆碱代谢通路的调控可能与其诱导细胞自噬性死亡密切相关，值得进一步研究。课题不仅能为中药抗肿瘤药效物质基础及机制研究提供新方向和新思路，同时可以为人参及其制剂的临床合理用药提供科学依据。