新化合物TMZ-POH损伤自噬流抗肿瘤的分子机制

The term “autophagic flux” is used to represent the dynamic process of autophagy, a crucial process for cells to maintain homeostasis and survival through degradation of cellular proteins and organelles in lysosomes, which plays an important role in development and outcome of cancer. Moreover, autophagy is also implicated in promoting chemoresistance of cancer cells so as to attenuate therapeutic efficacy of chemotherapy. Thus impairing autophagic flux seems to be a potential target to enhance the chemosensitivity, since impaired autophagic flux leads to blockage of recycling of metabolic substances mediated by autophagy and in turn to antophagic cell death. TMZ-POH is a novel compound via conjugating temozolomide (TMZ) and Perillyl alcohol (POH). In previous researches, we found TMZ-POH exerted more effective and broad-spectrum cytotoxicity compared to TMZ, POH or their combination. More importantly, unlike TMZ, POH or their combination which induced autophagy, TMZ-POH was able to cause impaired autophagic flux in lung cancer cells, indicating it will be an anti-tumor compound with unique mechanism and a great future potential. Therefore, focused on lung cancer, this project aims to figure out the direct connection between TMZ-POH impaired autophagic flux and its anti-tumor activities, and to explore the underlying mechanisms of TMZ-POH impaired autophagic flux, providing theoretical basis for TMZ-POH tumor therapy.

自噬是介导细胞内损伤的细胞器或蛋白质等成分进入溶酶体，以实现细胞本身代谢所需的能量和某些细胞器更新的过程，在肿瘤的发生及转归中起到重要作用，已成为肿瘤治疗的新靶点。自噬发生的动态过程被称为自噬流，在化疗药物作用下，肿瘤细胞能通过自噬耐受化疗药物的细胞毒性，损伤自噬流可以有效的避免因自噬而导致的化疗耐受，提高药物的治疗敏感性。TMZ-POH是通过化学键连接替莫唑胺(TMZ)和紫苏醇(POH)合成的一种新化合物。初步研究发现，TMZ-POH表现出比TMZ、POH或二者联合用药更显著且广谱的肿瘤细胞杀伤作用；更为重要的是，不同于它们诱导细胞自噬，TMZ-POH能够损伤肺癌细胞自噬流，预示着其可能是一种作用机制独特、极具潜力的抗肿瘤化合物。因此本项目以肺癌为研究对象，确定TMZ-POH对自噬流的损伤是其发挥抗肿瘤作用的关键，并探索其引起自噬流损伤的机制，为TMZ-POH用于肿瘤治疗提供理论依据。

替莫唑胺(TMZ)是临床用于脑胶质瘤配合放疗的药物，其作为肺癌治疗的二线药物，仅在肺癌脑转移治疗中应用较多，且疗效并不显著。紫苏醇(POH)是一种具有微弱抗癌作用的天然香料成分，联合TMZ可以增强TMZ的作用，在此基础上合成了一种新型化合物TMZ-POH。我们的研究证实：① 新化合物TMZ-POH在非小细胞肺癌、鼻咽癌中发挥抗肿瘤作用，表现出比TMZ、POH或二者联合用药更显著且广谱的肿瘤细胞杀伤作用；② 新化合物TMZ-POH调控DNA损伤修复蛋白MGMT泛素化降解，这表明TMZ-POH可能是通过调控MGMT来克服在其他烷化剂中发生的耐药；③ 新化合物TMZ-POH通过阻断自噬流损伤线粒体，诱导细胞自噬性死亡，可以有效的避免因自噬而导致的化疗耐受，提高药物的治疗敏感性。