新型化合物TMZ-POH抗鼻咽癌的作用及机制研究

Addition of temozolomide (TMZ) to radiation therapy is the standard therapy in clinical application. TMZ also has a limited effect on cancer stem cells (CSCs). But effectiveness of TMZ is limited by the tumor's overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer. Our data show that POH is an effective anti-glioma cytotoxic agent for TMZ-resistant glioma cells and CSCs. We synthesized a new compound TMZ-POH, which was more cytotoxic than TMZ to a variety of tumor cell lines including nasopharyngeal carcinoma, and had the radiosensitization and killing CSCs roles. Nasopharyngeal carcinoma is a common malignant tumor in China. There is no sensitive chemotherapeutic agent. Radiation therapy is the main treatment. But there is often radiation tolerance and recurrence. TMZ-POH is expected to be an effective drug for nasopharyngeal carcinoma because of its above-mentioned roles. The cytotoxic and radiosensitization effect of TMZ-POH on nasopharyngeal carcinoma and CSCs in vitro and in vivo will be observed. DNA damage repair signaling pathway, autophagy and apoptosis pathway in nasopharyngeal carcinoma and CSCs will be detected. Taking advantage of its fat-soluble feature, the feasibility of TMZ-POH, alone or combined with radiotherapy, for the treatment of nasopharyngeal carcinoma by nasal inhalation will be explored.

替莫唑胺(TMZ)是临床用于脑胶质瘤配合放疗的药物，对癌症干细胞样细胞(CSCs)也有一定的杀伤作用，但极易产生耐药性。紫苏醇(POH)是一种具有微弱抗癌作用的天然香料成分，POH联合TMZ可以有效消除癌细胞和CSCs对TMZ的耐药性，增强TMZ的作用。在此基础上，我们合成了一种新型化合物TMZ-POH，初步证实其对包括鼻咽癌在内的多种肿瘤细胞株均有比TMZ更强的细胞毒、放疗增敏和杀伤CSCs的作用。鼻咽癌是我国常见恶性肿瘤，尚无敏感的化疗药物，放疗是主要治疗手段，但易产生放疗耐受并复发。TMZ-POH有望因其上述作用成为鼻咽癌治疗的良药。本项目拟在体内外观察TMZ-POH对鼻咽癌及CSCs的细胞毒和放疗增敏作用，研究其对鼻咽癌和CSCs的DNA损伤修复信号通路、自噬和凋亡相关通路的影响，并利用其具脂溶性可滴鼻给药的特性，探讨通过滴鼻方式单独或联合射线治疗鼻咽癌的可行性。

替莫唑胺(TMZ)是临床用于脑胶质瘤配合放疗的药物，但极易产生耐药性。紫苏醇(POH)是一种具有微弱抗癌作用的天然香料成分，POH联合TMZ可以有效消除癌细胞和CSCs对TMZ的耐药性，增强TMZ的作用。在此基础上，我们合成了一种新型化合物TMZ-POH，初步证实其对包括鼻咽癌在内的多种肿瘤细胞株均有比TMZ更强的细胞毒作用。我们的研究证实：① 新化合物TMZ-POH在鼻咽癌、非小细胞肺癌及卵巢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。已发表SCI论文3篇，总影响因子大于15分。