转录因子Nrf2调控的抗氧化系统影响人脑胶质瘤替莫唑胺化疗敏感性的机制研究：涉及MGMT酶调控

The prognosis of glioma is significantly affected by temozolomide (TMZ) chemotherapy. But the resistance mechanism of TMZ in glioma chemotherapy remains to be unclear. It has been proved that Nrf2 regulates proliferation, apotiptosis, migration, angiogenesis and differentiation of glioma by our research team previous work. And the results of preliminary experiment also indicate that Nrf2 regulates the TMZ chemosensitivity in glioma. Some papers have reported Nrf2 can coordinately regulate the several antioxidants including GSH (known as Nrf2-antioxidant system). According to the results of the preliminary experiment and the existing literatures，we have ample reason to believe that this system maybe can resist TMZ cytotoxicity by increasing the cellular antioxidant capacity. Moreover, this system also probably can regulate MGMT enzyme activity via regulating intracellular cysteine/glutathione metabolism. Based on the these premises, we speculate that the nuclear factor Nrf2 maybe medicate the TMZ chemosensitivity via affecting intracellular antioxidants, and the hypothesis is that Nrf2-antioxidant system may involve in brain glioma TMZ chemosensitivity. Based on preliminary study, the role of Nrf2-antioxidant system in TMZ chemotherapy and the relationship of Nrf2-antioxidant system and MGMT in glioma would be further studied by molecular biological, immunostain, gene interference and drug intervention means in vivo and in vitro. Also the underlying mechanism would be explored simultaneously. This study is source of innovation. And the results will reveal the mechanism of glioma chemoresistance, which will provide new thread for effective therapy and new target for drug development.

替莫唑胺（temozolomide, TMZ）化学治疗显著影响胶质瘤患者预后，但其耐药确切机制需进一步研究。课题组前期研究已首次证实：转录因子Nrf2可调控胶质瘤的增殖、凋亡、迁移、血管生成和分化，我们预实验结果还提示Nrf2可调控胶质瘤替莫唑胺化疗的敏感性。基于1)Nrf2可共调控多种抗氧化成分（被称为Nrf2-抗氧化系统)；2）这个系统可能通过增强肿瘤细胞抗氧化应激能力对抗替莫唑胺化疗毒性；3)这个系统还可能通过影响细胞内半胱氨酸/谷胱甘肽代谢调控MGMT酶进而对抗替莫唑胺化疗毒性。基于以上前提，我们推测Nrf2影响TMZ化疗敏感性可能通过其下游的抗氧化系统实现，进而提出“Nrf2-抗氧化系统影响胶质瘤TMZ化疗敏感性”的假说。本项目拟在前期研究基础上，通过体内外实验及分子生物学、基因干预等手段，进一步验证Nrf2-抗氧化系统与胶质瘤TMZ耐药性的相关性，并同时发掘新的可能机制。

替莫唑胺（temozolomide，TMZ）应用临床以来，尽管较既往的化疗药物取得了显著的生存受益，但是众多临床研究表明，TMZ对恶性胶质瘤的有效率不足45%。肿瘤细胞对替莫唑胺耐药是造成化疗失败的主要原因，因此对其耐药确切机制仍需进一步研究。为了发掘新耐药机制，我们研究小组首次证实：转录因子Nrf2可调控胶质瘤替莫唑胺化疗敏感性。主要机制有三：1）Nrf2可共调控多种抗氧化成分（被称为Nrf2-抗氧化系统)；2）这个系统可通过增强肿瘤细胞抗氧化应激能力对抗替莫唑胺化疗毒性；3)这个系统还可通过影响细胞内半胱氨酸/谷胱甘肽代谢调控MGMT酶进而对抗替莫唑胺化疗毒性。本研究首次揭示Nrf2-抗氧化系统可调控人脑胶质瘤TMZ化疗敏感性及可能机制，具有源头创新性，其结果可为改善人脑胶质瘤治疗预后提供理论依据和实践基础，将有利于发掘克服人脑胶质瘤耐药性的新方法、新手段。