靶向铁死亡增强胶质母细胞瘤的辐射敏感性  

Targeting Ferroptosis to Enhance Radiosensitivity of Glioblastoma

作　　者：蒋希忠 乔诗宇 姜曈 阎英 徐莹 吴彤 JIANG Xi-Zhong;QIAO Shi-Yu;JIANG Tong;YAN Ying;XU Ying;WU Tong(Graduate Training Base of General Hospital of Northern Theater Command,China Medical University,Shenyang 110016,China;Department of Radiation Oncology,General Hospital of Northern Theater Command,Shenyang 110016,China)

机构地区：[1]中国医科大学北部战区总医院研究生培养基地,沈阳110016 [2]北部战区总医院放射治疗科,沈阳110016

出　　处：《生物化学与生物物理进展》2024年第6期1284-1291,共8页Progress In Biochemistry and Biophysics

基　　金：中国博士后科学基金(2023M734296)资助项目。

摘　　要：胶质母细胞瘤是一种高度恶性的脑肿瘤,具有快速生长、广泛浸润、高致死率的特点。放射治疗是利用电离辐射杀伤肿瘤细胞作为治疗胶质母细胞瘤的重要手段。由于胶质瘤患者五年生存率极低,因此迫切需要一些新的有效治疗策略。近年来,铁死亡作为一种新型的调节性细胞死亡方式,在胶质母细胞瘤的治疗中发挥了重要作用。已有研究揭示了铁死亡的关键过程,包括细胞内铁蓄积、活性氧产生、脂质过氧化、谷胱甘肽过氧化物酶4和胱氨酸-谷氨酸反向转运体活性抑制。研究表明,辐射可以通过产生活性氧、抑制抗氧化系统信号轴、耗竭谷胱甘肽、上调酰基辅酶A合成酶长链家族成员4以及诱导自噬来触发铁死亡。在放射治疗中可通过诱导铁超载、破坏抗氧化系统和线粒体功能等途径靶向铁死亡来增强胶质母细胞瘤的辐射敏感性。靶向铁死亡的辐射增敏治疗策略在胶质瘤的治疗中具有重要的潜在价值。本文综述了铁死亡及其发生机制,分析辐射诱导铁死亡的分子机理,介绍了调控铁死亡在提高胶质母细胞瘤放疗敏感性方面的应用和挑战,可为改善胶质母细胞瘤的治疗现状提供参考。Glioblastoma(GBM),one of the most common malignant tumors in the central nervous system(CNS),is characterized by diffuse and invasive growth as well as resistance to various combination therapies.GBM is the most prevalent type with the highest degree of malignancy and the worst prognosis.While current clinical treatments include surgical resection,radiotherapy,temozolomide chemotherapy,novel molecular targeted therapy,and immunotherapy,the median survival time of GBM patients is only about one year.Radiotherapy is one of the important treatment modalities for GBM,which relies on ionizing radiation to eradicate tumor cells.Approximately 60%to 70%of patients need to receive radiotherapy as postoperative radiotherapy or neoadjuvant radiotherapy during the treatment process.However,during radiotherapy,the radioresistant effect caused by DNA repair activation and cell apoptosis inhibition impedes the therapeutic effect of malignant glioblastoma.Ferroptosis was first proposed by Dr.Brent R.Stockwell in 2012.It is an iron-dependent mode of cell death induced by excessive lipid peroxidation.Although the application of ferroptosis in tumor therapy is still in the exploratory stage,it provides a completely new idea for tumor therapy as a novel form of cell death.Ferroptosis has played a significant role in the treatment of GBM.Specifically,research has revealed the key processes of ferroptosis occurrence,including intracellular iron accumulation,reactive oxygen species(ROS)generation,lipid peroxidation,and a decrease in the activity of the antioxidant system.Among them,glutathione peroxidase 4(GPX4)in the cytoplasm and mitochondria,ferroptosis suppressor protein 1(FSP1)on the plasma membrane,and dihydroorotate dehydrogenase(DHODH)in the mitochondria constitute an antioxidant protection system against ferroptosis.In iron metabolism,nuclear receptor coactivator 4(NCOA4)can mediate ferritin autophagy to regulate intracellular iron balance based on intracellular iron content.Heme oxygenase1(HMOX1)catalyzes heme degradation to

关 键 词：胶质母细胞瘤 辐射 铁死亡 辐射增敏 

分 类 号：R739.41[医药卫生—肿瘤] R815.2[医药卫生—临床医学]