胶质母细胞瘤是最具侵袭性的脑肿瘤之一,以明显的氧化还原失衡为特征,由于糖酵解和线粒体氧化代谢升高,在癌细胞的高氧化能力中表达。胶质母细胞瘤的氧化还原状态的评估和调节是可以提供高度特异性靶向和治疗的关键因素。我们的研究描述了使用氧化还原活性组合药物靶向胶质母细胞瘤的药理学策略。实验在体内对成胶质细胞瘤小鼠(颅内模型)和体外对用氧化还原循环对甲萘醌/抗坏血酸盐(M/A)处理的细胞系(癌症和正常)进行。使用MRI或离体组织和血液标本分析以下参数:肿瘤生长,生存,脑灌注,细胞密度,组织氧化还原状态,肿瘤相关NADH氧化酶(tNOX)和转化生长因子-β1(TGF-β1)的表达。M/A对细胞活力的剂量依赖性影响,线粒体功能,并在体外评估氧化还原稳态。M/A治疗抑制了肿瘤生长,并显着增加了生存率,没有不良副作用。这伴随着增加的氧化应激,减少还原能力,仅肿瘤中的细胞密度降低,以及脑灌注增加和tNOX和TGF-β1的下调。M/A诱导分离的胶质母细胞瘤细胞中线粒体超氧化物的选择性细胞毒性和过量产生,但不是在正常的小胶质细胞。这伴随着癌细胞过度还原状态的显著降低和它们的“前致癌”功能的损害,通过剂量依赖性减少评估:NADH,NAD+,琥珀酸盐,谷胱甘肽,细胞还原能力,线粒体电位,稳态ATP,和tNOX表达式。M/A对正常细胞的安全性受到西立伐他汀治疗的损害,一种非特异性异戊烯基转移酶抑制剂。总之,M/A通过氧化还原靶向将胶质母细胞瘤细胞和组织与正常细胞和组织区分,仅在肿瘤中引起严重的氧化应激。机制很复杂,很可能涉及正常细胞中甲萘醌的戊烯化,但不是在癌细胞中,调节免疫反应,耐药性的降低,以及在使胶质母细胞瘤对常规化疗敏感中的潜在作用。
Glioblastoma is one of the most aggressive brain tumors, characterized by a pronounced redox imbalance, expressed in a high oxidative capacity of cancer cells due to their elevated glycolytic and mitochondrial oxidative metabolism. The assessment and modulation of the redox state of glioblastoma are crucial factors that can provide highly specific targeting and treatment. Our study describes a pharmacological strategy for targeting glioblastoma using a redox-active combination drug. The experiments were conducted in vivo on glioblastoma mice (intracranial model) and in vitro on cell lines (cancer and normal) treated with the redox cycling pair menadione/ascorbate (M/A). The following parameters were analyzed in vivo using MRI or ex vivo on tissue and blood specimens: tumor growth, survival, cerebral perfusion, cellular density, tissue redox state, expression of tumor-associated NADH oxidase (tNOX) and transforming growth factor-beta 1 (TGF-β1). Dose-dependent effects of M/A on cell viability, mitochondrial functionality, and redox homeostasis were evaluated in vitro. M/A treatment suppressed tumor growth and significantly increased survival without adverse side effects. This was accompanied by increased oxidative stress, decreased reducing capacity, and decreased cellular density in the tumor only, as well as increased cerebral perfusion and down-regulation of tNOX and TGF-β1. M/A induced selective cytotoxicity and overproduction of mitochondrial superoxide in isolated glioblastoma cells, but not in normal microglial cells. This was accompanied by a significant decrease in the over-reduced state of cancer cells and impairment of their \"pro-oncogenic\" functionality, assessed by dose-dependent decreases in: NADH, NAD+, succinate, glutathione, cellular reducing capacity, mitochondrial potential, steady-state ATP, and tNOX expression. The safety of M/A on normal cells was compromised by treatment with cerivastatin, a non-specific prenyltransferase inhibitor. In conclusion, M/A differentiates glioblastoma cells and tissues from normal cells and tissues by redox targeting, causing severe oxidative stress only in the tumor. The mechanism is complex and most likely involves prenylation of menadione in normal cells, but not in cancer cells, modulation of the immune response, a decrease in drug resistance, and a potential role in sensitizing glioblastoma to conventional chemotherapy.