Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland.
Department of Neurosurgery and Paediatric Neurosurgery, Medical University of Lublin, 8 Jaczewski-ego Str., 20-090 Lublin, Poland.
Int J Mol Sci. 2022 Dec 11;23(24):15712. doi: 10.3390/ijms232415712.
Glioblastoma (GBM) is the most aggressive primary brain tumor. Recently, agents increasing the level of oxidative stress have been proposed as anticancer drugs. However, their efficacy may be lowered by the cytoprotective activity of antioxidant enzymes, often upregulated in neoplastic cells. Here, we assessed the mRNA and protein expression of thioredoxin reductase 1 (TrxR1), a master regulator of cellular redox homeostasis, in GBM and non-tumor brain tissues. Next, we examined the influence of an inhibitor of TrxR1, auranofin (AF), alone or in combination with a prooxidant menadione (MEN), on growth of GBM cell lines, patient-derived GBM cells and normal human astrocytes. We detected considerable amount of TrxR1 in the majority of GBM tissues. Treatment with AF decreased viability of GBM cells and their potential to form colonies and neurospheres. Moreover, it increased the intracellular level of reactive oxygen species (ROS). Pre-treatment with ROS scavenger prevented the AF-induced cell death, pointing to the important role of ROS in the reduction of cell viability. The cytotoxic effect of AF was potentiated by treatment with MEN. In conclusion, our results identify TrxR1 as an attractive drug target and highlights AF as an off-patent drug candidate in GBM therapy.
胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤。最近，人们提出了增加氧化应激水平的药物作为抗癌药物。然而，它们的疗效可能会被肿瘤细胞中经常上调的抗氧化酶的细胞保护活性降低。在这里，我们评估了硫氧还蛋白还原酶 1（TrxR1）在 GBM 和非肿瘤脑组织中的 mRNA 和蛋白表达。接下来，我们研究了 TrxR1 抑制剂 auranoffin（AF）单独或与促氧化剂 menadione（MEN）联合使用对 GBM 细胞系、患者来源的 GBM 细胞和正常人类星形胶质细胞生长的影响。我们在大多数 GBM 组织中检测到相当数量的 TrxR1。AF 处理降低了 GBM 细胞的活力及其形成集落和神经球的能力。此外，它增加了细胞内活性氧（ROS）的水平。ROS 清除剂的预处理阻止了 AF 诱导的细胞死亡，表明 ROS 在降低细胞活力方面的重要作用。用 MEN 处理增强了 AF 的细胞毒性作用。总之，我们的研究结果确定了 TrxR1 作为一个有吸引力的药物靶点，并强调了 AF 作为 GBM 治疗中的一种非专利药物候选物。
