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Published on: December 15, 2010
Menadione Potentiates Auranofin-Induced Glioblastoma Cell Death
Monika Szeliga1, Radosław Rola2
1Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland.
Abstract:
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.
Insights
This study shows that targeting thioredoxin reductase 1 (TrxR1) with auranofin (AF) can kill glioblastoma (GBM) cells by increasing oxidative stress. AF is a promising drug candidate for treating this aggressive brain cancer.
Area of Science:
- Oncology
- Biochemistry
- Cell Biology
Background:
- Glioblastoma (GBM) is an aggressive primary brain tumor.
- Antioxidant enzymes like thioredoxin reductase 1 (TrxR1) can protect cancer cells, limiting the efficacy of oxidative stress-inducing therapies.
- TrxR1 is a key regulator of cellular redox homeostasis.
Purpose of the Study:
- To assess TrxR1 expression in GBM and non-tumor brain tissues.
- To investigate the effects of TrxR1 inhibition using auranofin (AF) on GBM cell growth.
- To evaluate the combination therapy of AF with menadione (MEN) in GBM models.
Main Methods:
- Quantitative assessment of TrxR1 mRNA and protein expression in GBM and normal brain tissues.
- In vitro studies using GBM cell lines, patient-derived GBM cells, and normal human astrocytes.
- Treatment with auranofin (AF), menadione (MEN), and a reactive oxygen species (ROS) scavenger.
Main Results:
- Significant TrxR1 expression was detected in most GBM tissues.
- Auranofin (AF) treatment reduced GBM cell viability, colony formation, and neurosphere generation.
- AF treatment increased intracellular reactive oxygen species (ROS) levels, leading to cell death, which was preventable by ROS scavengers.
- The cytotoxic effect of AF was enhanced when combined with menadione (MEN).
Conclusions:
- Thioredoxin reductase 1 (TrxR1) is a viable drug target for glioblastoma (GBM) therapy.
- Auranofin (AF), an existing drug, shows potential as an off-patent therapeutic candidate for GBM.
- Targeting TrxR1 with AF induces GBM cell death via increased oxidative stress, suggesting combination therapies may improve efficacy.
