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Article

Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells

1
Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany
2
Faculty of Applied Natural Sciences, Cologne University of Applied Sciences, Kaiser-Wilhelm-Allee, 51368 Leverkusen, Germany
3
Department of General Neurosurgery, Center for Neurosurgery, University Hospital Cologne, 50937 Cologne, Germany
4
Applied Pharmacy, University of Applied Sciences Kaiserslautern, Campus Pirmasens, Carl-Schurz-Str. 10-16, 66953 Pirmasens, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(10), 2874; https://doi.org/10.3390/ijms19102874
Received: 14 August 2018 / Revised: 10 September 2018 / Accepted: 18 September 2018 / Published: 21 September 2018
Thioredoxin (Trx) overexpression is known to be a cause of chemotherapy resistance in various tumor entities. However, Trx effects on resistance are complex and depend strictly on tissue type. In the present study, we analyzed the impact of the Trx system on intrinsic chemoresistance of human glioblastoma multiforme (GBM) cells to cytostatic drugs. Resistance of GBM cell lines and primary cells to drugs and signaling inhibitors was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Impact of Trx inhibition on apoptosis was investigated by proteome profiling of a subset of proteins and annexin V apoptosis assays. Trx-interacting protein (TXNIP) was overexpressed by transfection and protein expression was determined by immunoblotting. Pharmacological inhibition of Trx by 1-methyl-2-imidazolyl-disulfide (PX-12) reduced viability of three GBM cell lines, induced expression of active caspase-3, and reduced phosphorylation of AKT-kinase and expression of β-catenin. Sensitivity to cisplatin could be restored by both PX-12 and recombinant expression of the upstream Trx inhibitor TXNIP, respectively. In addition, PX-12 also sensitized primary human GBM cells to temozolomide. Combined inhibition of Trx and the phosphatidylinositide 3-kinase (PI3K) pathway resulted in massive cell death. We conclude that the Trx system and the PI3K pathway act as a sequential cascade and could potentially present a new drug target. View Full-Text
Keywords: glioblastoma; drug resistance; thioredoxin; TXNIP; PX-12 glioblastoma; drug resistance; thioredoxin; TXNIP; PX-12
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MDPI and ACS Style

Haas, B.; Schütte, L.; Wos-Maganga, M.; Weickhardt, S.; Timmer, M.; Eckstein, N. Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells. Int. J. Mol. Sci. 2018, 19, 2874. https://doi.org/10.3390/ijms19102874

AMA Style

Haas B, Schütte L, Wos-Maganga M, Weickhardt S, Timmer M, Eckstein N. Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells. International Journal of Molecular Sciences. 2018; 19(10):2874. https://doi.org/10.3390/ijms19102874

Chicago/Turabian Style

Haas, Bodo, Lena Schütte, Maria Wos-Maganga, Sandra Weickhardt, Marco Timmer, and Niels Eckstein. 2018. "Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells" International Journal of Molecular Sciences 19, no. 10: 2874. https://doi.org/10.3390/ijms19102874

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