Volltext-Downloads (blau) und Frontdoor-Views (grau)

Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells

  • 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.

Export metadata

Additional Services

Share in Twitter Search Google Scholar

Statistics

frontdoor_oas
Metadaten
Author:Bodo Haas, Lena Schütte, Maria Wos-Maganga, Sandra Weickhardt, Marco Timmer, Niels Eckstein
URN:urn:nbn:de:hbz:832-epub4-20332
DOI:https://doi.org/10.3390/ijms19102874
ISSN:1422-0067
Parent Title (English):International Journal of Molecular Sciences
Publisher:MDPI
Document Type:Article
Language:English
Date of first Publication:2018/09/21
Date of Publication (online):2022/11/08
GND-Keyword:Arzneimittelresistenz; Glioblastom; Thioredoxine
Tag:Drug Resistance; Glioblastoma; PX-12; TXNIP; Thioredoxin
Volume:19
Issue:10
Page Number:13
Institutes:Angewandte Naturwissenschaften (F11)
Dewey Decimal Classification:500 Naturwissenschaften und Mathematik
Open Access:Open Access
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International