TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Haas, Bodo
A1  - Schütte, Lena
A1  - Wos-Maganga, Maria
A1  - Weickhardt, Sandra
A1  - Timmer, Marco
A1  - Eckstein, Niels
T1  - Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - Glioblastom
KW  - Glioblastoma
KW  - Drug Resistance
KW  - Thioredoxin
KW  - TXNIP
KW  - PX-12
KW  - Arzneimittelresistenz
KW  - Thioredoxine
Y1  - 2018
UN  - https://nbn-resolving.org/urn:nbn:de:hbz:832-epub4-20332
SN  - 1422-0067
SS  - 1422-0067
U6  - https://doi.org/10.3390/ijms19102874
DO  - https://doi.org/10.3390/ijms19102874
VL  - 19
IS  - 10
SP  - 13
S1  - 13
PB  - MDPI
ER  -