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Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells

Bodo Haas1, Lena Schütte2,3, Maria Wos-Maganga4

  • 1Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany. bodo.haas@bfarm.de.

International Journal of Molecular Sciences
|September 26, 2018
PubMed

Insights

Thioredoxin (Trx) system inhibition overcomes chemoresistance in glioblastoma multiforme (GBM) by increasing apoptosis and reducing key survival proteins. Targeting Trx and PI3K pathways offers a novel therapeutic strategy for GBM treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Thioredoxin (Trx) overexpression contributes to chemotherapy resistance across tumor types, but its role in glioblastoma multiforme (GBM) is tissue-specific.
  • Understanding the Trx system's impact on intrinsic chemoresistance in GBM is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the role of the thioredoxin (Trx) system in the intrinsic chemoresistance of human glioblastoma multiforme (GBM) cells.
  • To evaluate the therapeutic potential of inhibiting the Trx system, alone or in combination with other pathways, for GBM treatment.

Main Methods:

  • Assessed GBM cell line and primary cell resistance to drugs using MTT assays.
  • Investigated Trx inhibition effects on apoptosis via proteome profiling and annexin V assays.
  • Utilized pharmacological Trx inhibition (PX-12) and TXNIP overexpression.

Main Results:

  • PX-12 reduced GBM cell viability, induced active caspase-3, and decreased AKT-kinase phosphorylation and β-catenin expression.
  • Trx inhibition restored sensitivity to cisplatin in GBM cells and sensitized primary cells to temozolomide.
  • Combined inhibition of Trx and phosphatidylinositide 3-kinase (PI3K) pathway led to significant cell death.

Conclusions:

  • The thioredoxin (Trx) system is a key mediator of chemoresistance in glioblastoma multiforme (GBM).
  • Trx inhibition, particularly in combination with PI3K pathway targeting, presents a promising therapeutic strategy for GBM.
  • The Trx system and PI3K pathway function sequentially, offering a novel drug target for glioblastoma treatment.
Keywords:
PX-12TXNIPdrug resistanceglioblastomathioredoxin

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