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Updated: Jul 30, 2025

A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
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A Promising Way to Overcome Temozolomide Resistance through Inhibition of Protein Neddylation in Glioblastoma Cell

Barbara Brandt1, Marica Németh1, Gergely Berta1

  • 1Department of Medical Biology and Central Electron Microscopic Laboratory, Medical School, University of Pécs, 7624 Pécs, Hungary.

International Journal of Molecular Sciences
|May 13, 2023
PubMed

Insights

This study explored combining temozolomide (TMZ) with MLN4924 to overcome glioblastoma multiforme (GBM) resistance. The combination therapy effectively reduced cell viability and sensitized resistant GBM cells to TMZ.

Area of Science:

  • Oncology
  • Neuro-oncology
  • Cancer Biology

Background:

  • Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with limited effective therapies.
  • Temozolomide (TMZ) resistance significantly hinders GBM treatment outcomes.
  • Mechanisms of TMZ resistance include DNA repair, epigenetic changes, and protein neddylation.

Purpose of the Study:

  • To investigate the efficacy of combining TMZ with MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, in TMZ-resistant GBM.
  • To evaluate the impact of this combination therapy on GBM cell viability and key protein expressions (MGMT, p53).

Main Methods:

  • Utilized established TMZ-resistant glioblastoma multiforme (GBM) cell lines.
  • Administered combination treatment of temozolomide (TMZ) and MLN4924.
  • Assessed cell viability and protein expression levels of O6-methylguanine methyltransferase (MGMT) and p53.

Main Results:

  • The combination of TMZ and MLN4924 significantly decreased cell viability in TMZ-resistant GBM cells.
  • MLN4924 sensitized resistant GBM cells to TMZ, suggesting a reversal of resistance.
  • Observed effects on protein expression levels of MGMT and p53 warrant further investigation.

Conclusions:

  • Combination therapy with TMZ and MLN4924 presents a promising strategy to overcome temozolomide resistance in glioblastoma multiforme.
  • This approach may offer a new therapeutic avenue for patients with GBM, particularly those resistant to standard chemotherapy.
Keywords:
combination treatmentglioblastoma multiformeneddylationtemozolomide

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