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Akt inhibition is effective against PTEN-deleted, chemoirradiation-resistant glioblastoma stem cells

James Dimou1,2, Giovanna D'Abaco1, Lucy Paradiso1

  • 1Department of Surgery, The University of Melbourne, Parkville, Australia.

Growth Factors (Chur, Switzerland)
|March 13, 2025
PubMed

Insights

Targeting activated Akt in glioblastoma stem cells (GSCs) shows promise. Akt inhibition reduced GSC proliferation, particularly in PTEN-deficient cells, suggesting a new therapeutic strategy for glioblastoma.

Area of Science:

  • Oncology
  • Cancer Stem Cell Biology
  • Molecular Targeted Therapy

Background:

  • Activated Akt signaling and loss of phosphatase and tensin homolog (PTEN) tumor suppression contribute to chemo- and radio-resistance in glioblastoma stem cells (GSCs).
  • This resistance mechanism leads to treatment failure in glioblastoma patients.

Purpose of the Study:

  • To investigate the efficacy of Akt inhibition in reducing the proliferation of glioblastoma stem cells (GSCs) in vitro.
  • To explore the correlation between PTEN loss and the response to Akt inhibition in GSCs.

Main Methods:

  • Generation of sixteen GSC lines from glioma samples cultured under gliomasphere conditions.
  • Assessment of Akt phosphorylation (Ser473) via western blot analysis.
  • Measurement of in vitro GSC cytotoxicity using an LDH colorimetric assay following treatment with Akt inhibitors (Akt X and triciribine).
  • Evaluation of PTEN loss using western blot analysis.

Main Results:

  • Thirteen of sixteen GSC lines exhibited hyperphosphorylated Akt (Ser473); Akt phosphorylation did not correlate with EGFR expression.
  • Akt X (20 µM) demonstrated significantly higher in vitro GSC cytotoxicity (22-73%) compared to triciribine (0-27%) over 48 hours.
  • A statistically significant correlation was found between PTEN loss and the extent of Akt X-induced cytotoxicity (p=0.03).

Conclusions:

  • Akt inhibition effectively reduces in vitro proliferation of treatment-resistant GSC lines.
  • The efficacy of Akt inhibition is particularly pronounced in PTEN-deficient GSC lines.
  • These findings support further translational investigation of Akt inhibitors for glioblastoma treatment.
Keywords:
AktGlioblastomaPTENglioma stem cellsphenoxazine

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