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

Abstract

Activated Akt and loss of phosphatase and tensin homolog (PTEN) tumour suppression aid chemo- and radio-resistance in glioblastoma stem cells (GSC), contributing to treatment failure in glioblastoma. In this study, sixteen GSC lines were generated from 66 individual glioma samples, in gliomasphere culture conditions. Thirteen of 16 GSC lines expressed hyperphosphorylated Akt (Ser473); Akt phosphorylation did not correlated with EGFR expression. An LDH colorimetric assay was used to measure the in vitro cytotoxicity of eight of these lines. Akt X (20 µM) proved more effective at inducing in vitro GSC cytotoxicity (range: 22-73%) over 48 hours than triciribine (20 µM) (0-27%), although both agents inhibited Akt phosphorylation as detected by western blot analysis. A statistically significant correlation between PTEN loss (western blot) and the extent of Akt X-induced cytotoxicity was found (p = 0.03). Akt inhibition reduces in vitro proliferation of treatment-resistant GSC lines, especially in PTEN-deficient lines, warranting further translational investigation in glioblastoma.