Akt inhibitor shows anticancer and radiosensitizing effects in malignant glioma cells by inducing autophagy

Keishi Fujiwara, Eiji Iwado, Gordon B. Mills, Raymond Sawaya, Seiji Kondo, Yasuko Kondo

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

Autophagy, or programmed cell death type II, is one of the responses of cancer cells to various therapies, including ionizing radiation. Recently, we have shown that radiation induces autophagy, but not apoptosis, in various malignant glioma cell lines. Autophagy is mainly regulated by the mammalian target of rapamycin (mTOR) pathway. The Akt/mTOR pathway also mediates oncogenesis and radioresistance. Thus, we hypothesized that inhibiting this pathway has both an anticancer and radiosensitizing effect by activating autophagy. The purpose of our study was therefore to determine whether and by which mechanisms an Akt inhibitor, 1L-6-hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate, had anticancer and radiosensitizing effects on malignant glioma U87-MG and radioresistant U87-MG cells with a consistitutively active form of epidermal growth factor receptor (U87-MGΔEGFR). Treatment with the Akt inhibitor successfully inhibited Akt activity and reduced cell viability in both cell lines. In terms of the mechanism, the Akt inhibitor decreased phosphorylated p70S6 kinase, a downstream target of Akt, and induced autophagy, but not apoptosis. Furthermore, the Akt inhibitor radiosensitized both U87-MG and U87-MGΔEGFR cells by enhancing autophagy. Specific inhibition of Akt using the dominant-negative Akt plasmid also resulted in enhanced radiation-induced autophagy. In conclusion, an Akt inhibitor showed anticancer and radio-sensitizing effect on U87-MG and U87-MGΔEGFR cells by inducing autophagy. Thus, Akt inhibitors may represent a promising new therapy as a single treatment or used in combination with radiation for malignant gliomas, including radioresistant ones that express ΔEGFR.

Original languageEnglish (US)
Pages (from-to)753-760
Number of pages8
JournalInternational Journal of Oncology
Volume31
Issue number4
DOIs
StatePublished - Oct 2007
Externally publishedYes

Keywords

  • Akt inhibitor
  • Autophagy
  • Malignant glioma
  • Radiosensitization

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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