Characterization of structurally distinct, isoform-selective phosphoinositide 3'-kinase inhibitors in combination with radiation in the treatment of glioblastoma

Mol Cancer Ther. 2008 Apr;7(4):841-50. doi: 10.1158/1535-7163.MCT-07-0393.


The phosphoinositide 3'-kinase (PI3K)-mediated signaling pathway plays a key role in fundamental cellular functions important in normal cellular homeostasis and malignant transformation. Deregulated signaling through this pathway contributes to development of gliomas and their resistance to radiation and chemotherapy. Targeting the PI3K signaling pathway has thus emerged as a promising approach to successful treatment of gliomas. We assessed the radiosensitizing potential of four small-molecule inhibitors that differ in their activities against specific isoforms of the PI3K 110-kDa catalytic subunit (p110). p110alpha inhibitors blocked phosphorylation of both protein kinase B/Akt and S6 in all cell lines examined, effectively decreased cellular proliferation, and produced additive cytotoxic effects in combination with radiation therapy. The p110beta inhibitor exhibited limited biochemical effects and failed to decrease cellular proliferation or viability as either a single agent or in combination with radiation or rapamycin. In vivo studies examining the effects of the p110alpha inhibitor in combination with radiation indicated a significant reduction in tumor growth rate induced by the combined treatment compared with each treatment modality alone. This translated into a trend toward prolonged time-to-failure for mice in the combination treatment group. In conclusion, PI3K inhibitors are promising agents in the treatment of glioblastomas, especially when used in combination with ionizing radiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aniline Compounds / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Astrocytes / drug effects
  • Astrocytes / radiation effects
  • Blotting, Western
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / radiotherapy
  • Brain Neoplasms / therapy*
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Cells, Cultured
  • Chromones / pharmacology*
  • Combined Modality Therapy
  • Furans / pharmacology*
  • Glioblastoma / drug therapy
  • Glioblastoma / radiotherapy
  • Glioblastoma / therapy*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Protein Isoforms
  • Pyridines / pharmacology*
  • Pyrimidines / pharmacology*
  • Radiation, Ionizing
  • Xenograft Model Antitumor Assays


  • Aniline Compounds
  • Chromones
  • Furans
  • PI103
  • PIK-108
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Isoforms
  • Pyridines
  • Pyrimidines
  • PTEN Phosphohydrolase
  • PTEN protein, human