Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma
Open Access
- 1 April 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 7 (4), 841-850
- https://doi.org/10.1158/1535-7163.mct-07-0393
Abstract
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). p110α 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 p110β 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 p110α 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. [Mol Cancer Ther 2008;7(4):841–50]This publication has 25 references indexed in Scilit:
- Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?Oncogene, 2006
- A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in gliomaCancer Cell, 2006
- A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin SignalingCell, 2006
- Use of an Orthotopic Xenograft Model for Assessing the Effect of Epidermal Growth Factor Receptor Amplification on Glioblastoma Radiation ResponseClinical Cancer Research, 2006
- The Akt/PKB pathway: molecular target for cancer drug discoveryOncogene, 2005
- Biochemical characterization of the ataxia-telangiectasia mutated (ATM) protein from human cellsDNA Repair, 2004
- The Prognostic Significance of Phosphatidylinositol 3-Kinase Pathway Activation in Human GliomasJournal of Clinical Oncology, 2004
- Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cellsInternational Journal of Cancer, 2003
- TSC1–TSC2: a complex tale of PKB-mediated S6K regulationNature, 2002
- The p53 gene and its role in human brain tumorsGlia, 1995