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

Jack S. Chen, Linda J. Zhou, Michal Entin-Meer, Xiaodong Yang, Mila Donker, Zachary A. Knight, William Weiss, Kevan M. Shokat, Daphne Haas-Kogan, David Stokoe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)841-850
Number of pages10
JournalMolecular Cancer Therapeutics
Volume7
Issue number4
DOIs
StatePublished - 1 Apr 2008
Externally publishedYes

Funding

FundersFunder number
National Cancer InstituteP50CA097257
National Cancer Institute

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