Characterization of structurally distinct, isoform-selective phosphoinositide 3'-kinase inhibitors in combination with radiation in the treatment of glioblastoma.
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.
Chen
Jack S
JS
Department of Radiation Oncology, Comprehensive Cancer Center at the University of California at San Francisco, San Francisco, California, USA.
Zhou
Linda J
LJ
Entin-Meer
Michal
M
Yang
Xiaodong
X
Donker
Mila
M
Knight
Zachary A
ZA
Weiss
William
W
Shokat
Kevan M
KM
Haas-Kogan
Daphne
D
Stokoe
David
D
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001253:Astrocytes / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology*; D003131:Combined Modality Therapy; D005663:Furans / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D020033:Protein Isoforms; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011839:Radiation, Ionizing; D023041:Xenograft Model Antitumor Assays
D000814:Aniline Compounds; D002867:Chromones; D005663:Furans; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011725:Pyridines; D011743:Pyrimidines; C522973:PI103; C575625:PIK-108; C494929:PTEN protein, human