Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy.
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Date
2017-07-18Author
Agliano, A
Balarajah, G
Ciobota, DM
Sidhu, J
Clarke, PA
Jones, C
Workman, P
Leach, MO
Al-Saffar, NMS
Type
Journal Article
Metadata
Show full item recordAbstract
Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. In this study, we show that NVP-BEZ235, a dual PI3K/mTOR inhibitor, potentiates the effects of irradiation in both adult and pediatric glioblastoma cell lines, resulting in early metabolic changes detected by nuclear magnetic resonance (NMR) spectroscopy. NVP-BEZ235 radiosensitises cells to X ray exposure, inducing cell death through the inhibition of CDC25A and the activation of p21cip1(CDKN1A). Lactate and phosphocholine levels, increased with radiation, are decreased after NVP-BEZ235 and combination treatment, suggesting that inhibiting the PI3K/mTOR pathway reverses radiation induced metabolic changes. Importantly, NVP-BEZ235 potentiates the effects of irradiation in a xenograft model of adult glioblastoma, where we observed a decrease in lactate and phosphocholine levels after seven days of combination treatment. Although tumor size was not affected due to the short length of the treatment, a significant increase in CASP3 mRNA was observed in the combination group. Taken together, our data suggest that NMR metabolites could be used as biomarkers to detect an early response to combination therapy with PI3K/mTOR inhibitors and radiotherapy in adult and pediatric glioblastoma patients.
Subject
Cell Line, Tumor
Animals
Humans
Mice
Glioblastoma
Choline
Imidazoles
Quinolines
Glucose
Protein Kinase Inhibitors
Radiation-Sensitizing Agents
Magnetic Resonance Spectroscopy
Signal Transduction
Cell Survival
Energy Metabolism
X-Rays
Radiation Tolerance
Adult
Child
Female
Metabolomics
TOR Serine-Threonine Kinases
Proton Magnetic Resonance Spectroscopy
Biomarkers
Phosphoinositide-3 Kinase Inhibitors
Research team
Signal Transduction & Molecular Pharmacology
Glioma Team
Magnetic Resonance
Language
eng
Date accepted
2017-04-29
License start date
2017-07
Citation
Oncotarget, 2017, 8 (29), pp. 47969 - 47983
Publisher
IMPACT JOURNALS LLC