In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells.

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Date
2017-01ICR Author
Author
Al-Saffar, NMS
Agliano, A
Marshall, LV
Jackson, LE
Balarajah, G
Sidhu, J
Clarke, PA
Jones, C
Workman, P
Pearson, ADJ
Leach, MO
Type
Journal Article
Metadata
Show full item recordAbstract
Recent experimental data showed that the PI3K pathway contributes to resistance to temozolomide (TMZ) in paediatric glioblastoma and that this effect is reversed by combination treatment of TMZ with a PI3K inhibitor. Our aim is to assess whether this combination results in metabolic changes that are detectable by nuclear magnetic resonance (NMR) spectroscopy, potentially providing metabolic biomarkers for PI3K inhibition and TMZ combination treatment. Using two genetically distinct paediatric glioblastoma cell lines, SF188 and KNS42, in vitro 1H-NMR analysis following treatment with the dual pan-Class I PI3K/mTOR inhibitor PI-103 resulted in a decrease in lactate and phosphocholine (PC) levels (P<0.02) relative to control. In contrast, treatment with TMZ caused an increase in glycerolphosphocholine (GPC) levels (P≤0.05). Combination of PI-103 with TMZ showed metabolic effects of both agents including a decrease in the levels of lactate and PC (P<0.02) while an increase in GPC (P<0.05). We also report a decrease in the protein expression levels of HK2, LDHA and CHKA providing likely mechanisms for the depletion of lactate and PC, respectively. Our results show that our in vitro NMR-detected changes in lactate and choline metabolites may have potential as non-invasive biomarkers for monitoring response to combination of PI3K/mTOR inhibitors with TMZ during clinical trials in children with glioblastoma, subject to further in vivo validation.
Subject
Cell Line, Tumor
Humans
Glioblastoma
Brain Neoplasms
Phosphorylcholine
Lactic Acid
Dacarbazine
Furans
Pyridines
Pyrimidines
Antineoplastic Combined Chemotherapy Protocols
Treatment Outcome
Cell Proliferation
Child
Proton Magnetic Resonance Spectroscopy
Biomarkers, Tumor
Temozolomide
Research team
Signal Transduction & Molecular Pharmacology
Glioma Team
Magnetic Resonance
Language
eng
Date accepted
2017-06-13
License start date
2017-01
Citation
PloS one, 2017, 12 (7), pp. e0180263 - ?