In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells.
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...
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Public Library of Science (PLoS)
2017-01-01
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| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180263&type=printable |
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| author | Nada M S Al-Saffar Alice Agliano Lynley V Marshall L Elizabeth Jackson Geetha Balarajah Jasmin Sidhu Paul A Clarke Chris Jones Paul Workman Andrew D J Pearson Martin O Leach |
| author_facet | Nada M S Al-Saffar Alice Agliano Lynley V Marshall L Elizabeth Jackson Geetha Balarajah Jasmin Sidhu Paul A Clarke Chris Jones Paul Workman Andrew D J Pearson Martin O Leach |
| author_sort | Nada M S Al-Saffar |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cb11a1ee5827424e87467afe500fd721 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-cb11a1ee5827424e87467afe500fd7212025-08-20T02:31:51ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01127e018026310.1371/journal.pone.0180263In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells.Nada M S Al-SaffarAlice AglianoLynley V MarshallL Elizabeth JacksonGeetha BalarajahJasmin SidhuPaul A ClarkeChris JonesPaul WorkmanAndrew D J PearsonMartin O LeachRecent 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180263&type=printable |
| spellingShingle | Nada M S Al-Saffar Alice Agliano Lynley V Marshall L Elizabeth Jackson Geetha Balarajah Jasmin Sidhu Paul A Clarke Chris Jones Paul Workman Andrew D J Pearson Martin O Leach In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells. PLoS ONE |
| title | In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells. |
| title_full | In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells. |
| title_fullStr | In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells. |
| title_full_unstemmed | In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells. |
| title_short | In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells. |
| title_sort | in vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with pi3k inhibition in paediatric glioblastoma cells |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180263&type=printable |
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