RESEARCH ARTICLE
In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells Nada M. S. Al-Saffar1*, Alice Agliano1☯, Lynley V. Marshall2,3☯, L. Elizabeth Jackson1¤a, Geetha Balarajah1¤b, Jasmin Sidhu1, Paul A. Clarke4, Chris Jones2, Paul Workman4, Andrew D. J. Pearson3¤a, Martin O. Leach1
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OPEN ACCESS Citation: Al-Saffar NMS, Agliano A, Marshall LV, Jackson LE, Balarajah G, Sidhu J, et al. (2017) In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells. PLoS ONE 12(7): e0180263. https://doi.org/10.1371/journal.pone.0180263 Editor: Daniel Monleon, Instituto de Investigacion Sanitaria INCLIVA, SPAIN Received: January 10, 2017 Accepted: June 13, 2017 Published: July 13, 2017 Copyright: © 2017 Al-Saffar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are available from the Figshare database (DOI: 10. 6084/m9.figshare.5039305). Funding: This work was funded by the Brain Tumour Charity grant 6/54 for N.M.S.A, A.A and G. B; the Oak Foundation grant OCay-04-169 for L.V. M; Cancer Research UK and EPSRC Cancer Imaging Centre at ICR and RMH in association with the MRC and Department of Health (England) grant C1060/A10334 and C1060/A16464 for M.O.L, N.M.
1 Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom, 2 Divisions of Cancer Therapeutics and Molecular Pathology, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom, 3 Divisions of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom, 4 Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom ☯ These authors contributed equally to this work. ¤a Current address: Retired. ¤b Current address: The Centre for Molecular Pathology, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom. * [email protected]
Abstract 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 1 H-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
In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells Nada M. S. Al-Saffar1*, Alice Agliano1☯, Lynley V. Marshall2,3☯, L. Elizabeth Jackson1¤a, Geetha Balarajah1¤b, Jasmin Sidhu1, Paul A. Clarke4, Chris Jones2, Paul Workman4, Andrew D. J. Pearson3¤a, Martin O. Leach1
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OPEN ACCESS Citation: Al-Saffar NMS, Agliano A, Marshall LV, Jackson LE, Balarajah G, Sidhu J, et al. (2017) In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells. PLoS ONE 12(7): e0180263. https://doi.org/10.1371/journal.pone.0180263 Editor: Daniel Monleon, Instituto de Investigacion Sanitaria INCLIVA, SPAIN Received: January 10, 2017 Accepted: June 13, 2017 Published: July 13, 2017 Copyright: © 2017 Al-Saffar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are available from the Figshare database (DOI: 10. 6084/m9.figshare.5039305). Funding: This work was funded by the Brain Tumour Charity grant 6/54 for N.M.S.A, A.A and G. B; the Oak Foundation grant OCay-04-169 for L.V. M; Cancer Research UK and EPSRC Cancer Imaging Centre at ICR and RMH in association with the MRC and Department of Health (England) grant C1060/A10334 and C1060/A16464 for M.O.L, N.M.
1 Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom, 2 Divisions of Cancer Therapeutics and Molecular Pathology, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom, 3 Divisions of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom, 4 Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom ☯ These authors contributed equally to this work. ¤a Current address: Retired. ¤b Current address: The Centre for Molecular Pathology, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom. * [email protected]
Abstract 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 1 H-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
