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Int. J. Mol. Sci. 2018, 19(9), 2586; https://doi.org/10.3390/ijms19092586

Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma

1
Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
2
Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
3
Institute of Functional Genomics, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany
4
Department of Neuropathology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
Equal contribution.
*
Author to whom correspondence should be addressed.
Received: 15 July 2018 / Revised: 24 August 2018 / Accepted: 28 August 2018 / Published: 31 August 2018
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Abstract

Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use. Here, we explored whether a combined treatment of metformin and diclofenac, which is a non-steroidal anti-inflammatory drug (NSAID) shown to inhibit glycolysis by interfering with lactate efflux, may lead to additive or even synergistic effects on BTICs (BTIC-8, -11, -13 and -18) and tumor cell lines (TCs, U87, and HTZ349). Therefore, we investigated the functional effects, including proliferation and migration, metabolic effects including oxygen consumption and extracellular lactate levels, and effects on the protein level, including signaling pathways. Functional investigation revealed synergistic anti-migratory and anti-proliferative effects of the combined treatment with metformin and diclofenac on BTICs and TCs. Signaling pathways did not sufficiently explain synergistic effects. However, we observed that metformin inhibited cellular oxygen consumption and increased extracellular lactate levels, indicating glycolytic rescue mechanisms. Combined treatment inhibited metformin-induced lactate increase. The combination of metformin and diclofenac may represent a promising new strategy in the treatment of glioblastoma. Combined treatment may reduce the effective doses of the single agents and prevent metabolic rescue mechanisms. Further studies are needed in order to determine possible side effects in humans. View Full-Text
Keywords: glioma; BTICs; metformin; diclofenac; lactate glioma; BTICs; metformin; diclofenac; lactate
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Gerthofer, V.; Kreutz, M.; Renner, K.; Jachnik, B.; Dettmer, K.; Oefner, P.; Riemenschneider, M.J.; Proescholdt, M.; Vollmann-Zwerenz, A.; Hau, P.; Seliger, C. Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma. Int. J. Mol. Sci. 2018, 19, 2586.

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