Oncotarget

Research Papers:

Vacquinol-1 inducible cell death in glioblastoma multiforme is counter regulated by TRPM7 activity induced by exogenous ATP

Philip Sander, Haouraa Mostafa, Ayman Soboh, Julian M. Schneider, Andrej Pala, Ann-Kathrin Baron, Barbara Moepps, C. Rainer Wirtz, Michael Georgieff and E. Marion Schneider _

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Oncotarget. 2017; 8:35124-35137. https://doi.org/10.18632/oncotarget.16703

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Abstract

Philip Sander1, Haouraa Mostafa1, Ayman Soboh1, Julian M. Schneider1, Andrej Pala2, Ann-Kathrin Baron3, Barbara Moepps4, C. Rainer Wirtz2, Michael Georgieff5 and Marion Schneider1

1Division of Experimental Anesthesiology, University Hospital Ulm, 89081 Ulm, Germany

2Department of Neurosurgery, Bezirkskrankenhaus Guenzburg, 89312 Guenzburg, Germany

3Department of Operative Dentistry and Periodontology, University Hospital Ulm, 89081 Ulm, Germany

4Institute of Pharmacology and Toxicology, University Hospital Ulm, 89081 Ulm, Germany

5Department of Anesthesiology, University Hospital Ulm, 89081 Ulm, Germany

Correspondence to:

Marion Schneider, email: marion.schneider@uni-ulm.de

Keywords: glioblastoma multiforme, Vacquinol-1, ATP, TRPM7, methuosis

Received: February 03, 2017    Accepted: March 15, 2017    Published: March 30, 2017

ABSTRACT

Glioblastomas (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. New therapeutic options are urgently needed. A novel drug, Vacquinol-1 (Vac), a quinolone derivative, displays promising properties by inducing rapid cell death in GBM but not in non-transformed tissues. Features of this type of cell death are compatible with a process termed methuosis. Here we tested Vac on a highly malignant glioma cell line observed by long-term video microscopy. Human dental-pulp stem cells (DPSCs) served as controls. A major finding was that an exogenous ATP concentration of as little as 1 μM counter regulated the Vac-induced cell death. Studies using carvacrol, an inhibitor of transient receptor potential cation channel, subfamily M, member 7 (TRPM7), demonstrated that the ATP-inducible inhibitory effect is likely to be via TRPM7. Exogenous ATP is of relevance in GBM with large necrotic areas. Our results support the use of GBM cultures with different grades of malignancy to address their sensitivity to methuosis. The video-microscopy approach presented here allows decoding of signaling pathways as well as mechanisms of chemotherapeutic resistance by long-term observation. Before implementing Vac as a novel therapeutic drug in GBM, cells from each individual patient need to be assessed for their ATP sensitivity. In summary, the current investigation supports the concept of methuosis, described as non-apoptotic cell death and a promising approach for GBM treatment. Tissue-resident ATP/necrosis may interfere with this cell-death pathway but can be overcome by a natural compound, carvacrol that even penetrates the blood-brain barrier.


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