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

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

doi:10.18632/oncotarget.16703

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.

Highlights

30% of all primary brain tumors are diagnosed as Glioblastoma multiforme (GBM), a highly fatal malignancy with high mutagenicity and extreme migration and invasion potentials, explaining the poor survival rate [1]
We investigated the kinetics of Vac on the viability of the established glioma cell line U-87 and the new, highly aggressive glioma cell line designated #12537-GB, and confirmed and extended endpoint observations reported by Kitambi and colleagues [8]
When trying to interfere with Vac-induced cell death, we identified that exogenous ATP exhibited the most pronounced counter regulatory effect (Figure 1A, 1B)

Summary

Introduction

30% of all primary brain tumors are diagnosed as Glioblastoma multiforme (GBM), a highly fatal malignancy with high mutagenicity and extreme migration and invasion potentials, explaining the poor survival rate [1]. In addition to standard radiochemotherapy inducing apoptosis-related cell death, new effective therapeutic modalities for GBM are urgently required. Established apoptosis-directed therapy has not resulted in an improved prognosis [2]. GBM disseminate within the brain and lack hematogenous spreading [3,4,5]. Major changes of the patients’ immune system are consistently found [6], implying an as yet not fully understood crosstalk between the tumor environment and hematological/immunological elements. Alterations of the immune system are relevant to survival [6, 7]

Methods

Results

Conclusion