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Cancer Res. 2017 Apr 1;77(7):1741-1752. doi: 10.1158/0008-5472.CAN-16-2274. Epub 2017 Jan 13.

Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses.

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Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Science, Utrecht University, Utrecht, the Netherlands.
Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
Oncomatrix Research Lab, Department of Biomedicine, University of Bergen, Bergen, Norway.
Science for Life Laboratory, Department of Applied Physics, Royal Institute of Technology, Stockholm, Sweden.
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.
Chemical Biology Consortium Sweden, Division of Translational Medicine and Chemical Biology, Department of Medical Chemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.


Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas. Cancer Res; 77(7); 1741-52. ©2017 AACR.

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