Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells.
- Venturini E Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
- Leanza L Department of Biology, University of Padova, Padova, Italy.
- Azzolini M CNR Institute of Neurosciences and Department of Biomedical Sciences and Neuroscience Center, University of Padova, Padova, Italy.
- Kadow S Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
- Mattarei A Department of Chemical Sciences, University of Padova, Padova, Italy.
- Weller M Laboratory of Molecular Neuro-Oncology, Department of Neurology and Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
- Tabatabai G Interdisciplinary Division of Neuro-Oncology, Departments of Vascular Neurology and Neurosurgery, University Hospital Tübingen, Tübingen, Germany.
- Edwards MJ Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA.
- Zoratti M CNR Institute of Neurosciences and Department of Biomedical Sciences and Neuroscience Center, University of Padova, Padova, Italy.
- Paradisi C Department of Chemical Sciences, University of Padova, Padova, Italy.
- Szabò I Department of Biology, University of Padova, Padova, Italy.
- Gulbins E Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
- Becker KA Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
- 2017-09-05
Published in:
- Neuro-Signals. - 2017
Glioblastoma
Inhibitors
Kv1.3
Mitochondria
Animals
Antineoplastic Agents
Apoptosis
Brain Neoplasms
Cell Line, Tumor
Clofazimine
Coumarins
Glioblastoma
Humans
Immunohistochemistry
Kv1.3 Potassium Channel
Mice
Organophosphorus Compounds
Potassium Channel Blockers
English
BACKGROUND/AIMS
Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells.
METHODS
We investigated the expression of Kv1.3 in different glioma cell lines by immunocytochemistry, western blotting and electron microscopy and analyzed the effect of newly synthesized, mitochondria-targeted, Kv1.3 inhibitors on the induction of cell death in these cells. Finally, we performed in vivo studies on glioma bearing mice.
RESULTS
Here, we report that Kv1.3 is expressed in mitochondria of human and murine GL261, A172 and LN308 glioma cells. Treatment with the novel Kv1.3 inhibitors PAPTP or PCARBTP as well as with clofazimine induced massive cell death in glioma cells, while Psora-4 and PAP-1 were almost without effect. However, in vivo experiments revealed that the drugs had no effect on orthotopic brain tumors in vivo.
CONCLUSION
These data serve as proof of principle that Kv1.3 inhibitors kills GBM cells, but drugs that act in vivo against glioblastoma must be developed to translate these findings in vivo.
Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells.
METHODS
We investigated the expression of Kv1.3 in different glioma cell lines by immunocytochemistry, western blotting and electron microscopy and analyzed the effect of newly synthesized, mitochondria-targeted, Kv1.3 inhibitors on the induction of cell death in these cells. Finally, we performed in vivo studies on glioma bearing mice.
RESULTS
Here, we report that Kv1.3 is expressed in mitochondria of human and murine GL261, A172 and LN308 glioma cells. Treatment with the novel Kv1.3 inhibitors PAPTP or PCARBTP as well as with clofazimine induced massive cell death in glioma cells, while Psora-4 and PAP-1 were almost without effect. However, in vivo experiments revealed that the drugs had no effect on orthotopic brain tumors in vivo.
CONCLUSION
These data serve as proof of principle that Kv1.3 inhibitors kills GBM cells, but drugs that act in vivo against glioblastoma must be developed to translate these findings in vivo.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1159/000480643
- PMID 28869943
- Persistent URL
- https://sonar.ch/global/documents/90839
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