The sodium pump alpha1 subunit as a potential target to combat apoptosis-resistant glioblastomas.
OBJECTIVE
To review the involvement of the ion transporter Na+/K+-ATPase (NaK) in the migration and proliferation of glioma cells. Preliminary studies indicate that NaK alpha1 subunits seem to be upregulated in a proportion of glioblastomas but not in normal brain tissues.


METHODS
The present review focuses on (1) the natural resistance of migrating malignant glioma cells to apoptosis, (2) autophagic cell death as an alternative to combat malignant gliomas, (3) the fact that reducing the levels of malignant glioma cell motility can restore proapoptotic drug sensitivity,and (4) on the observation that inhibiting the NaK activity reduces both glioma cell proliferation and migration.


RESULTS
The natural ligands of the NaK are the cardiotonic steroids. A hemisynthetic derivative of 2"-oxovoruscharin (UNBS1450), a novel cardenolide, displays unique structural features, making its binding affinity to NaK alpha subunits (including alpha1) 10 to 100 times higher than that of other cardenolides. UNBS1450 markedly decreases intracellular ATP concentration in glioma cells, disorganizes the actin cytoskeleton, and leads to autophagic cell death in NaK alpha1 over-expressing glioma cells.


CONCLUSIONS
Glioblastoma patients who do not respond to chemotherapy and whose tumors over-express NaK alpha1 subunits could benefit from a treatment using ligands with marked binding affinity for the NaK alpha1 subunit.
Lefranc
Florence
F
Department of Neurosurgery, Erasme University Hospital,Université Libre de Bruxelles, Brussels, Belgium. fllefran@ulb.ac.be
Kiss
Robert
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002298:Cardenolides / Q000494:pharmacology / Q000627:therapeutic use*; D002301:Cardiac Glycosides / Q000494:pharmacology / Q000627:therapeutic use*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008024:Ligands; D051379:Mice; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects* / Q000378:metabolism
D002298:Cardenolides; D002301:Cardiac Glycosides; D008024:Ligands; C510008:UNBS 1450; C499076:ATP1A1 protein, human; D000254:Sodium-Potassium-Exchanging ATPase