The sodium pump alpha(1) subunit as a potential target to combat apoptosis-resistant glioblastomas

PURPOSE: 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 alpha(1) subunits seem to be upregulated in a proportion of glioblastomas but not in normal brain tissues. DESIGN: 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 alpha(1)) 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 alpha(1) over-expressing glioma cells. CONCLUSIONS: Glioblastoma patients who do not respond to chemotherapy and whose tumors over-express NaK alpha(1) subunits could benefit from a treatment using ligands with marked binding affinity for the NaK alpha(1) subunit.