Persistent Current Blockers of Voltage-Gated Sodium Channels: A Clinical Opportunity for Controlling Metastatic Disease
Mustafa B.A. Djamgoz and Rustem Onkal
Affiliation: Division of Cell & Molecular Biology, Neuroscience Solutions to Cancer Research Group, Sir Alexander Fleming Building, South Kensington Campus, Imperial College London, London SW7 2AZ, UK.
Keywords: Hypoxia, metastasis, persistent current, ranolazine, riluzole, voltage-gated sodium channel
A range of experimental and clinical data suggests strongly (i) that metastatic progression in carcinomas is accompanied
(maybe even preceded) by upregulation of functional voltage-gated sodium channels (VGSCs) and (ii) that
VGSC activity enhances cancer cell invasiveness. First, this review outlines the available in vitro and in vivo evidence for
the VGSC expression and its proposed pathophysiological role. Second, we question the mechanism(s) whereby VGSC
activity can induce such a cancer-promoting effect. We advance the hypothesis that it is the hypoxia-sensitive persistent
component of the VGSC current (INaP) that is central to the phenomenon. Indeed, blockers of INaP are very effective in
suppressing cancer cell invasiveness in vitro. Based upon these data, UK and international patent applications have been
filed which describe the use of INaP blockers, like ranolazine (“Ranexa”) and riluzole (“Rilutex”), as anti-metastatic agents.
Importantly, since these drugs are already in clinical use, against conditions like cardiac angina and amyotrophic lateral
scelerosis, there are no issues of dosage, unacceptable side effects or long-term use. Thus, INaP blockers have the potential
to turn cancer into a chronic condition.
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