title: Persistent current blockers of voltage-gated sodium channels: a clinical opportunity for controlling metastatic disease.
abstract: 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.
authors.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. m.djamgoz@imperial.ac.uk
authors.forename: Mustafa B A
authors.initials: MB
authors.lastname: Djamgoz
authors.forename: Rustem
authors.initials: R
authors.lastname: Onkal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D015687:Cell Hypoxia; D015195:Drug Design; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D007880:Legislation, Drug; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010330:Patents as Topic; D026941:Sodium Channel Blockers / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D059016:Tumor Microenvironment; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels