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.

Ion channels in cancer: future perspectives and clinical potential

“…Expression of the Nav1.5a subunit is correlated with poor prognosis in breast cancer [121]. Some evidence points to a decisive role of the hypoxia-sensitive persistent component of the voltage-gated Na þ channel current [1].…”

“…Those include the Cl 2 channel inhibitor tamoxifen [145] and chlorotoxin or TM-601 [146][147][148], substances accomplishing internalization of ClC-3 thus inhibiting migration of glioma cells [5,99]. Inhibitors of voltage-gated Na þ channels may be particularly valuable in the suppression of tumour metastasis [1,121]. In this respect, the voltage-gated Na þ channel blockers ranolazine and riluzole have been claimed as anti-metastatic agents [1].…”

“…All those functions are critically important for tumour cell survival and metastasis [1]. Moreover, ion channels participate in the regulation of other cell functions again relevant for migration [7], and thus metastasis.…”

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

“…The significant involvement of the sigma-1 receptor in VGSC expression/activity may have wide-reaching clinical implications since VGSCs, and in particular nNa v 1.5, have already been proposed as a novel anti-metastatic target in a range of cancers (Fraser et al 2014;Onkal and Djamgoz 2009;Djamgoz and Onkal 2013).…”

Functional properties of ion channels and transporters in tumour vascularization

“…Voltage-gated Na þ channels (VGSCs) are also expressed in non-excitable cells and functionally upregulated in metastatic tumour cells [73][74][75]. Recently, a clear relationship between functional expression and biological role of VGSCs in EC has been described [36].…”