Voltage-gated sodium channel blockade for inhibition of EMT

Abstract

We read the excellent review article by Davis et al. entitled ‘Targeting EMT in cancer: opportunities for pharmacological intervention’ [1xTargeting EMT in cancer: opportunities for pharmacological intervention. Davis, F.M. et al. Trends Pharmacol. Sci. 2014; 35: 479–488Abstract | Full Text | Full Text PDF | PubMed | Scopus (34)See all References[1] with great interest. The authors listed possible targets for inhibiting epithelial–mesenchymal transition (EMT)-associated metastasis. We think that the concept of blockade of voltage-gated sodium channels (VGSCs) for inhibiting the metastatic process deserves further consideration.It is known that VGSCs, which are normally expressed in excitable cells, are expressed aberrantly in many types of cancer cells [2xVoltage-gated sodium channels and metastatic disease. Brackenbury, W.J. Channels. 2012; 6: 352–361Crossref | PubMed | Scopus (41)See all References[2]. Their expression is associated with the aggressive clinical behavior of cancer cells. VGSCs (as other ion channels) are thought to be associated with many characteristics of cancer [3xIon channels and the hallmarks of cancer. Prevarskaya, N. et al. Trends Mol. Med. 2010; 16: 107–121Abstract | Full Text | Full Text PDF | PubMed | Scopus (123)See all References[3]. VGSCs are known to strengthen the migratory and invasive properties of cancer cells via regulation of pH, gene expression, and intracellular calcium (Ca2+) levels [4xVoltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Fraser, S.P. et al. Clin. Cancer Res. 2005; 11: 5381–5389Crossref | PubMed | Scopus (145)See all References, 5xNav1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae. Brisson, L. et al. Oncogene. 2011; 30: 2070–2076Crossref | PubMed | Scopus (51)See all References, 6xVoltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion. House, C.D. et al. Cancer Res. 2010; 70: 6957–6967Crossref | PubMed | Scopus (74)See all References, 7xTherapeutic potential for phenytoin: targeting Nav1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Yang, M. et al. Breast Cancer Res. Treat. 2012; 134: 603–615Crossref | PubMed | Scopus (42)See all References]. Recently, Davis and colleagues [8xInduction of epithelial–mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Davis, F.M. et al. Oncogene. 2013; 33: 2307–2316Crossref | PubMed | Scopus (42)See all References[8] reported that attenuation of Ca2+ signaling via intracellular Ca2+ chelation inhibits epidermal growth factor (EGF)- and hypoxia-induced EMT in breast cancer cell lines. In addition, Ca2+ chelation causes downregulation of EGF-induced activation of STAT3 phosphorylation and expression of the EMT marker vimentin [8xInduction of epithelial–mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Davis, F.M. et al. Oncogene. 2013; 33: 2307–2316Crossref | PubMed | Scopus (42)See all References[8]. Blockade of VGSCs inhibits metastatic capacity, but not proliferation, of cancer cells, and this has been shown in breast and prostate cancer models [9xVoltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Fraser, S.P. et al. Clin. Cancer Res. 2005; 11: 5381–5389Crossref | PubMed | Scopus (178)See all References, 10xContribution of functional voltage-gated Na+ channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer. I. Lateral motility. Fraser, S.P. et al. J. Cell. Physiol. 2003; 195: 479–487Crossref | PubMed | Scopus (94)See all References]. The researchers reported that the mechanisms governing primary and secondary tumor growth (i.e., colonization at secondary sites) differ, which might be why proliferation at secondary sites is not affected by VGSCs. Blockade of VGSCs via tetrodotoxin – a potent highly-selective sodium channel blocker – significantly decreased the number, but not the size, of metastatic lesions in an xenograft model of prostate carcinoma [11xVoltage-gated sodium channel activity promotes prostate cancer metastasis in vivo. Yildirim, S. et al. Cancer Lett. 2012; 323: 58–61Abstract | Full Text | Full Text PDF | PubMed | Scopus (30)See all References[11]. The researchers concluded that VGSC blockers were unable to inhibit proliferation at secondary sites. We think this effect of VGSG blockade is due to inhibition of EMT and a consequent reduction in the metastatic capacity of cancer cells. Because inhibition of VGSCs does not appear to have a significant effect on proliferation at secondary sites, the size of the metastatic lesions was not affected. This also indicates that VGSCs do not have strong inhibitory activity on the mesenchymal–epithelial transition (MET). We agree that inhibition of EMT (i.e., strategies to promote MET) might hasten the colonization of cancer cells that have already left the primary site and/or reinforce the viability of metastatic deposits; however, we also know that proliferating cells are more sensitive to the effects of cytotoxic chemotherapy and targeted therapies. In the presence of effective systemic treatment, inhibition of EMT might be of less potential hazard. Inexpensive drugs without serious side effects that have significant sodium channel-blocking activity, such as local anesthetics, anticonvulsants, anti-arrhythmics, and anti-hypertensives, could be tested in future trials on blockade of VGSCs and inhibition of EMT [12xPersistent current blockers of voltage-gated sodium channels: a clinical opportunity for controlling metastatic disease. Djamgoz, M.B. et al. Recent Pat. Anticancer Drug Discov. 2013; 8: 66–84Crossref | PubMedSee all References[12].In conclusion, blockade of VGSCs could be a potential strategy for inhibiting EMT, and might reduce the invasion, migratory capacity, and chemoresistance of cancer cells. Because blockade of VGSCs does not appear to negatively affect MET, we think this treatment strategy could even be combined with cytotoxic chemotherapy or targeted therapies.