Pharmacological and nutritional targeting of voltage-gated sodium channels in the treatment of cancers

Voltage-gated sodium (NaV) channels, initially characterized in excitable cells, have been shown to be aberrantly expressed non-excitable cancer tissues and cells from epithelial origins such as breast, lung, prostate, colon, cervix, whereas they are not cognate non-cancer tissues. Their activity was demonstrated promote aggressive invasive potencies of both vitro vivo, their deregulated expression has associated with metastatic progression cancer-related death. This review proposes NaV channels pharmacological targets for anticancer treatments providing opportunities repurposing existing NaV-inhibitors or developing new nutritional interventions. composed pore-forming NaVα auxiliary NaVβ subunits, were which responsible the triggering propagation action potentials. physiological activity, through a transient depolarizing inward current cell types cardiomyocytes, skeletal muscle neurons, is well being initiation excitation-contraction, excitation-secretion, excitation-expression couplings. As such, these ion critical numerous functions mutations encoding genes, dysregulation may lead serious pathologies called “sodium channelopathies.” multiple inhibitory molecules that FDA approved clinically used treatment cardiac angina arrhythmias, epilepsies, chronic pain, anesthesiology. Although about 70 years ago, recent data obtained past 5 shed light on protein structure, arrangement, functioning at molecular level. Indeed, i.e. currents (INa), first recorded by Hodgkin Huxley 1952 squid giant axon, using voltage-clamp technique. These pioneering experiments led ionic theory membrane excitability (Hodgkin Huxley, 1952Hodgkin A.L. A.F. A quantitative description its application conduction excitation nerve.J. Physiol. 1952; 117: 500-544Crossref PubMed Google Scholar). However, time structure known evidence properties came beginning 1980s identification channel proteins radiolabeled-neurotoxins highly selective combination solubilization purification methods (Agnew et al., 1980Agnew W.S. Moore A.C. Levinson S.R. Raftery M.A. Identification large weight peptide tetrodotoxin binding electroplax Electrophorus electricus.Biochem. Biophys. Res. Commun. 1980; 92: 860-866Crossref Scholar; Beneski Catterall, 1980Beneski D.A. Catterall W.A. Covalent labeling components photoactivable derivative scorpion toxin.Proc. Natl. Acad. Sci. U S A. 77: 639-643Crossref Further structural insights into cloning screening cDNA libraries leading discovery amino acid sequence allowing modeling secondary structures based aliphatic profiles (Noda 1984Noda M. Shimizu S. Tanabe T. Takai Kayano Ikeda Takahashi H. Nakayama Kanaoka Y. Minamino N. al.Primary electricus deduced sequence.Nature. 1984; 312: 121-127Crossref Scopus (942) Scholar, Noda 1986Noda Suzuki Takeshima Kurasaki Numa Existence distinct messenger RNAs rat brain.Nature. 1986; 320: 188-192Crossref (679) seminal studies allowed development model principal subunit eukaryotes, later NaVα-subunit, single polypeptide chain approximately 260 kDa containing four repeated homologous domains (I–IV) six transmembrane segments (S1–S6). identified interact one two single-span NaVβ-subunits (30–40 kDa), bringing regulatory (Isom 1992Isom L.L. De Jongh K.S. Patton D.E. Reber B.F. Offord J. Charbonneau Walsh K. Goldin Primary functional beta 1 brain channel.Science. 1992; 256: 839-842Crossref Isom 1994Isom Auxiliary subunits voltage-gated channels.Neuron. 1994; 12: 1183-1194Abstract Full Text PDF (477) Scholar) macromolecular complex eukaryotic (Brackenbury Isom, 2011Brackenbury W.J. Na subunits: overachievers family.Front. Pharmacol. 2011; 2: 53Crossref (0) 2000Catterall From mechanisms: function 2000; 26: 13-25Abstract Interestingly, understanding organization level substantially progressed very recently use X-ray crystallography cryo-electron microscopy, studying tetrameric prokaryotic sharing 25–30% identity human channels. Thus information regarding voltage-dependent gating; selectivity; drug binding; open, closed, inactivated states acquired Arcobacter butzleri (NavAb) (Payandeh 2011Payandeh Scheuer Zheng The crystal channel.Nature. 475: 353-358Crossref (978) Payandeh 2012Payandeh Gamal El-Din T.M. Crystal potentially states.Nature. 2012; 486: 135-139Crossref (347) (Lenaeus 2017Lenaeus M.J. Ing C. Ramanadane Pomes R. Structures closed open channel.Proc. 2017; 114: E3051-E3060Crossref (61) high-resolution complete (NaVMs) Magnetococcus marinus activated state, electrophysiological recordings (Sula 2017Sula Booker Ng L.C. Naylor C.E. Decaen P.G. Wallace B.A. an channel.Nat. 8: 14205Crossref (83) Recently, NaVAb provided gating mechanism voltage sensor function, pore opening, activation gate (Wisedchaisri 2019Wisedchaisri G. Tonggu L. Mccord E. Wang Resting-state channel.Cell. 2019; 178: 993-1003 e12Abstract (48) near-atomic resolution monomeric study NaVPaS American cockroach, NaV1.2, NaV1.4, NaV1.7, β-subunits published (Pan 2018Pan X. Li Z. Zhou Q. Shen Wu Huang Chen Zhang Zhu Lei al.Structure Nav1.4 beta1.Science. 2018; 362: eaau2486Crossref (138) Pan 2019Pan Gao Liu Yan Molecular basis blockade Na(+) Nav1.2 mu-conotoxin KIIIA.Science. 363: 1309-1313Crossref (74) 2019Shen D. Nav1.7 animal toxins.Science. 1303-1308Crossref (140) provide important insight mechanisms underlying channelopathies discovery. Briefly, each domain presents modules: S1–S4 comprise voltage-sensor module (VSM), sections (S5 - P loop S6) constitute (PM). positively charged arginine lysine residues, positioned every third residue within S4 segment module, sense changes potential transform this electrical stimulus fast conformational change opening conductive pore, permitting Na+ influx. One milliseconds after another happens protein, occluding influx, process inactivation. Another challenged initial paradigms contain subunit. NaVα-subunits appear assemble dimers, physical interaction permits coupled (Clatot 2017Clatot Hoshi Wan Jain Shinlapawittayatorn Marionneau Ficker Ha Deschenes I. dimers.Nat. 2077Crossref (50) In humans, there nine different genes NaVα-subunits, them clustered chromosome SCN1A (NaV1.1), SCN2A (NaV1.2), SCN3A (NaV1.3), SCN9A (NaV1.7); three others located 3: SCN5A (NaV1.5), SCN10A (NaV1.8), SCN11A (NaV1.9); more 12 17: SCN8A (NaV1.6) SCN4A (NaV1.4), respectively (Goldin, 2002Goldin Evolution channels.J. Exp. Biol. 2002; 205: 575-584Crossref homology among subtypes higher than 70% extracellular motifs so no subfamilies; nonetheless, some isoforms closely related other, chromosomal localization sensitivity (TTX), explained early genomic duplication during evolution genes. To date, NaVβ-subunits, 19: SCN1B (encoding splicing variants, NaVβ1 soluble NaVβ1B) other 11: SCN2B (NaVβ2), SCN3B (NaVβ3), SCN4B (NaVβ4). NaVβ-subunit comprised N-terminal immunoglobulin-like domain, followed juxtamembrane region, 34-44 amino-acid-length intracellular except splice variant NaVβ1B, macromolecule Furthermore, it worth noting only influence NaVα-subunit trafficking biophysical modulation but also experimentally act adhesion (CAMs), participating homophilic heterophilic interactions, contactin, N-cadherin, NrCAM, several neurofascin tenascin main (Isom, 2002Isom role adhesion.Front. Biosci. 7: 12-23Crossref Bouza 2018Bouza A.A. diseases.Handb 246: 423-450Crossref differentially developmentally (Black Waxman, 2013Black J.A. Waxman S.G. Noncanonical roles 2013; 80: 280-291Abstract (114) Roger 2015Roger Gillet Le Guennec J.Y. Besson P. cancer: primary role?.Front. 2015; 6: 152Crossref (57) Initial distributed mammalian central peripheral nervous systems muscle. system mainly NaV1.1, NaV1.3, NaV1.6 isoforms, include NaV1.8, NaV1.9. NaV1.4 NaV1.5 heart 2001Goldin Resurgence research.Annu. Rev. 2001; 63: 871-894Crossref (570) Scholar), dorsal root ganglion (Wang 2008Wang Ou S.W. Y.J. Zong Z.H. Lin Kameyama New variants Nav1.5/SCN5A encode brain.J. Neurogenet. 2008; 22: 57-75Crossref 2009Wang Analysis novel cloned brain.Neurosci. 2009; 64: 339-347Crossref 2018aWang Bai Y.F. Xu Z.D. Luan G.M. Downregulation adult neonatal Nav1.5 ganglia axon sensory neurons rats spared nerve injury.Int. Mol. Med. 41: 2225-2232PubMed 2018bWang Z.Y. Qiu B. frontal lobe brain.Int. 915-923PubMed Bergareche 2015Bergareche Bednarz Sanchez Krebs Ruiz-Martinez La Riva Makarov V. Gorostidi Jurkat-Rott Marti-Masso J.F. Paisan-Ruiz mutation pathogenetically contributes autosomal dominant essential tremor increase susceptibility epilepsy.Hum. Genet. 24: 7111-7120PubMed Therefore, long considered hallmark cells. Again, paradigm changed (mRNA protein) sometimes plasma (transient currents) chondrocytes, endothelial microglia, astrocytes, fibroblasts, keratinocytes, islet β-cells, red blood T-lymphocytes, dendritic macrophages, others, biological subcellular distribution Navs still elusive emerged carcinoma progression, suggesting could serve markers prognostic factors. pro-cancerous and, importantly, contribute disease vivo models. Recent signaling pathways under control proteins, coupling cellular properties. inhibition small synthetic compounds FDA-approved drugs natural dietary opens up therapeutic strategies. review, we summarize knowledge cancers, highlight involved, discuss strategies represent treatments. β, reported altered (Table 1). detected biology biochemical techniques, membrane, INa, recorded. Most upregulated downregulated. aberrant correlated oncogenic models cancer, mostly solid tumors including carcinomas (Figure 1).Table 1Expression cancerIsoformExpression levelsCancer typeRole proposed mechanismReferencesNaV1.1UpregulatedaCancer tissue versus non-cancerous tissue. (mRNA, protein)Lymph nodes CRCUnknown, unknownLin 2019Lin Lv Mao Lu W. Over-expression Nav1.6 lymph node metastases colorectal cancer.World Surg. Oncol. 175Crossref (1) ScholarNaV1.2UpregulatedaCancer (Protein)LiverUnknown, unknownThe Human Atlas (www.proteinatlas.org)NaV1.3UpregulatedaCancer (mRNA)OvarianUnknown, unknownGao 2010Gao Cai Expression alpha ovarian cancer.Oncol. Rep. 2010; 23: 1293-1299PubMed ScholarNaV1.4UpregulatedaCancer (mRNA)CervixUnknown, unknownDiaz 2007Diaz Delgadillo D.M. Hernandez-Gallegos Ramirez-Dominguez M.E. Hinojosa L.M. Ortiz C.S. Berumen Camacho Gomora J.C. Functional cultures cervical cancer.J. 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