• Arrhythmia
• Brugada syndrome
• Ephaptic coupling
• Perinexus
• SCN1B (β1/β1B)
• Voltage-gated sodium channel

• F31 HL164088 NHLBI NIH HHS
• R01 HL056728 NHLBI NIH HHS
• R01 HL141855 NHLBI NIH HHS
• R35 HL161237 NHLBI NIH HHS

• ATP-binding cassette
• SCN5A
• acute myeloid leukemia
• apoptosis
• multidrug resistance

• Humans
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters/genetics
• ATP-Binding Cassette Transporters/pharmacology
• Drug Resistance, Neoplasm/genetics
• Neoplasm Proteins/genetics
• Drug Resistance, Multiple/genetics
• Leukemia, Myeloid, Acute/drug therapy
• Leukemia, Myeloid, Acute/genetics
• Leukemia, Myeloid, Acute/metabolism
• ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
• ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
• Apoptosis/genetics
• NAV1.5 Voltage-Gated Sodium Channel/genetics

• Sodium leak channel
• calcium oscillations
• invasion
• oncochannelopathy
• vesicle secretion

• Male
• Humans
• Sodium/metabolism
• Ion Channels/metabolism
• Ion Transport
• Prostatic Neoplasms
• Membrane Proteins/genetics
• Membrane Proteins/metabolism

• SCN5A
• arrhythmia
• electrophysiology
• genetics
• ion channels

• Humans
• Channelopathies/genetics
• Channelopathies/metabolism
• Arrhythmias, Cardiac/genetics
• Arrhythmias, Cardiac/metabolism
• NAV1.5 Voltage-Gated Sodium Channel/genetics
• NAV1.5 Voltage-Gated Sodium Channel/metabolism
• Mutation
• Cardiomyopathies/genetics
• Epilepsy/genetics

• Netherlands Organisation for Health Research and Development (ZonMW)
• Netherlands CardioVascular Research Initiative (CVON)
• Fondation Leducq

• cervical cancer
• endometrial cancer
• gynecological cancer
• ion channels
• ovarian cancer
• personalized medicine

• This work was partially supported by Conacyt grant A1-S-9783 to JdlG Consejo Nacional de Ciencia y Tecnología

• EF2-kinase
• Metastasis
• Na(V)1.5 channel
• Oncogene
• Triple-negative breast cancer
• siRNA

• Humans
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/pathology
• Signal Transduction
• NAV1.5 Voltage-Gated Sodium Channel
• Lung Neoplasms/genetics
• Lung Neoplasms/secondary
• Cell Line, Tumor
• Neoplasm Metastasis
• Cell Proliferation
• Cell Movement

• Calcium Channels/metabolism
• Cell Adhesion Molecules/drug effects
• Cell Adhesion Molecules/metabolism
• Humans
• Ion Channels/drug effects
• Ion Channels/metabolism
• Membrane Proteins/drug effects
• Membrane Proteins/metabolism
• Peptide Hydrolases/metabolism
• Peptides/metabolism
• Potassium/metabolism
• Potassium Channels, Voltage-Gated
• Proteolysis/drug effects
• Sodium/metabolism

• R37 NS076752 NINDS NIH HHS

Although in the last decades the clinical outcome of cancer patients considerably improved, the major drawbacks still associated with chemotherapy are the unwanted side effects and the development of drug resistance. Therefore, a continuous effort in trying to discover new tumor markers, possibly of diagnostic, prognostic and therapeutic value, is being made. This review is aimed at highlighting the anti-tumor activity that several antiepileptic drugs (AEDs) exert in breast, prostate and other types of cancers, mainly focusing on their ability to block the voltage-gated Na⁺ and Ca⁺⁺ channels, as well as to inhibit the activity of histone deacetylases (HDACs), all well-documented tumor markers and/or molecular targets. The existence of additional AEDs molecular targets is highly suspected. Therefore, the repurposing of already available drugs as adjuvants in cancer treatment would have several advantages, such as reductions in dose-related toxicity CVs will be sent in a separate mail to the indicated address of combined treatments, lower production costs, and faster approval for clinical use.

Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients’ outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.

• HDAC inhibitors
• adjuvant anti-cancer therapy
• antiepileptic drugs
• cancer
• carbamazepine
• drug repositioning
• gabapentin
• lamotrigine
• phenytoin
• valproic acid
• voltage gated calcium channels
• voltage gated sodium channels

The human TE671 cell line was originally used as a model of medulloblastoma but has since been reassigned as rhabdomyosarcoma. Despite the characterised endogenous expression of voltage‐sensitive sodium currents in these cells, the specific voltage‐gated sodium channel (VGSC) subtype underlying these currents remains unknown. To profile the VGSC subtype in undifferentiated TE671 cells, endpoint and quantitative reverse transcription–PCR (qRT‐PCR), western blot and whole‐cell patch clamp electrophysiology were performed. qRT‐PCR profiling revealed that expression of the SCN9A gene was ∼215‐fold greater than the SCN4A gene and over 400‐fold greater than any of the other VGSC genes, while western blot confirmed that the dominant SCN9A RNA was translated to a protein with a molecular mass of ∼250 kDa. Elicited sodium currents had a mean amplitude of 2.6 ± 0.7 nA with activation and fast inactivation V₅₀ values of −31.9 ± 1.1 and −69.6 ± 1.0 mV, respectively. The currents were completely and reversibly blocked by tetrodotoxin at concentrations greater than 100 nm (IC₅₀ = 22.3 nm). They were also very susceptible to the Na_V1.7 specific blockers Huwentoxin‐IV and Protoxin‐II with IC₅₀ values of 14.6 nm and 0.8 nm, respectively, characteristic of those previously determined for Na_V1.7. Combined, the results revealed the non‐canonical and highly dominant expression of Na_V1.7 in the human TE671 rhabdomyosarcoma cell line. We show that the TE671 cell line is an easy to maintain and cost‐effective model for the study of Na_V1.7, a major target for the development of analgesic drugs and more generally for the study of pain.

Undifferentiated TE671 cells produce a voltage‐sensitive sodium current when depolarised.

• Huwentoxin-IV
• NaV1.7
• Protoxin-II
• TE671 cells
• patch-clamp
• tetrodotoxin
• voltage-gated sodium channel

• Akt/NF-κB
• Ca2+
• Carcinogenesis
• Metastasis
• Wnt/β-catenin
• pH

• Apoptosis
• Cell proliferation
• Channels
• Melanocyte
• Melanoma
• Metastasis
• Mutation
• Nevus
• Prognosis
• Transporters
• Tumor development
• Tumor progression

• cancer
• ion channels
• scorpion venom
• toxins
• voltage-dependent

• Nav1.5
• Wnt/β-catenin signaling pathway
• oral squamous cell carcinoma (OSCC)

Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics driven by a combination of poor vascular perfusion, regional hypoxia, and increased the flux of carbons through fermentative glycolysis. This leads to extracellular acidosis and intracellular alkalinization. Dysregulated pH dynamics influence cancer cell biology, from cell transformation and tumorigenesis to proliferation, local growth, invasion, and metastasis. Moreover, this dysregulated intracellular pH (pHi) drives a metabolic shift to increased aerobic glycolysis and reduced mitochondrial oxidative phosphorylation, referred to as the Warburg effect, or Warburg metabolism, which is a selective feature of cancer. This metabolic reprogramming confers a thermodynamic advantage on cancer cells and tissues by protecting them against oxidative stress, enhancing their resistance to hypoxia, and allowing a rapid conversion of nutrients into biomass to enable cell proliferation. Indeed, most cancers have increased glucose uptake and lactic acid production. Furthermore, cancer cells have very dysregulated electrolyte balances, and in the interaction of the pH dynamics with electrolyte, dynamics is less well known. In this review, we highlight the interconnected roles of dysregulated pH dynamics and electrolytes imbalance in cancer initiation, progression, adaptation, and in determining the programming and reprogramming of tumor cell metabolism.

• cancer
• electrolytes
• metabolism
• pH

• Nav1.5
• Rac1
• breast cancer
• membrane potential
• migration

• Biosensing Techniques
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Membrane/genetics
• Cell Membrane/metabolism
• Cell Movement/genetics
• Cellular Microenvironment/genetics
• Cytoskeleton/chemistry
• Cytoskeleton/genetics
• Female
• GTP Phosphohydrolases/chemistry
• GTP Phosphohydrolases/genetics
• Humans
• Ion Channels/genetics
• Membrane Potentials/genetics
• NAV1.5 Voltage-Gated Sodium Channel/chemistry
• NAV1.5 Voltage-Gated Sodium Channel/genetics
• Signal Transduction/genetics
• rac1 GTP-Binding Protein/chemistry
• rac1 GTP-Binding Protein/genetics

• 25922 Cancer Research UK
• 30380 Cancer Research UK
• G1000508 Medical Research Council
• A25922 Cancer Research UK
• Medical Research Council
• Cancer Research UK

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment choice for peritoneal cancer. However, patients commonly suffer from severe postoperative pain. The pathophysiology of postoperative pain is considered to be from both nociceptive and neuropathic origins.

The recent advances on the etiology of postoperative pain after CRS + HIPEC treatment were described, and the treatment strategy and outcomes were summarized.

Conventional analgesics could provide short-term symptomatic relief. Thoracic epidural analgesia combined with opioids administration could be an effective treatment choice. In addition, a transversus abdominis plane block could also be an alternative option, although further studies should be performed.

• Analgesics
• Cytoreductive surgery
• Hyperthermic intraperitoneal chemotherapy
• Neuropathic
• Nociceptive
• Pain
• Peritoneal cancer

• ALKBH5
• Glioblastoma
• Imidazobenzoxazin-5-thione scaffold
• Off-target interaction

• AlkB Homolog 5, RNA Demethylase/antagonists & inhibitors
• AlkB Homolog 5, RNA Demethylase/metabolism
• Benzoxazines/chemical synthesis
• Benzoxazines/chemistry
• Benzoxazines/pharmacology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Survival/drug effects
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Enzyme Inhibitors/chemical synthesis
• Enzyme Inhibitors/chemistry
• Enzyme Inhibitors/pharmacology
• Humans
• Molecular Structure
• Proteome/drug effects
• Structure-Activity Relationship

Loss of epithelial polarity and gain in invasiveness by carcinoma cells are critical events in the aggressive progression of cancers and depend on phenotypic transition programs such as the epithelial-to-mesenchymal transition (EMT). Many studies have reported the aberrant expression of voltage-gated sodium channels (Na_V) in carcinomas and specifically the Na_V1.5 isoform, encoded by the SCN5A gene, in breast cancer. Na_V1.5 activity, through an entry of sodium ions, in breast cancer cells is associated with increased invasiveness, but its participation to the EMT has to be clarified. In this study, we show that reducing the expression of Na_V1.5 in highly aggressive human MDA-MB-231 breast cancer cells reverted the mesenchymal phenotype, reduced cancer cell invasiveness and the expression of the EMT-promoting transcription factor SNAI1. The heterologous expression of Na_V1.5 in weakly invasive MCF-7 breast cancer cells induced their expression of both SNAI1 and ZEB1 and increased their invasive capacities. In MCF-7 cells the stimulation with the EMT-activator signal TGF-β1 increased the expression of SCN5A. Moreover, the reduction of the salt-inducible kinase 1 (SIK1) expression promoted Na_V1.5-dependent invasiveness and expression of EMT-associated transcription factor SNAI1. Altogether, these results indicated a prominent role of SIK1 in regulating Na_V1.5-dependent EMT and invasiveness.

• cancer biology
• development
• drosophila
• neuroscience
• proliferation
• stem cells

• Animals
• Apoptosis
• Cell Count
• Cell Lineage/genetics
• Cell Proliferation/genetics
• Drosophila/cytology
• Drosophila/genetics
• Drosophila Proteins/genetics
• Drosophila Proteins/metabolism
• Gene Expression
• Gene Knockdown Techniques
• Neural Stem Cells/cytology
• Sodium Channels/genetics
• Sodium Channels/metabolism

• K99 DA041500 NIDA NIH HHS
• P40 OD018537 NIH HHS
• R35 NS097227 NINDS NIH HHS
• Howard Hughes Medical Institute
• Michigan State University
• NIH
• Damon Runyon Cancer Research Foundation
• Howard Hughes Medical Institute

• Erythrocytes
• Ion homeostasis
• Microelectrodes
• Plasma membrane potential
• Potentiometric dyes

• Clinical targets
• Colorectal cancer
• Esophageal cancer
• Gastric cancer
• Gastrointestinal cancer
• Hepatocellular carcinoma
• Ion channels
• Novel therapies
• Pancreatic cancer
• Prognostic biomarker

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Carcinogenesis/drug effects
• Carcinogenesis/pathology
• Disease Models, Animal
• Disease Progression
• Disease-Free Survival
• Down-Regulation
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/mortality
• Gastrointestinal Neoplasms/pathology
• Humans
• Ion Channels/antagonists & inhibitors
• Ion Channels/metabolism
• Up-Regulation

• R15 CA195061 NCI NIH HHS

Background: Endometrial cancer is the most common gynecologic malignancy in women in the developed countries. Despite recent progress in functional characterization of voltage-gated sodium channel (Na_v) in multiple cancers, very little was known about the expression of Na_v in human endometrial cancer. The present study sought to determine the role of Na_v and molecular nature of this channel in the endometrial cancer.

Methods: PCR approach was introduced to determine expression level of Na_v subunits in endometrial cancer specimens. Pharmacological agents were used to investigate Na_v function in endometrial cancer cells. Flow cytometry were used to test cancer apoptosis, and invasion assays were applied to test tumor metastasis.

Results: Transcriptional levels of the all Na_v α and β subunits were determined by real time-PCR in endometrial cancer with pair tissues of carcinoma and adjacent nonneoplastic tissue, Na_v1.7 was the most highly expressed Na_v subtype in endometrial cancer tissues. Na_v1.7 level was closely associated with tumor size, local lymph node metastasis, and 5-year and 10-year survival ratio. Inhibition of this channel by Na_v1.7 blocker PF-05089771, promoted cancer apoptosis and attenuated cancer cell invasion.

Conclusion: These results establish a relationship between voltage-gated sodium channel protein and endometrial cancer, and suggest that Na_v1.7 is a potential prognostic biomarker and could serve as a novel therapeutic target for endometrial cancer.

• Endometrial Cancer
• Ion Channels.
• Nav1.7
• Voltage-Gated Sodium Channel

• Bone sarcoma
• Cancer
• Ion channels
• Sarcoma
• Soft tissue sarcoma
• Tumor

• Nav1.5
• invasion
• migration
• oral squamous cell carcinoma
• proliferation

• Auxiliary subunit
• Calcium channel
• Cancer
• Chloride channel
• Potassium channel
• Sodium channel

• Animals
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Ion Channels/genetics
• Ion Channels/metabolism
• Neoplasms/metabolism
• Oncogenes/genetics
• Protein Subunits/genetics
• Protein Subunits/metabolism
• Signal Transduction
• Tumor Suppressor Proteins/genetics

• BB/M011151/1 Biotechnology and Biological Sciences Research Council

• Biomarkers, Tumor/biosynthesis
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/mortality
• Databases, Nucleic Acid
• Disease-Free Survival
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• RNA, Neoplasm/biosynthesis
• Survival Rate
• Tongue Neoplasms/metabolism
• Tongue Neoplasms/mortality

• PC3 cells
• invasion
• metastasis
• prostate cancer
• voltage-gated sodium channels

• Animals
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Movement/physiology
• Cell Proliferation/drug effects
• Cell Proliferation/physiology
• Drug Evaluation, Preclinical/methods
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/pathology
• Sodium Channel Blockers/chemistry
• Sodium Channel Blockers/pharmacology
• Sodium Channel Blockers/therapeutic use
• Treatment Outcome
• Xenograft Model Antitumor Assays/methods

• 81171991 National Natural Science Foundation of China
• 81603347 National Natural Science Foundation of China
• 81673167 National Natural Science Foundation of China

• Breast cancer
• Cancer cell invasion
• Metastasis
• Sodium current
• Voltage-gated sodium channel
• nNa(v)1.5

• Euthyroid Sick Syndromes/blood
• Euthyroid Sick Syndromes/etiology
• Humans
• Integrin alphaVbeta3/physiology
• Neoplasms/blood
• Neoplasms/complications
• Paraneoplastic Syndromes/blood
• Paraneoplastic Syndromes/etiology
• Thyroxine/blood
• Thyroxine/physiology
• Triiodothyronine/blood
• Triiodothyronine/physiology

• Hela cells
• Lampetra japonica
• cysteine-rich buccal gland protein
• cysteine-rich secretory proteins
• voltage-gated sodium channels

Breast cancer is the most common cancer among women and its metastatic potential is responsible for numerous deaths. Thus, the need to find new targets for improving treatment, and even finding the cure, becomes increasingly greater. Ion channels are known to participate in several physiological functions, such as muscle contraction, cell volume regulation, immune response and cell proliferation. In breast cancer, different types of ion channels have been associated with tumorigenesis. Recently, voltage-gated Na⁺ channels (VGSC) have been implicated in the processes that lead to increased tumor aggressiveness. To explain this relationship, different theories, associated with pH changes, gene expression and intracellular Ca²⁺, have been proposed in an attempt to better understand the role of these ion channels in breast cancer. However, these theories are having difficulty being accepted because most of the findings are contrary to the present scientific knowledge. Several studies have shown that VGSC are related to different types of cancer, making them a promising pharmacological target against this debilitating disease. Molecular biology and cell electrophysiology have been used to look for new forms of treatment aiming to reduce aggressiveness and the disease progress.

• ANG-2
• CoroNa Green
• Fluorescent dye
• Prostate cancer cells
• SBFI
• Sodium imaging

• Atrial fibrillation
• electrophysiology
• fibroblasts

• Anticonvulsants
• Breast neoplasms
• Colonic neoplasms
• Prostatic neoplasms
• Sodium channels

• Adult
• Aged
• Anti-Arrhythmia Agents/therapeutic use
• Anticonvulsants/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/mortality
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/mortality
• Female
• Humans
• Male
• Middle Aged
• Primary Health Care
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/mortality
• Research Design
• Retrospective Studies
• Sodium Channel Blockers/therapeutic use
• Survival Analysis
• United Kingdom/epidemiology

• Wellcome Trust
• G1000508 Medical Research Council
• 09782 Wellcome Trust

• Gastric cancer
• MACC1
• NHE1
• Nav1.7
• Tumor progression

• Axon initial segment
• Axon pathfinding
• Cardiac arrhythmia
• Cell adhesion molecule
• Cell migration
• Channelome
• Dravet syndrome
• Epilepsy
• Immunoglobulin superfamily
• Neurite outgrowth
• Nodes of Ranvier
• Voltage-gated ion channel

• Animals
• Arrhythmias, Cardiac/metabolism
• Arrhythmias, Cardiac/pathology
• Cell Adhesion Molecules/metabolism
• Central Nervous System/growth & development
• Central Nervous System/metabolism
• Epilepsy/metabolism
• Epilepsy/pathology
• Evolution, Molecular
• Myocytes, Cardiac/metabolism
• Neurons/metabolism
• Protein Subunits/chemistry
• Protein Subunits/classification
• Protein Subunits/genetics
• Protein Subunits/metabolism
• Voltage-Gated Sodium Channels/chemistry
• Voltage-Gated Sodium Channels/classification
• Voltage-Gated Sodium Channels/genetics
• Voltage-Gated Sodium Channels/metabolism

• R01 NS076752 NINDS NIH HHS
• R56 NS076752 NINDS NIH HHS

• EAE
• astrocytes
• microglia
• multiple sclerosis
• sodium channels
• sodium-calcium exchanger

• Biophysical Phenomena
• Cell Communication/physiology
• Electrophysiological Phenomena
• Gap Junctions/metabolism
• Humans
• Ion Channels/metabolism
• Membrane Potentials/physiology
• Models, Biological
• Neoplasms/physiopathology

• Cancer
• Inflammatory pain
• Neuropathic pain
• Nociceptors
• Sensory neurons
• Sodium channels
• Transgenic mice

• Adult
• Animals
• Enkephalins/genetics
• Enkephalins/metabolism
• Female
• Humans
• Male
• Mice
• Mice, Knockout
• NAV1.7 Voltage-Gated Sodium Channel/genetics
• NAV1.7 Voltage-Gated Sodium Channel/metabolism
• Pain Insensitivity, Congenital/genetics
• Pain Insensitivity, Congenital/metabolism
• Pain Insensitivity, Congenital/physiopathology
• Sensation
• Sensory Receptor Cells/metabolism

• G0901905 Medical Research Council
• 101054 Wellcome Trust
• G1100340 Medical Research Council
• Wellcome Trust
• BB/F000227/1 Biotechnology and Biological Sciences Research Council