Therapeutic potential for phenytoin: Targeting Nav1.5 sodium channels to reduce migration and invasion in metastatic breast cancer

Ming Yang, David J. Kozminski, Lindsey A. Wold, Rohan Modak, Jeffrey D. Calhoun, Lori L. Isom, William J. Brackenbury*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Voltage-gated Na+ channels (VGSCs) are heteromeric membrane protein complexes containing poreforming a subunits and smaller, non-pore-forming b subunits. VGSCs are classically expressed in excitable cells, including neurons and muscle cells, where they mediate action potential firing, neurite outgrowth, pathfinding, and migration. VGSCs are also expressed in metastatic cells from a number of cancers. The Nav1.5 α subunit (encoded by SCN5A) is expressed in breast cancer (BCa) cell lines, where it enhances migration and invasion. We studied the expression of SCN5A in BCa array data, and tested the effect of the VGSC-blocking anticonvulsant phenytoin (5,5-diphenylhydantoin) on Na+ current, migration, and invasion in BCa cells. SCN5A was up-regulated in BCa samples in several datasets, and was more highly expressed in samples from patients who had a recurrence, metastasis, or died within 5 years. SCN5A was also overexpressed as an outlier in a subset of samples, and associated with increased odds of developing metastasis. Phenytoin inhibited transient and persistent Na+ current recorded from strongly metastatic MDA-MB-231 cells, and this effect was more potent at depolarized holding voltages. It may thus be an effective VGSC-blocking drug in cancer cells, which typically have depolarized membrane potentials. At a concentration within the therapeutic range used to treat epilepsy, phenytoin significantly inhibited the migration and invasion of MDA-MB-231 cells, but had no effect on weakly metastatic MCF-7 cells, which do not express Na+ currents. We conclude that phenytoin suppresses Na+ current in VGSC-expressing metastatic BCa cells, thus inhibiting VGSC-dependent migration and invasion. Together, our data support the hypothesis that SCN5A is up-regulated in BCa, favoring an invasive/metastatic phenotype. We therefore propose that repurposing existing VGSC-blocking therapeutic drugs should be further investigated as a potential new strategy to improve patient outcomes in metastatic BCa.

Original languageEnglish (US)
Pages (from-to)603-615
Number of pages13
JournalBreast Cancer Research and Treatment
Volume134
Issue number2
DOIs
StatePublished - Jul 2012
Externally publishedYes

Keywords

  • Electrophysiology
  • Invasion
  • Metastasis
  • Migration
  • Phenytoin
  • Voltage-gated Nachannel

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Therapeutic potential for phenytoin: Targeting Na<sub>v</sub>1.5 sodium channels to reduce migration and invasion in metastatic breast cancer'. Together they form a unique fingerprint.

Cite this