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Open Access 01-07-2012 | Preclinical Study

Therapeutic potential for phenytoin: targeting Na_v1.5 sodium channels to reduce migration and invasion in metastatic breast cancer

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

Published in: Breast Cancer Research and Treatment | Issue 2/2012

Abstract

Voltage-gated Na⁺ channels (VGSCs) are heteromeric membrane protein complexes containing pore-forming α subunits and smaller, non-pore-forming β 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 Na_v1.5 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.

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Title: Therapeutic potential for phenytoin: targeting Nav1.5 sodium channels to reduce migration and invasion in metastatic breast cancer
Authors: Ming Yang
David J. Kozminski
Lindsey A. Wold
Rohan Modak
Jeffrey D. Calhoun
Lori L. Isom
William J. Brackenbury
Publication date: 01-07-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-2102-9

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