Nelson, Michaela, Yang, Ming, Dowle, Adam et al. (2 more authors) (2015) The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis. Molecular Cancer. 13. ISSN 1476-4598
Abstract
Background Voltage-gated Na+ channels (VGSCs) are heteromeric protein complexes containing pore-forming ? subunits and smaller, non-pore-forming ? subunits. VGSCs are classically expressed in electrically excitable cells, e.g. neurons. VGSCs are also expressed in tumour cells, including breast cancer (BCa) cells, where they enhance cellular migration and invasion. However, despite extensive work defining in detail the molecular mechanisms underlying the expression of VGSCs and their pro-invasive role in cancer cells, there has been a notable lack of clinically relevant in vivo data exploring their value as potential therapeutic targets. Findings We have previously reported that the VGSC-blocking antiepileptic drug phenytoin inhibits the migration and invasion of metastatic MDA-MB-231 cells in vitro. The purpose of the present study was to establish whether VGSCs might be viable therapeutic targets by testing the effect of phenytoin on tumour growth and metastasis in vivo. We found that expression of Nav1.5, previously detected in MDA-MB-231 cells in vitro, was retained on cells in orthotopic xenografts. Treatment with phenytoin, at a dose equivalent to that used to treat epilepsy (60 mg/kg; daily), significantly reduced tumour growth, without affecting animal weight. Phenytoin also reduced cancer cell proliferation in vivo and invasion into surrounding mammary tissue. Finally, phenytoin significantly reduced metastasis to the liver, lungs and spleen. Conclusions This is the first study showing that phenytoin reduces breast tumour growth and metastasis in vivo. We propose that pharmacologically targeting VGSCs, by repurposing antiepileptic or antiarrhythmic drugs, should be further studied as a potentially novel anti-cancer therapy.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015 Nelson et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL (MRC) G1000508 |
Depositing User: | Pure (York) |
Date Deposited: | 26 Oct 2015 12:56 |
Last Modified: | 13 Dec 2024 00:04 |
Published Version: | https://doi.org/10.1186/s12943-014-0277-x |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1186/s12943-014-0277-x |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:83453 |