title: The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis.
abstract: BACKGROUND
  Voltage-gated Na(+) channels (VGSCs) are heteromeric protein complexes containing pore-forming α subunits and smaller, non-pore-forming β 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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Biology, University of York, Heslington, York, YO10 5DD, UK. michaela.nelson@york.ac.uk.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nelson
authors.affiliation: Department of Biology, University of York, Heslington, York, YO10 5DD, UK. my552@york.ac.uk.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Biology, University of York, Heslington, York, YO10 5DD, UK. adam.dowle@york.ac.uk.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Dowle
authors.affiliation: Department of Biology, University of York, Heslington, York, YO10 5DD, UK. jerry.thomas@york.ac.uk.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Thomas
authors.affiliation: Department of Biology, University of York, Heslington, York, YO10 5DD, UK. william.brackenbury@york.ac.uk.
authors.forename: William J
authors.initials: WJ
authors.lastname: Brackenbury
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010672:Phenytoin / Q000008:administration & dosage / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D010672:Phenytoin