Williams Cancer Institute

Antiepileptic drug: A New Frontier in Cancer Therapy?

Voltage-gated Na(+) channels (VGSCs) are known for their role in electrically excitable cells, such as neurons. These channels are heteromeric protein complexes comprising pore-forming α subunits and non-pore-forming β subunits. Interestingly, VGSCs are also found in tumor cells, including those of breast cancer (BCa). In these cells, VGSCs enhance cellular migration and invasion, critical steps in cancer metastasis. Despite significant research into the molecular mechanisms of VGSC expression and their pro-invasive roles, there has been a notable gap in clinically relevant in vivo data on their potential as therapeutic targets.

Previous studies have shown that phenytoin, an antiepileptic drug that blocks VGSCs, inhibits the migration and invasion of metastatic breast cancer cells (MDA-MB-231) in vitro. The current study aimed to explore whether VGSCs could be viable therapeutic targets by testing the effects of phenytoin on tumor growth and metastasis in vivo.

The study revealed that the expression of Nav1.5, a VGSC previously detected in vitro, was retained in cells within orthotopic xenografts. Treatment with phenytoin, at a dosage equivalent to that used for epilepsy (60 mg/kg daily), significantly reduced tumor growth without affecting animal weight. Additionally, phenytoin reduced cancer cell proliferation and invasion into surrounding mammary tissue in vivo. Importantly, phenytoin also significantly decreased metastasis to the liver, lungs, and spleen.

This research is the first to demonstrate that phenytoin can reduce breast tumor growth and metastasis in vivo. The findings suggest that pharmacologically targeting VGSCs by repurposing antiepileptic or antiarrhythmic drugs could be a promising novel approach to cancer therapy. Further studies are needed to validate these results and explore the potential of VGSCs as therapeutic targets in cancer treatment.

Reference: Nelson, M., Yang, M., Dowle, A. A., Thomas, J. R., & Brackenbury, W. J. (Jan 27, 2015). The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320839

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