Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs

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Abstract

Objective: To determine the exact role of sodium channel proteins in migration, invasion and metastasis and understand the possible anti-invasion and anti-metastatic activity of repurposed drugs with voltage gated sodium channel blocking properties.

Material and methods: A review of the published medical literature was performed searching for pharmaceuticals used in daily practice, with inhibitory activity on voltage gated sodium channels. For every drug found, the literature was reviewed in order to define if it may act against cancer cells as an anti-invasion and anti-metastatic agent and if it was tested with this purpose in the experimental and clinical settings.

Results: The following pharmaceuticals that fulfill the above mentioned effects, were found: phenytoin, carbamazepine, valproate, lamotrigine, ranolazine, resveratrol, ropivacaine, lidocaine, mexiletine, flunarizine, and riluzole. Each of them are independently described and analyzed.

Conclusions: The above mentioned pharmaceuticals have shown anti-metastatic and anti-invasion activity and many of them deserve to be tested in well-planned clinical trials as adjunct therapies for solid tumors and as anti-metastatic agents. Antiepileptic drugs like phenytoin, carbamazepine and valproate and the vasodilator flunarizine emerged as particularly useful for anti-metastatic purposes.

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Most cited references 124

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Metastasis: a question of life or death.

Patrick Mehlen, Alain Puisieux (2006)

The metastatic process is highly inefficient--very few of the many cells that migrate from the primary tumour successfully colonize distant sites. One proposed mechanism to explain this inefficiency is provided by the cancer stem cell model, which hypothesizes that micrometastases can only be established by tumour stem cells, which are few in number. However, recent in vitro and in vivo observations indicate that apoptosis is an important process regulating metastasis. Here we stress that the inhibition of cell death, apart from its extensively described function in primary tumour development, is a crucial characteristic of metastatic cancer cells.

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The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function.

Danielle Murphy, Sara A. Courtneidge (2011)

Podosomes and invadopodia are actin-based dynamic protrusions of the plasma membrane of metazoan cells that represent sites of attachment to - and degradation of - the extracellular matrix. The key proteins in these structures include the actin regulators cortactin and neural Wiskott-Aldrich syndrome protein (N-WASP), the adaptor proteins Tyr kinase substrate with four SH3 domains (TKS4) and Tyr kinase substrate with five SH3 domains (TKS5), and the metalloprotease membrane type 1 matrix metalloprotease (MT1MMP; also known as MMP14). Many cell types can produce these structures, including invasive cancer cells, vascular smooth muscle and endothelial cells, and immune cells such as macrophages and dendritic cells. Recently, progress has been made in our understanding of the regulatory and functional aspects of podosome and invadopodium biology and their role in human disease.

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Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis.

Carlo Palmieri, J Slade, Esra Battaloglu … (2005)

Ion channel activity is involved in several basic cellular behaviors that are integral to metastasis (e.g., proliferation, motility, secretion, and invasion), although their contribution to cancer progression has largely been ignored. The purpose of this study was to investigate voltage-gated Na(+) channel (VGSC) expression and its possible role in human breast cancer. Functional VGSC expression was investigated in human breast cancer cell lines by patch clamp recording. The contribution of VGSC activity to directional motility, endocytosis, and invasion was evaluated by in vitro assays. Subsequent identification of the VGSC alpha-subunit(s) expressed in vitro was achieved using reverse transcription-PCR, immunocytochemistry, and Western blot techniques and used to investigate VGSCalpha expression and its association with metastasis in vivo. VGSC expression was significantly up-regulated in metastatic human breast cancer cells and tissues, and VGSC activity potentiated cellular directional motility, endocytosis, and invasion. Reverse transcription-PCR revealed that Na(v)1.5, in its newly identified "neonatal" splice form, was specifically associated with strong metastatic potential in vitro and breast cancer progression in vivo. An antibody specific for this form confirmed up-regulation of neonatal Na(v)1.5 protein in breast cancer cells and tissues. Furthermore, a strong correlation was found between neonatal Na(v)1.5 expression and clinically assessed lymph node metastasis. Up-regulation of neonatal Na(v)1.5 occurs as an integral part of the metastatic process in human breast cancer and could serve both as a novel marker of the metastatic phenotype and a therapeutic target.

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Author and article information

Journal

Journal ID (nlm-ta): F1000Res

Journal ID (iso-abbrev): F1000Res

Journal ID (pmc): F1000Research

Title: F1000Research

Publisher: F1000Research (London, UK )

ISSN (Electronic): 2046-1402

Publication date (Electronic): 22 July 2015

Publication date Collection: 2015

Volume: 4

Electronic Location Identifier: 297

Affiliations

[1 ]Centro de Diagnóstico y Tratamiento de la Obra Social del Personal de la Industria de la Alimentación, Talar, Buenos Aires, C1122AAL, Argentina

[1 ]Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Chuo-ku, Japan

[1 ]Department of Neurology, Yale University, New Haven, CT, USA

Author notes

[a ] tkoltai@ 123456hotmail.com

Competing interests: The authors declared no competing interests.

Competing interests: No competing interests were disclosed.

Article

DOI: 10.12688/f1000research.6789.1

PMC ID: 4920216

PubMed ID: 27408684

SO-VID: 77ca0705-59ac-4ca5-bf3e-284a4d6bd616

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 20 July 2015

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The author(s) declared that no funds were involved in supporting this work.

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Voltage-gated sodium channel as a target for metastatic risk reduction with re-purposed drugs

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Karger: Oncology

Most cited references 124

Metastasis: a question of life or death.

The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function.

Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis.

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