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Results show hypoxia-enhanced inhibition of invasiveness and suppression of metastasis in breast, prostate, and melanoma, supported by epidemiological findings and reduced chemotherapy harms. Conclusions propose ranolazine alone or combined with appropriate therapies as a safer anti-metastatic 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\nRanolazine: a potential anti-metastatic drug targeting voltage-gated sodium channels  \n 1,2 ✉  \nMustafa B. A. Djamgoz   \n© The Author(s) 2024  \n|  |  |  |\n| --- | --- | --- |\n|  | BACKGROUND: Multi-faceted evidence from a range of cancers suggests strongly that de novo expression of voltage-gated sodium channels (VGSCs) plays a significant role in driving cancer cell invasiveness. Under hypoxic conditions, common to growing tumours, VGSCs develop a persistent current (INaP) which can be blocked selectively by ranolazine.\u003Cbr>METHODS: Several different carcinomas were examined. We used data from a range of experimental approaches relating to cellular invasiveness and metastasis. These were supplemented by survival data mined from cancer patients.\u003Cbr>RESULTS: In vitro, ranolazine inhibited invasiveness of cancer cells especially under hypoxia. In vivo, ranolazine suppressed the metastatic abilities of breast and prostate cancers and melanoma. These data were supported by a major retrospective epidemiological study on breast, colon and prostate cancer patients. This showed that risk of dying from cancer was reduced by ca.60% among those taking ranolazine, even if this started 4 years after the diagnosis. Ranolazine was also shown to reduce the adverse effects of chemotherapy on heart and brain. Furthermore, its anti-cancer effectiveness could be boosted by coadministration with other drugs.\u003Cbr>CONCLUSIONS: Ranolazine, alone or in combination with appropriate therapies, could be reformulated as a safe anti-metastatic |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| drug offering many potential advantages over current systemic treatment modalities. |  |  |\n|  | British Journal of Cancer (2024) 130:1415–1419; [https://doi.org/10.1038/s41416-024-02622-w](https://doi.org/10.1038/s41416-024-02622-w) |  |\n|  |  |  |\n\nBACKGROUND  \nMost cancers are carcinomas and, overall, the main cause of death from cancer is metastasis which necessitates systemic treatment. Although advances are constantly being made in the clinical management of metastatic disease, several limitations remain especially as regards early, functional diagnosis, and effective and durable therapies with minimum side effects. A relatively recent development in oncology is the discipline of ‘cancer neuroscience’  \n[1] . This involves (i) using neuroscience concepts and techniques to understand the intricacies of the cancer process drawing benefits from several decades of research on the nervous system and (ii) aiming to exploit cancer’s ‘neuronal’ properties to combat the disease. Cancer neuroscience falls into two broad areas: extrinsic and intrinsic. Extrinsic refers to the fact that many tumours are under the influence of the nervous system, either directly (through innervation) or indirectly (via circulating neurochemicals) . This aspect has been reviewed extensively elsewhere [2] and is not considered further here. Intrinsic relates to the carcinomas’ inherent ‘neuronal’ characteristics [3] . The latter include the expression of molecular mechanisms like neuronal cell adhesion molecule, neurone-restrictive silencing factor and voltage-gated ion channels.  \nWe have discovered that (i) cancer cells that are capable of metastasis have electrically excitable membranes and (ii) it is the  \nelectrical excitation that makes cancer cells aggressive, hyperactive, invasive and, ultimately, metastatic; we call this the ‘Celex Model’ (celex = cellular excitability) [4] . At the core of this novel phenomenon is de novo expression of voltage-gated sodium channels (VGSCs) accompanied by downregulation of outward currents due mainly to the activity of voltage-gated potassium channels. This combination enables cancer cells to generate tetrodotoxin (TTX)-sensitive, all-or-none action potentials ","cbCaiar3T0VLIgOD","https://ap.wps.com/l/cbCaiar3T0VLIgOD","pdf",325170,"English","# Background\n## Cancer neuroscience and VGSC-driven invasiveness\n# Methods and Evidence Synthesis\n# Results\n## In vitro anti-invasive effects under hypoxia\n## In vivo suppression of metastasis\n## Epidemiology and safety/chemotherapy effects\n# Conclusions","[{\"question\":\"Why are voltage-gated sodium channels important in cancer metastasis?\",\"answer\":\"De novo expression of VGSCs is linked to driving cancer cell invasiveness, and hypoxic conditions can generate a persistent sodium current that supports aggressive behavior.\"},{\"question\":\"How was ranolazine evaluated in the review?\",\"answer\":\"The review synthesizes experimental findings across several carcinomas on cellular invasiveness and metastasis, and it incorporates mined survival data from cancer patients.\"},{\"question\":\"What benefits does ranolazine show according to the reported evidence?\",\"answer\":\"Ranolazine inhibits cancer-cell invasiveness especially under hypoxia, suppresses metastatic abilities in multiple tumor types, reduces risk of dying by about 60% in certain cohorts, and may lessen adverse chemotherapy effects on heart and brain.\"}]","Ranolazine: a potential anti-metastatic drug targeting voltage-gated sodium channels | PDF",1789977415,13]