Abstract
BackgroundNaV1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients’ death. In breast cancer cells, NaV1.5 activity promotes the proteolytic degradation of the extracellular matrix and enhances cell invasiveness.FindingsIn this study, we showed that the extinction of NaV1.5 expression in human breast cancer cells almost completely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated that ranolazine (50 μM) inhibited NaV1.5 currents in breast cancer cells and reduced NaV1.5-related cancer cell invasiveness in vitro. In vivo, the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by NaV1.5-expressing human breast cancer cells.ConclusionsTaken together, our results demonstrate the importance of NaV1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with NaV activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-264) contains supplementary material, which is available to authorized users.
Highlights
NaV1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients’ death
Taken together, our results demonstrate the importance of NaV1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with Voltage-gated sodium channels (NaV) activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments
Voltage-gated sodium channels (NaV) are essential for action potential firing and as such are characteristic of excitable cells [2]
Summary
NaV1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients’ death. To the best of our knowledge, the importance of NaV1.5 expression, and the relevance for its pharmacological inhibition, on the metastatic organ colonisation by breast cancer cells have never been reported so far. In this study we investigated how NaV1.5 expression in human breast cancer cells affected metastatic colonisation of organs in immunodepressed mice, and whether its pharmacological inhibition by ranolazine reduced cancer cell invasiveness both in vitro and in vivo.
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