Ranolazine inhibits NaV1.5-mediated breast cancer cell invasiveness and lung colonization
Résumé
Background : NaV1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expressionlevel is associated with metastatic occurrence and patients’death. In breast cancer cells, NaV1.5 activity promotes theproteolytic degradation of the extracellular matrix and enhances cell invasiveness.
Findings : In this study, we showed that the extinction of NaV1.5 expression in human breast cancer cells almostcompletely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated thatranolazine (50μM) inhibited NaV1.5 currents in breast cancer cells and reduced NaV1.5-related cancer cell invasivenessin vitro. In vivo, the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by NaV1.5-expressinghuman breast cancer cells.
Conclusions : Taken together, our results demonstrate the importance of NaV1.5 in the metastatic colonisation oforgans by breast cancer cells and indicate that small molecules interfering with NaVactivity, such as ranolazine, mayrepresent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments.
Domaines
Cancer| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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