Search

Anti‐invasive effects of riluzole and ranolazine, a neuro‐protectant and an anti‐anginal drug, respectively, on Mat‐LyLu rat prostate cancer (PCa) cells were tested in vitro (a) at non‐toxic doses and (b) under both normoxic and hypoxic conditions, the latter common to growing tumours. Tetrodotoxin (TTX) was used as a positive control. Hypoxia had no effect on cell viability but reduced growth at 48 hours. Riluzole (5 μmol/L) or ranolazine (20 μmol/L) had no effect on cell viability or growth under normoxia or hypoxia over 24 hours. Matrigel invasion was not affected by hypoxia but inhibited by TTX, ranolazine and riluzole under a range of conditions. The expression of Nav1.7 mRNA, the prevailing, pro‐invasive voltage‐gated sodium channel α‐subunit (VGSCα), was up‐regulated by hypoxia. Riluzole had no effect on Nav1.7 mRNA expression in normoxia but significantly reduced it in hypoxia. VGSCα protein expression in plasma membrane was reduced in hypoxia; riluzole increased it but only under hypoxia. It was concluded (a) that riluzole and ranolazine have anti‐invasive effects on rat PCa cells and (b) that Nav1.7 mRNA and protein expression can be modulated by riluzole under hypoxia. Overall, therefore, riluzole and ranolazine may ultimately be "repurposed" as anti‐metastatic drugs against PCa. [ABSTRACT FROM AUTHOR]

Metastasis is the main cause of death in most cancer patients. Voltage-gated sodium channels (VGSCs) are functionally expressed in prostate cancer (PCa), as well as in several other carcinomas, where their activity potentiates various metastatic cell behaviours. Accordingly, VGSC blocking pharmacological agents have been proposed as potential anti-cancer drugs. In the present study, we investigated the anti-metastatic potential of the neuroprotective VGSC blocking drug, riluzole, at clinical doses. The strongly metastatic rat PCa Mat-LyLu cells were used as a model. Exposure of Mat-LyLu cells to hypoxia (24h, 2% O2) significantly increased the mRNA expression of Nav1.7, the predominant VGSC a-subunit expressed in rat and human PCa, by ~400%. Under normoxic conditions, riluzole (2.5 - 5 µM) had no effect on Nav1.7 mRNA expression, whilst in hypoxia (24h, 2% O2) significant reduction of ~40% was observed. On the other hand, immunocytochemistry and confocal imaging showed no effect of riluzole (2.5 µM) on sub cellular distribution of VGSCa protein levels. Riluzole treatment (5 µM) under both normoxic and hypoxic (2% O2) conditions had no effect on cell viability and proliferation. Hypoxia (2% O2) alone had no significant effect on Matrigel invasion. In contrast, riluzole and TTX ('internal control') treatments caused significant reduction in invasion by >45%. We conclude (1) that that riluzole can significantly suppress the invasiveness of PCa cells especially under normoxic conditions; (2) that it is possible to control invasiveness without killing cancer cells; and (3) riluzole could be 'repurposed as a safe anti-anti-metastatic drug. [ABSTRACT FROM AUTHOR]