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

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.

Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

“…The use of ranolazine as a cardioprotective agent to reverse diastolic dysfunction may be viewed as a potential secondary prevention for late anthracycline cardiotoxicity. An interesting aspect of the potential use of ranolazine in oncological settings could also emerge from the current research showing that drugs targeting voltage-gated Na + channels may have anti-invasion and anti-metastatic effects (Djamgoz and Onkal, 2013;Driffort et al, 2014;Koltai, 2015).…”

Translating the anticancer properties of eEF2K

“…Intriguingly, early studies indicated that patients treated with these drugs had a significant reduction in HIV-associated tumors. 3 Further studies have demonstrated that Nelfinavir (NFR), one of the first HIV-PIs to be approved by the FDA, showed promising anticancer properties in mice and in non-infected cancer patients. This led to phase I and phase II clinical trials that were designed to evaluate NFR repositioning in various cancer types.…”

“…This led to phase I and phase II clinical trials that were designed to evaluate NFR repositioning in various cancer types. 3 Nevertheless, the mechanisms underlying NFR and HIV-PIs anti-tumoral properties remained poorly understood. 3 In a previous study we showed that NFR targets translation program by inducing the integrated stress response (ISR).…”

“…3 Nevertheless, the mechanisms underlying NFR and HIV-PIs anti-tumoral properties remained poorly understood. 3 In a previous study we showed that NFR targets translation program by inducing the integrated stress response (ISR). 4 This response is driven by the phosphorylation of the translation initiation factor eIF2a to decrease overall translation initiation and increase production of stress factors including the transcription factor ATF4.…”

Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights

“…Ranolazine was found previously also to reduce metastatic dissemination in a breast cancer xenograft model [167]. Thus, ranolazine and other available VGSC/INaP blockers could be 'repurposed' as novel anti-metastatic drugs in clinical management of CRC [168][169][170][171].…”