Voltage-Gated Sodium Channels as Potential Biomarkers and Therapeutic Targets for Epithelial Ovarian Cancer

SIMPLE SUMMARY: Voltage-gated sodium channels are membrane proteins that change conformation in response to depolarization of the membrane potential, allowing sodium ions to flow into cells. While voltage-gated sodium channels are normally studied in terms of neuron impulses and skeletal or cardiac muscle contraction, abnormal ion channel expression is a feature of many cancer cells. The aim of our study was to assess the expression of voltage-gated sodium channels in ovarian cancer cells. We found that ovarian cancer cells generally express lower levels of voltage-gated sodium channels than normal cells and that two voltage-gated sodium channels, SCN8A and SCN1B, were prognostic biomarkers for ovarian cancer overall survival. In vitro studies suggested that drugs that block voltage-gated sodium channels, such as certain anti-epileptic drugs and local anesthetics, might sensitize ovarian cancer cells to chemotherapy. These findings suggest that voltage-gated sodium channels may be interesting targets for ovarian cancer therapy. ABSTRACT: Abnormal ion channel expression distinguishes several types of carcinoma. Here, we explore the relationship between voltage-gated sodium channels (VGSC) and epithelial ovarian cancer (EOC). We find that EOC cell lines express most VGSC, but at lower levels than fallopian tube secretory epithelial cells (the cells of origin for most EOC) or control fibroblasts. Among patient tumor samples, lower SCN8A expression was associated with improved overall survival (OS) (median 111 vs. 52 months; HR 2.04 95% CI: 1.21–3.44; p = 0.007), while lower SCN1B expression was associated with poorer OS (median 45 vs. 56 months; HR 0.69 95% CI 0.54–0.87; p = 0.002). VGSC blockade using either anti-epileptic drugs or local anesthetics (LA) decreased the proliferation of cancer cells. LA increased cell line sensitivity to platinum and taxane chemotherapies. While lidocaine had similar additive effects with chemotherapy among EOC cells and fibroblasts, bupivacaine showed a more pronounced impact on EOC than fibroblasts when combined with either carboplatin (ΔAUC −37% vs. −16%, p = 0.003) or paclitaxel (ΔAUC −37% vs. −22%, p = 0.02). Together, these data suggest VGSC are prognostic biomarkers in EOC and may inform new targets for therapy.