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. 2021 Oct 29;13(21):5437.
doi: 10.3390/cancers13215437.

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

Iris S Brummelhuis  1   2   3 , Stephen J Fiascone  3   4   5 , Kathleen T Hasselblatt  3 , Gyorgy Frendl  2   5   6 , Kevin M Elias  2   3   4   5
Affiliations

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

Iris S Brummelhuis et al. Cancers (Basel). .

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.

Keywords: high-grade serous ovarian cancer; local anesthetics; sodium channels.

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Conflict of interest statement

The authors have no financial conflict to disclose.

Figures

Figure 1
Figure 1
(A) Expression of voltage-gated sodium channels by RNAseq among 48 ovarian cancer cell lines in the Cancer Cell Line Encyclopedia. (B) Relative expression of voltage-gated sodium channels by RNAseq in epithelial ovarian cancer cells (EOC) compared to fallopian tube secretory epithelial cells (FTSEC). (C) Box and whisker plots showing relative expression of voltage-gated sodium channels by qRT-PCR in EOC versus fibroblasts. *** p < 0.001 Adjusted for multiple testing.
Figure 2
Figure 2
Overall survival after optimal cytoreductive surgery followed by platinum-based chemotherapy stratified by tumor voltage gated sodium channel expression of (A) SCN8A and (B) SCN1B.
Figure 3
Figure 3
Effect of treatment with anti-epileptic drugs (AEDs) on epithelial ovarian cancer cell proliferation. Two-way ANOVA adjusted for multiple comparisons.
Figure 4
Figure 4
Concentration-dependent effects of local anesthetics on cell proliferation in various cell lines for (A) lidocaine, (B) bupivacaine, (C) procaine, and (D) benzocaine.
Figure 5
Figure 5
Effects of lidocaine and bupivacaine on ovarian cancer cell (KURAMOCHI, OVSAHO, OVCAR5) or fibroblast (BJ, WI38) responses to carboplatin treatment (A–E) or paclitaxel treatment (F–J).
Figure 6
Figure 6
Change in AUC after addition of local anesthetic for (A) carboplatin and (B) paclitaxel by cell line. Comparisons for each cell line are relative to chemotherapy alone. Relative change in AUC between fibroblasts and ovarian cancer cells after addition of local anesthetic for (C) carboplatin and (D) paclitaxel. * p < 0.05, ** p < 0.01, *** p < 0.001, ns—not significant.
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