Voltage-Gated Sodium Channel NaV1.7 Inhibitors with Potent Anticancer Activities in Medullary Thyroid Cancer Cells

Abstract

Our results from quantitative RT-PCR, Western blotting, immunohistochemistry, and the tissue microarray of medullary thyroid cancer (MTC) cell lines and patient specimens confirm that VGSC subtype Na_V1.7 is uniquely expressed in aggressive MTC and not expressed in normal thyroid cells and tissues. We establish the druggability of Na_V1.7 in MTC by identifying a novel inhibitor (<b>SV188</b>) and investigate its mode of binding and ability to inhibit <i>I</i>_Na current in Na_V1.7. The whole-cell patch-clamp studies of the <b>SV188</b> in the Na_V1.7 channels expressed in HEK-293 cells show that <b>SV188</b> inhibited the <i>I</i>_Na current in Na_V1.7 with an IC₅₀ value of 3.6 µM by a voltage- and use-dependent blockade mechanism, and the maximum inhibitory effect is observed when the channel is open. <b>SV188</b> inhibited the viability of MTC cell lines, MZ-CRC-1 and TT, with IC₅₀ values of 8.47 μM and 9.32 μM, respectively, and significantly inhibited the invasion of MZ-CRC-1 cells by 35% and 52% at 3 μM and 6 μM, respectively. In contrast, <b>SV188</b> had no effect on the invasion of TT cells derived from primary tumor, which have lower basal expression of Na_V1.7. In addition, <b>SV188</b> at 3 μM significantly inhibited the migration of MZ-CRC-1 and TT cells by 27% and 57%, respectively.