Voltage-Gated Sodium Channel Na V 1.7 Inhibitors with Potent Anticancer Activities in Medullary Thyroid Cancer Cells.

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 V 1.7 is uniquely expressed in aggressive MTC and not expressed in normal thyroid cells and tissues. We establish the druggability of Na V 1.7 in MTC by identifying a novel inhibitor ( SV188 ) and investigate its mode of binding and ability to inhibit I Na current in Na V 1.7. The whole-cell patch-clamp studies of the SV188 in the Na V 1.7 channels expressed in HEK-293 cells show that SV188 inhibited the I Na current in Na V 1.7 with an IC 50 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. SV188 inhibited the viability of MTC cell lines, MZ-CRC-1 and TT, with IC 50 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, SV188 had no effect on the invasion of TT cells derived from primary tumor, which have lower basal expression of Na V 1.7. In addition, SV188 at 3 μM significantly inhibited the migration of MZ-CRC-1 and TT cells by 27% and 57%, respectively.