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