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

• Published in: Cancers Vol. 15; no. 10
• Main Authors: Pukkanasut, Piyasuda, Whitt, Jason, Guenter, Rachael, Lynch, Shannon E, Gallegos, Carlos, Rosendo-Pineda, Margarita Jacaranda, Gomora, Juan Carlos, Chen, Herbert, Lin, Diana, Sorace, Anna, Jaskula-Sztul, Renata, Velu, Sadanandan E
• Format: Journal Article
• Language: English
• Published: Switzerland 17-05-2023
• Subjects: cell viability; metastasis; medullary thyroid cancer; neuroendocrine tumor; cell invasion; voltage-gated sodium channels; NaV1.7
• ISSN: 2072-6694; 2072-6694

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