AUTHOR=Fuchs Eva , Messerer David Alexander Christian , Karpel-Massler Georg , Fauler Michael , Zimmer Thomas , Jungwirth Bettina , Föhr Karl Josef 

TITLE=Block of Voltage-Gated Sodium Channels as a Potential Novel Anti-cancer Mechanism of TIC10

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.737637

DOI=10.3389/fphar.2021.737637

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Tumor therapeutics are aimed to affect tumor cells selectively while sparing healthy ones. For this purpose, a huge variety of different drugs are in use. Recently, also blockers of voltage-gated sodium channels (VGSCs) have been recognized to possess potentially beneficial effects in tumor therapy. As these channels are a frequent target of numerous drugs, we hypothesized that currently used tumor therapeutics might have the potential to block VGSCs in addition to their classical anti-cancer activity. In the present work, we have analyzed the imipridone TIC10, which belongs to a novel class of anti-cancer compounds, for its potency to interact with VGSCs.</p><p><bold>Methods:</bold> Electrophysiological experiments were performed by means of the patch-clamp technique using heterologously expressed human heart muscle sodium channels (hNav1.5), which are among the most common subtypes of VGSCs occurring in tumor cells.</p><p><bold>Results:</bold> TIC10 angular inhibited the hNa<sub>v</sub>1.5 channel in a state- but not use-dependent manner. The affinity for the resting state was weak with an extrapolated K<sub>r</sub> of about 600 μM. TIC10 most probably did not interact with fast inactivation. In protocols for slow inactivation, a half-maximal inhibition occurred around 2 µM. This observation was confirmed by kinetic studies indicating that the interaction occurred with a slow time constant. Furthermore, TIC10 also interacted with the open channel with an affinity of approximately 4 µM. The binding site for local anesthetics or a closely related site is suggested as a possible target as the affinity for the well-characterized F1760K mutant was reduced more than 20-fold compared to wild type. Among the analyzed derivatives, ONC212 was similarly effective as TIC10 angular, while TIC10 linear more selectively interacted with the different states.</p><p><bold>Conclusion:</bold> The inhibition of VGSCs at low micromolar concentrations might add to the anti-tumor properties of TIC10.</p>