title: Characterization of small-molecule inhibitors of the sodium iodide symporter.
abstract: The sodium/iodide symporter (NIS) mediates the active transport of iodide from the bloodstream into thyrocytes. NIS function is strategic for the diagnosis and treatment of various thyroid diseases. In addition, a promising anti-cancer strategy based on targeted NIS gene transfer in non-thyroidal cells is currently developed. However, only little information is available concerning the molecular mechanism of NIS-mediated iodide translocation. Ten small molecules have recently been identified using a high-throughput screening method for their inhibitory effect on iodide uptake of NIS-expressing mammalian cells. In the present study, we analyzed these compounds for their rapid and reversible effects on the iodide-induced current in NIS-expressing Xenopus oocytes. Four molecules almost completely inhibited the iodide-induced current; for three of them the effect was irreversible, for one compound the initial current could be fully re-established after washout. Three molecules showed a rapid inhibitory effect of about 75%, half of which was reversible. Another three compounds inhibited the iodide-induced current from 10 to 50%. Some molecules altered the membrane conductance by themselves, i.e. in the absence of iodide. For one of these molecules the observed effect was also found in water-injected oocytes whereas for some others the iodide-independent effect was associated with NIS expression. The tested molecules show a surprisingly high variability in their possible mode of action, and thus are promising tools for further functional characterization of NIS on a molecular level, and they could be useful for medical applications.
authors.affiliation: TIRO, CEA DSV-iBEB-SBTN, CAL, School of Medicine, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Lindenthal
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lecat-Guillet
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ondo-Mendez
authors.forename: Yves
authors.initials: Y
authors.lastname: Ambroise
authors.forename: Bernard
authors.initials: B
authors.lastname: Rousseau
authors.forename: Thierry
authors.initials: T
authors.lastname: Pourcher
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D007454:Iodides / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009865:Oocytes / Q000378:metabolism; D054852:Small Molecule Libraries; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014982:Xenopus laevis; D000099209:Sodium-Iodide Symporters
chemical_list: D007454:Iodides; D054852:Small Molecule Libraries; D027981:Symporters; D000099209:Sodium-Iodide Symporters