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 NISmediated iodide translocation. Ten small molecules have recently been identified using a high-throughput screening method for their inhibitory effect on iodide uptake of NISexpressing 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 iodideinduced 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 iodideinduced 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.

Synthesis and Structure–Activity Relationships of a Class of Sodium Iodide Symporter Function Inhibitors

“…ITB5 was shown to be a powerful inhibitor with a half maximal inhibitory concentration (IC 50 ) value of 40 n M . Further analysis of the effect of ITB5 on iodide‐induced current in NIS‐expressing Xenopus oocytes showed that the inhibition was rapid (<5 s) and reversible 8. These results indicated that ITB5 acts by disrupting NIS either directly or at a post‐translational level.…”

Iodine‑131 metabolic radiotherapy leads to cell death and genomic alterations through NIS overexpression on cholangiocarcinoma

“…This expression decreases with increasing doses and increases with time following exposure. Studies have reported different molecules that influence NIS expression, such as pregnancy-associated hormones, among others (47,48). These molecules, when suppressed, such as the MAP kinase and PI3K/Akt pathways, and HDAC, can induce an increase in NIS expression.…”

Exploration of marine natural resources in Indonesia and development of efficient strategies for the production of microbial halogenated metabolites

“…Among the samples screened, an EtOH extract of the marine sponge Dysidea sp. also exerted potent inhibitory effects on osteoblastogenesis, and repeated column purification based on this activity led to the isolation of three active constituents [123]: dysidenin (28) [124][125][126], herbasterol (29) [127], and stellettasterol (30) (Fig. 7) [128].…”