Repurposing disulfiram as a therapeutic agent to enhance sodium iodide symporter activity in radioiodide therapy

Martin Read, Kate Brookes, Ling Zha, Mehjabi Moolla, Merve Kocbiyik, Selvambigai Manivannan, Rachel Hoare, Vinodh Kannappan, Weiguang Wang, Kavitha Sunassee, Philip Blower, Hannah Nieto, Vicki Smith, Christopher McCabe

Research output: Contribution to journalAbstractpeer-review

Abstract

Background: New drug approaches are urgently needed that enhance radioiodide (RAI) uptake leading to efficient ablation of thyroid cancer, especially in RAI-refractory disease. We recently utilised high-throughput screening and identified FDA-approved compounds that induce sodium iodide symporter (NIS) function to enhance iodide uptake, including the proteasomal/ VCP inhibitor disulfiram. In vivo, disulfiram is rapidly metabolized to diethyldithiocarbamate (DDC), which binds metal ions, and is being investigated for use in wide-ranging therapeutic applications including cancer. Here, we aimed to gain a mechanistic understanding of how disulfiram and its related DDC-metal complexes impact NIS function in vitro and in vivo.

Methods: NIS function was monitored in vitro by RAI (125I) uptake assays, and NIS expression via TaqMan-RTPCR and Western blotting. Technetium-99m pertechnetate (99mTc) uptake was used to evaluate NIS function in BALB/c mice.

Results: Disulfiram, as well as DDC-metal complexes Cu(DDC)2 and Zn(DDC)2, induced significant NIS protein expression (36.2-fold;250nM;P<0.001) and 125I uptake (5.7-fold;250nM;P<0.001) in multiple thyroid cell types, including human primary thyrocytes. Disulfiram and Cu(DDC)2 retained the ability to enhance NIS function in VCP-ablated cells, indicating their effect on NIS was via VCP-independent pathways. Importantly, Cu(DDC)2 revealed potent transcriptional activity, inducing NIS mRNA expression in TPC-1 (13.9-fold;P<0.001) and 8505C (104.8-fold;P<0.001) cells. Similarly, Cu(DDC)2 induced expression of other thyroid-specific genes, including thyroid peroxidase (28.3-fold;P<0.001). MTS assay IC50 values of Cu(DDC)2- and Zn(DDC)2-treated TPC-1 cells (0.39µM and 26.32µM respectively) demonstrated greater sensitivity to Cu(DDC)2. In BALB/c mice, disulfiram failed to enhance thyroidal uptake of 99mTc. However, Cu(DDC)2 significantly induced 99mTc uptake at 30min post-administration (~47%;n=5; 3 mg/kg dose;P=0.0095), demonstrating in vivo activity.
Conclusions: Our results demonstrate that disulfiram-related DDC-metal complexes represent a promising drug strategy to modulate NIS function, with clinical potential to enhance radioiodide therapy.
Original languageEnglish
Article numberOC2.6
Number of pages1
JournalEndocrine Abstracts
Volume86
DOIs
Publication statusPublished - 16 Nov 2022
EventSociety for Endocrinology BES 2022 - Harrogate Convention Centre, Harrogate, United Kingdom
Duration: 14 Nov 202216 Nov 2022
https://www.endocrinology.org/events/sfe-bes-conference/sfe-bes-2022/

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