Repurposing of disulfiram and diethyldithiocarbamate (DDC)-metal complexes to enhance sodium iodide symporter function in radioiodide therapy

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

Research output: Contribution to journalAbstractpeer-review

Abstract

Objective New drug approaches are urgently needed that enhance radioiodide (RAI) uptake leading to efficient ablation of thyroid cancer cells, especially in RAI-refractory disease. We recently utilised high throughput screening and identified FDAapproved compounds capable of inducing 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 (e.g. copper or zinc), and is currently being investigated for use in wideranging therapeutic applications including cancer treatment. Here, we aimed to gain a mechanistic understanding of how disulfiram and its related DDC metal complexes (e.g. Cu(DDC)2) impact NIS function in thyroid cells in vitro and in vivo.

Methods: NIS function was monitored in cultured cells 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 following intravenous administration.

Results: Disulfiram, as well as the DDC-metal complexes Cu(DDC)2 and Zn(DDC)2, induced significant NIS protein expression (up to 36.2-fold; 250nM; P < 0.001) and 125I uptake (up to 5.7- fold; 250nM; P < 0.001) in multiple thyroid cell types, including human primary thyrocytes. Importantly, disulfiram and Cu(DDC)2 retained the ability to enhance NIS function in thyroid cells ablated for expression of either VCP or its co-factor NPL4, indicating their effect on NIS was via VCP-independent pathways. Indeed, Cu(DDC)2 revealed potent transcriptional activity, inducing NIS mRNA expression in thyroid TPC-1 (8.5-fold; P < 0.01) and 8505C (104.8-fold; P < 0.001) cells. Similarly, Cu(DDC)2 induced mRNA expression of other thyroid-specific genes, including thyroglobulin (up to 6.1-fold; P < 0.001) and thyroid peroxidase (up to 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 at 24h) demonstrated greater sensitivity to Cu(DDC)2. In wild-type Balb/c mice, disulfiram failed to enhance thyroidal uptake of 99mTc. However, Cu(DDC)2 significantly induced 99mTc uptake at 30 min postadministration (*46.6% increase; n = 5 per group; 3 mg/kg dose; P = 0.0095), demonstrating direct in vivo activity.

Conclusions: These results demonstrate that disulfiramrelated DDC-metal complexes represent a promising drug strategy to modulate NIS function in vivo, with real clinical potential to enhance radioiodide therapy.
Original languageEnglish
Article numberOC40
Pages (from-to)A96-A97
Number of pages2
JournalThyroid
Volume32
Issue numberS1
DOIs
Publication statusPublished - 11 Oct 2022
EventAMERICAN THYROID ASSOCIATION 2022 ANNUAL MEETING - Palais des Congrès de Montréal, Montreal, Canada
Duration: 19 Oct 202223 Oct 2022
Conference number: 91
https://www.thyroid.org/91st-annual-meeting-ata/

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