SFEBES2022 Oral Communications Endocrine Cancer and Late Effects (6 abstracts)
Repurposing disulfiram as a therapeutic agent to enhance sodium iodide symporter activity in radioiodide therapy
Martin Read 1 , Katie Brookes 1 , Ling Zha 1 , Jana Kim 2 , Mehjabi Moolla 1 , Merve Kocbiyik 1 , Selvambigai Manivannan 1 , Rachel Hoare 1 , Vinodh Kannappan 3,4 , Weiguang Wang 3,4 , Kavitha Sunassee 2 , Philip Blower 2 , Hannah Nieto 1 , Vicki Smith 1 & Christopher McCabe 1
1Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom; 2School of Biomedical Engineering & Imaging Sciences, King’s College London, London, United Kingdom; 3Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, United Kingdom; 4Disulfican Ltd, University of Wolverhampton Science Park, Wolverhampton, United Kingdom
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.
Volume 86
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Endocrine Abstracts
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