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

doi:10.1530/endoabs.86.OC2.6

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 IC₅₀values 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 language	English
Article number	OC2.6
Number of pages	1
Journal	Endocrine Abstracts
Volume	86
DOIs	https://doi.org/10.1530/endoabs.86.OC2.6
Publication status	Published - 16 Nov 2022
Event	Society for Endocrinology BES 2022 - Harrogate Convention Centre, Harrogate, United Kingdom Duration: 14 Nov 2022 → 16 Nov 2022 https://www.endocrinology.org/events/sfe-bes-conference/sfe-bes-2022/

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https://www.endocrine-abstracts.org/ea/0086/ea0086OC2.6Licence: Unspecified

Making Radioiodine Treatment a Realistic Therapeutic Opportunity in Breast Cancer
McCabe, C. (Principal Investigator)
US ARMY
30/09/21 → 29/09/26
Project: Research

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Read, M., Brookes, K., Zha, L., Moolla, M., Kocbiyik, M., Manivannan, S., Hoare, R., Kannappan, V., Wang, W., Sunassee, K., Blower, P., Nieto, H., Smith, V., & McCabe, C. (2022). Repurposing disulfiram as a therapeutic agent to enhance sodium iodide symporter activity in radioiodide therapy. Endocrine Abstracts, 86, Article OC2.6. https://doi.org/10.1530/endoabs.86.OC2.6

@article{075e0bf108e94d1bb9ff5fe2e9575d4d,

title = "Repurposing disulfiram as a therapeutic agent to enhance sodium iodide symporter activity in radioiodide therapy",

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 (\textasciitilde{}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.",

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

year = "2022",

month = nov,

day = "16",

doi = "10.1530/endoabs.86.OC2.6",

language = "English",

volume = "86",

journal = "Endocrine Abstracts",

issn = "1470-3947",

publisher = "BioScientifica",

note = "Society for Endocrinology BES 2022, SfE BES 2022 ; Conference date: 14-11-2022 Through 16-11-2022",

url = "https://www.endocrinology.org/events/sfe-bes-conference/sfe-bes-2022/",

}

TY - JOUR

T1 - Repurposing disulfiram as a therapeutic agent to enhance sodium iodide symporter activity in radioiodide therapy

AU - Read, Martin

AU - Brookes, Kate

AU - Zha, Ling

AU - Moolla, Mehjabi

AU - Kocbiyik, Merve

AU - Manivannan, Selvambigai

AU - Hoare, Rachel

AU - Kannappan, Vinodh

AU - Wang, Weiguang

AU - Sunassee, Kavitha

AU - Blower, Philip

AU - Nieto, Hannah

AU - Smith, Vicki

AU - McCabe, Christopher

PY - 2022/11/16

Y1 - 2022/11/16

N2 - 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.

AB - 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.

U2 - 10.1530/endoabs.86.OC2.6

DO - 10.1530/endoabs.86.OC2.6

M3 - Abstract

SN - 1470-3947

VL - 86

JO - Endocrine Abstracts

JF - Endocrine Abstracts

M1 - OC2.6

T2 - Society for Endocrinology BES 2022

Y2 - 14 November 2022 through 16 November 2022

ER -

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

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Making Radioiodine Treatment a Realistic Therapeutic Opportunity in Breast Cancer

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