A copper-based metabolite of disulfiram upregulates sodium iodide symporter (NIS) gene expression to enhance thyroidal uptake of radionuclides in vivo

Katie Brookes, Ling Zha, Benjamin Small, Jana Kim, Selvambigai Manivannan, Caitlin Thornton, Vinodh Kannappan, Weiguang Wang, Hannah Nieto, Kavitha Sunassee, Philip Blower, Vicki Smith, Martin Read, Christopher McCabe

Research output: Contribution to journalAbstractpeer-review


Introduction: New approaches to improve radioiodide (RAI) uptake are urgently required in RAI-refractory thyroid cancer. We previously identified disulfiram as a leading candidate to induce sodium iodide symporter (NIS) activity and promote RAI uptake. In vivo, DSF is metabolised to diethyldithiocarbamate (DDC) which binds metal ions. Here, we aimed to gain a mechanistic understanding of how DSF and it’s related metabolite Cu(DDC)2 impact NIS activity.

Methods: NIS function was monitored by RAI (125I) uptake assays. Global gene expression changes in response to Cu(DDC)2 were appraised via in vitro RNAseq analysis. Technetium-99m pertechnetate (99mTc) uptake was used to evaluate NIS function in wild-type BALB/c mice.

Results: The ability of DSF to increase RAI uptake in TPC-1 (3.1-fold; P<0.01) and 8505C (4.9-fold; P<0.001) cells was potentiated by combination with Cu2+ to 5.1- and 18.9-fold increases, respectively. Similarly, Cu(DDC)2 was highly effective at increasing RAI uptake (up to 8-fold;250nM; P<0.001) in multiple thyroid cell types and induced NIS protein expression, whilst methylated-DDC lacking Cu2+ had no effect. Interestingly, a potent transcriptional effect of Cu(DDC)2 was revealed via NIS mRNA induction in TPC-1 (8.5-fold; P<0.001) and 8505C (104.8-fold; P<0.001) cells. RNA-Seq analysis of Cu(DDC)2-treated 8505C cells revealed altered expression of NIS transcriptional regulators, including PAX8 (+4.02-fold; P=0.009), CREM (+1.97-fold; P=0.003), SMAD3 (-1.66-fold; P=0.012) and NKX2-1 (-1.93-fold; P=0.026). Intraperitoneal administration of Cu(DDC)2 in wild-type BALB/c mice significantly induced thyroidal uptake of 99mTc after 30 min (~40% increase;3mg/kg dose; P<0.001), as well as increasing thyroidal NIS (1.9-fold; P<0.01), thyroid peroxidase (1.8-fold; P<0.001) and thyroglobulin (1.3-fold; P<0.05) mRNA expression. Importantly, there was a significant positive correlation between thyroidal 99mTc uptake and NIS mRNA levels (rs=0.448, P=0.0169) in Cu(DDC)2-treated mice.

Discussion: Our study demonstrates that a copper-disulfiram metabolite induces a transcriptional response to increase NIS activity in vitro and in vivo, with clinical potential to improve RAI-refractory thyroid cancer treatment.
Original languageEnglish
Article numberOC7.1
Number of pages1
JournalEndocrine Abstracts
Publication statusPublished - 30 Oct 2023
EventSociety for Endocrinology BES 2023 - SEC, Glasgow, United Kingdom
Duration: 13 Nov 202315 Nov 2023


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