SFEBES2023 Oral Communications Thyroid (6 abstracts)
A copper-based metabolite of disulfiram upregulates sodium iodide symporter (NIS) gene expression to enhance thyroidal uptake of radionuclides in vivo
Katie Brookes 1 , Ling Zha 1 , Benjamin Small 2 , Jana Kim 3 , Selvambigai Manivannan 1 , Caitlin Thornton 1 , Vinodh Kannappan 2 , Weiguang Wang 2 , Hannah Nieto 2 , Kavitha Sunassee 3 , Philip Blower 3 , Vicki Smith 1 , Martin Read 1 & Christopher McCabe 1
1University of Birmingham, Birmingham, United Kingdom. 2University of Wolverhampton, Wolverhampton, United Kingdom. 3King’s College London, London, United Kingdom
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.
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Endocrine Abstracts
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