A critical role for copper in enhanced radioiodide uptake in thyroid cancer cells

New drug approaches are urgently required to improve radioiodide (RAI) uptake for efficient ablation of thyroid cancer cells in RAI-refractory disease. Employing high-throughput screening of FDA-approved compounds we recently identified drugs capable of robust induction of sodium iodide symporter (NIS) activity to promote RAI uptake1. In particular, a leading drug candidate - the well-established anti-alcoholism drug disulfiram (DSF) - had not been previously implicated in regulating NIS. Here, we demonstrate that the ability of DSF to increase RAI-uptake in thyroid TPC-1 (3.1-fold; p<0.01) and 8505C (4.9-fold; p<0.001) cells can be significantly potentiated by combination with Cu²⁺ to 5.1-fold and 18.9-fold increases respectively. Despite promising data, DSF is known to have poor bioavailability in vivo due to its rapid metabolism to diethyldithiocarbamate (DDC) within the stomach and circulation with subsequent methylation in the liver. Whilst methylated-DDC did not have any effect on NIS function, DDC chelated to divalent copper ions [Cu(DDC)₂] was highly effective at increasing RAI uptake (up to 8-fold; P<0.001) in multiple thyroid cell types and induced significant NIS protein expression (up to 36.2-fold; 250nM; P<0.001). Importantly, 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 its effect on NIS was via VCP-independent pathways. Instead, a transcriptional effect of Cu(DDC)₂ was revealed by significant induction of NIS mRNA levels in TPC-1 (8.5-fold; P<0.001) and 8505C (104.8-fold; P<0.001) cells. In wild-type Balb/c mice the intraperitoneal administration of albumin nano-encapsulated Cu(DDC)₂ significantly induced thyroidal uptake of technetium-99m (^99mTc) after 30 min (~40% increase; n=11 per group; 3 mg/kg dose; P<0.001). Thus, our study demonstrates a promising drug strategy utilizing copper to significantly enhance NIS function with clinical potential to improve treatment effectiveness in RAI-refractory thyroid cancer patients.

¹Read ML, Brookes K, Thornton CEM, Fletcher A, Nieto HR, Alshahrani M, Khan R, Borges de Souza P, Zha L, Webster JRM, Alderwick LJ, Campbell MJ, Boelaert K, Smith VE, McCabe CJ (2022) Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter. Cell Chem Biol. 29(3):502-516.e7.