Copper unlocks therapeutic potential of disulfiram

Copper supplementation is required for cytotoxicity of disulfiram in prostate cancer cells and could be essential for therapeutic efficacy of this agent in men with prostate cancer, according to a study published in Cancer Research.

Elevated circulating and intracellular copper levels have previously been found in men with prostate cancer, but the potential of this attribute as a therapeutic target was unclear. Now, Rachid Safi and colleagues from Duke University, NC, USA, investigated whether the copper signalling axis could be exploited as a therapeutic modality.

The researchers performed a series of in vitro studies on prostate cancer cell lines that express normal levels, elevated levels or a constitutively active splice-variant of the androgen receptor (AR). Chelation of Cu²⁺ in the culture medium was cytotoxic, but the effect was also observed in transformed normal prostate epithelial cells.

To utilize the high copper turnover of prostate cancer cells in a more specific manner, the team tested small molecule drugs that induced copper-dependent apoptosis in AR-overexpressing cells. One of the agents identified was disulfiram, a dithiocarbamate chelator that is used for the treatment of alcohol dependence. Disulfiram treatment was cytotoxic in a Cu²⁺-dependent manner in AR-negative, AR-positive and constitutively-active-AR-expressing prostate cancer cells, but not in transformed normal prostate epithelial cells.

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Safi and colleagues then tested the therapeutic activity of disulfiram in subcutaneous prostate cancer xenografts in mice. Similarly to results from a previous clinical trial, disulfiram treatment alone had only minimal effects. However, when mice receiving disulfiram were supplemented with Cu²⁺, a significant reduction in tumour growth was observed. Notably, results were similar in a mouse model of castration-resistant prostate cancer xenografts.

Further in vitro studies into the mechanisms behind the efficacy of the combination demonstrated that disulfiram–copper complexes induced intracellular reactive oxygen species and apoptosis. Interestingly, the researchers also found that CTR1, ATP7B and STEAP4, which encode proteins involved in copper homeostasis, seemed to be AR target genes and might increase the sensitivity to disulfiram–copper complexes in late-stage disease.

The team are now planning a clinical trial to examine the antitumour activity of a combination of disulfiram and parenteral Cu²⁺ in men with advanced prostate cancer.