Clioquinol (5-chloro-7-iodo-quinolin-8-ol) was used in the 1950s-1970s as an oral anti-parasitic agent. More recently, studies have demonstrated that Clioquinol displays preclinical efficacy in the treatment of malignancy. Its anticancer activity relates, at least in part, to its ability to inhibit the proteasome through mechanisms dependent and independent of its ability to bind heavy metals such as copper. By acting as a metal ionophore Clioquinol transports metal ions from the extracellular environment into the cell and mobilizes weakly bound intracellular stores. It then directs the metal to the proteasome resulting in disruption of this enzymatic complex. In addition, Clioquinol is capable of directly inhibiting the proteasome at higher concentrations. Thus, Clioquinol represents a novel therapeutic strategy to inhibit the proteasome. Given the prior toxicology and pharmacology studies, Clioquinol could be rapidly repositioned for a new anticancer indication. This review highlights the mechanism of action of Clioquinol as a proteasome inhibitor. In addition, it discusses the human pharmacology and toxicology studies and how this information would guide a phase I clinical trial of this agent for patients with malignancy.
Keywords: Proteasome inhibitors, drug repositioning, metal ionophore, copper
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