Clioquinol (5-chloro-7-iodo-quinolin-8-ol) was used in the 1950's-1970's as an oral anti-parasitic agent. More recently, studies have demonstrated that
Clioquinol displays preclinical efficacy in the treatment of
malignancy. Its anti-
cancer 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 anti-
cancer 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.