2.B.98.  The Copper/Zinc Ion Ionophore Clioquinol (Clinoquinol) Family

Clioquinol (5-chloro-7-iodo-quinolin-8-ol; a 8-hydroxyquinoline) 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 (Schimmer 2011). It then directs the metal to the proteasome resulting in disruption of this enzymatic complex. Clioquinol is capable of directly inhibiting the proteasome at higher concentrations. Thus, Clioquinol represents a novel therapeutic strategy to inhibit the proteasome. Given prior toxicology and pharmacology studies, Clioquinol could be rapidly repositioned as a new anti-cancer agent. The review by Schimmer 2011, 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.



Schimmer, A.D. (2011). Clioquinol - a novel copper-dependent and independent proteasome inhibitor. Curr Cancer Drug Targets 11: 325-331.