Repositioning the Old, Existing Copper-Binding Drugs for Cancer Treatment

Abstract

Copyright: © 2012 Dou. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The conventional approach toward anti-cancer drug development is expensive and time-consuming. One approach to expedite this process and achieve more affordable means is to discover new uses of old, existing drugs, since their pharmacokinetics and pharmacological profiles have been well established [1]. Recent studies reveal anti-cancer activities of several approved copper (Cu)-binding drugs including disulfiram (an anti-alcoholism drug), clioquinol (a drug for treatment of Alzheimer’s and Huntington’s diseases) and ditiocarb (or diethyldithiocarbamate, a drug for treatment of HIV-1 infection) [2,3]. In vitro and in vivo studies have discovered a new mechanism in which these old drugs target and react with tumor cellular copper, forming complexes that act as potent proteasome inhibitors and apoptosis inducers in human cancer cells [4]. Extensive studies have strongly supported the idea that Cu could be used as a novel, selective target for human cancer therapies. First, Cu, but not other metals, is a co-factor essential for the processes of tumor angiogenesis [4,5]. Secondly, high tissue levels of Cu have been found in many types of human cancers, including breast, prostate, colon, lung and brain [4,6,7]. Thirdly, significant decrease in Cu levels in mammalian organs does not cause detectable side effects [8]. Finally, in clinical trials with patients suffering from metastatic cancers, use of the Cu chelator tetrathiomolybdate achieved the Cu-deficiency and stabilization of disease in a large portion of the patients, demonstrating the clinical feasibility [9]. It has been found that some organic Cu complexes can selectively inhibit the cancer cellular 26S proteasome activity, resulting in induction of apoptosis [10]. Furthermore, a Cubinding ligand alone can induce proteasome inhibition and apoptosis in Cu-enriched human cancer cells that mimic in vivo situations of many human tumors [4,10]. Some of the Cu ligands tested include disulfiram, clioquinol and ditiocarb. All of them are able to interact with Cu, forming complexes with potent proteasome-inhibitory and apoptosis-inducing abilities in tumor cells in vitro and in vivo [4]. This identified mechanism of action of these approved Cu-binding drugs may be responsible for their observed anticancer activities.