New applications of old metal-binding drugs in the treatment of human cancer

Abstract

Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and ruthenium-based compounds are currently being investigated in clinical trials. Since the process of drug development can be expensive and cumbersome, finding new applications of existing drugs may provide effective means to expedite the regulatory process in bringing new drugs to the clinical setting. Encouraging findings from laboratory studies reveal significant anticancer activity from different classes of metal-chelating compounds, such as disulfiram, clioquinol, and dithiocarbamate derivatives that are currently approved for the treatment of various pathological disorders. Their use as coordination complexes with metals such as copper, zinc, and gold that target the ubiquitin-proteasome pathway have shown significant promise as potential anticancer agents. This review discusses the unique role of several selected metals in relation to their anti-cancer properties as well as the new therapeutic potential of several previously approved metal-chelating drugs. In vitro and in vivo experimental evidence along with mechanisms of action (e.g., via targeting the tumor proteasome) will also be discussed with anticipation of strengthening this exciting new concept.

Figure 1

Chemical structures of platinum- and ruthenium-based drugs, as well as the proteasome inhibitor bortezomib, used in the treatment of human cancers. Chemical structure of bortezomib, the first proteasome inhibitor clinically tested is shown. Cisplatin, oxaliplatin, and carboplatin are platinum-containing drugs used for the treatment of human cancers. NAMI-A and KP1019 are ruthenium-based drugs under investigation for the potential treatment of human cancers.

Figure 2

Schematic representation of the ubiquitin-proteasome pathway (UPP). The UPP is a highly regulated ATP-dependent pathway, which is vital for the processing of intracellular proteins. It is also a promising target for anticancer therapeutics, and many metal-based or metal-binding compounds, such as CQ, DSF and Au-complexes, have been shown to be potent inhibitors of the proteasomal activity.

Figure 3

Chemical structures of gold-based compounds. Auranofin, one of the first clinically used gold-based drugs, prompted the search for novel gold- compounds that may be effective in the treatment of various pathological disorders such as cancer. Au(DMDT)Br₂, AUL12, and AUL15 are gold compounds with proteasome-inhibitory activity.

Figure 4

Chemical structures of dithiocarbamates. DDTC, PDTC, and DSF have all been used previously in the clinical setting for a variety of diseases. These complexes are able to chelate copper, and DSF-Cu complexes are active against human tumor cells. EtDTC and PyDTC are metal chelating compounds from the dithiocarbamate family that have been investigated for their proteasome-inhibitory activity.

Figure 5

Chemical structures of hydroxyquinolines. CQ and 8-OHQ are members of the hydroxyquinoline family, and are able to bind copper and actively inhibit the proteasome. Analogs of 8-OHQ with methyl group additions were investigated, and found to exhibit proteasome-inhibitory activity when complexed with copper.

Figure 6

Chemical structures of synthetic non-copper binding CQ and 8-OHQ analogs. Four molecules similar in structure to CQ and 8-OHQ without the ability to bind copper were synthesized. In contrast to CQ and 8-OHQ, these analogs exhibited no proteasome-inhibitory or apoptosis-inducing activity alone or in combination with copper.