Novel copper complexes as potential proteasome inhibitors for cancer treatment

Abstract

The use of metal complexes in the pharmaceutical industry has recently increased and as a result, novel metal‑based complexes have initiated an interest as potential anticancer agents. Copper (Cu), which is an essential trace element in all living organisms, is important in maintaining the function of numerous proteins and enzymes. It has recently been demonstrated that Cu complexes may be used as tumor‑specific proteasome inhibitors and apoptosis inducers, by targeting the ubiquitin‑proteasome pathway (UPP). Cu complexes have demonstrated promising results in preclinical studies. The UPP is important in controlling the expression, activity and location of various proteins. Therefore, selective proteasome inhibition and apoptotic induction in cancer cells have been regarded as potential anticancer strategies. The present short review discusses recent progress in the development of Cu complexes, including clioquinol, dithiocarbamates and Schiff bases, as proteasome inhibitors for cancer treatment. A discussion of recent research regarding the understanding of metal inhibitors based on Cu and ligand platforms is presented.

Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II

“…On the contrary, ionophores trigger intracellular copper accumulation, cytotoxicity, and activate apoptosis inhibitor factor (XIAP) [ 24 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Other CuC are proteasome inhibitors [ 47 , 48 ]. Several CuC are actually on clinical trials: a number of copper/disulfiram-based drug combinations for therapy and as diagnostic tools (metastatic breast cancer and germ cell tumor), several casiopeínas compounds and elesclomol (leukemia), and thiosemicarbazone-based copper complexes labeled with a radioactive isotope for positron emission tomography imaging of hypoxia (in head and neck cancers) [ 49 ].…”

A Proteomic View of Cellular Responses to Anticancer Quinoline-Copper Complexes

“…Taking gold complexes as another example, the suggested mechanisms range from DNA lesions [14] to mitochondrial stress [15] and to proteasome inhibition [4]. The facts that proteasome inhibition is a well-established avenue in anticancer treatments (reviewed in [16]), and that metals are known inhibitors of the proteasome [17,18,19], have paved the way to thorough investigations of this effect in metallodrugs [4,6,17,20,21,22,23,24,25,26,27]. Nevertheless, other mechanisms have been put forward to explain the anticancer activities of the metallodrugs, including direct induction of apoptosis [15], topoisomerase inhibition [28] or redox imbalance [29,30].…”

Comparative Study of Antioxidant and Pro-Oxidant Properties of Homoleptic and Heteroleptic Copper Complexes with Amino Acids, Dipeptides and 1,10-Phenanthroline: The Quest for Antitumor Compounds

“…Some of them involve the interaction of the copper complex with critical biomolecules in tumor cell development, carrying out Lewis acid-base reactions in a general sense. Some examples include the interaction with nucleic acids and their constituents [7]; the interaction with crucial proteins, such as topoisomerases, kinases and proteasomes [8]; and the interaction with angiogenesis inhibitors [9]. However, their therapeutic efficacy as antitumor agents is not limited to these actions.…”