Transition metal complexes as proteasome inhibitors for cancer treatment

The discovery of cisplatin, a platinum-based drug, was a major breakthrough in cancer treatment strategies. However, the toxicity and drug resistance associated with cisplatin regulated the drug discovery research towards the rationale development of metal-containing agents with more specific activity and less toxicity and mode of action different from cisplatin and its derivatives. Consequently, the ubiquitin-proteasome pathway (UPP) developed as a novel and encouraging cancer treatment target. The metal-based compounds bearing proteasome inhibitory activity explored extensively as one of the important cancer treatment strategies. The bortezomib, a boron-containing compound, approved by the FDA as a first proteasome inhibitor for cancer treatment. Undoubtedly, bortezomib treatment benefited several cancer patients, but it is also associated with serious side effects such as drug resistance and ineffectiveness against solid tumors. To overcome bortezomib drawbacks researchers made efforts to discover new and structurally diverse anti-proteasome agents. In the last few years, several potential metal-based complexes discovered as proteasome inhibitors with reduced toxicity and improved clinical effectiveness. This mini-review article delivers to the reader the current update on the proteasome inhibition activity of transition metal complexes of copper, manganese, cadmium and gold. The recently reported transition metal complexes are included with discussion on the structure and the activity of the most potent complex of the series. The ubiquitin-proteasome pathway inhibition emerged as a promising target in the treatment of cancer and further research effort is obligatory in this area.