Targeting the ubiquitin-proteasome pathway with inorganic compounds to fight cancer: a challenge for the future.

Proteasomes are large multicatalytic complexes endowed with proteinase activity, located both in the cytosol and in the nucleus of eukaryotic cells. The ubiquitin-proteasome system is responsible for selective degradation of most intracellular proteins and therefore plays an essential regulatory role in many critical cellular processes. The proteasomal activity can also contribute to the pathological states of many diseases, including inflammation, neurodegeneration and cancer, through a disregulation in the level of regulatory proteins. These diseases may be targeted by modulating components of the ubiquitin-proteasome pathway, using small molecules as inhibitors. Bortezomib (Velcade(®)), used for the treatment of relapsed multiple myeloma, is the first and, up to now, the only proteasome inhibitor approved by the US FDA. Nowadays, the discovery that some metal-based complexes exert their antiproliferative action by affecting proteasomal activities provides the possibility of developing new opportunities in cancer therapy.