Proteasome Inhibition: A Promising Strategy for Treating Cancer, but What About Neurotoxicity?

A.      Gilardini; P.      Marmiroli; G.      Cavaletti

doi:10.2174/092986708786848622

Abstract

The inhibition of protein degradation through the ubiquitin – proteasome pathway is a recently developed approach to cancer treatment which extends the range of cellular targets for chemotherapy. This therapeutic strategy is very interesting since the proteasomes carry out the regulated degradation of unnecessary or damaged cellular proteins, a process that is dysregulated in many cancer cells. Based on this hypothesis, the proteasome complex inhibitor bortezomib was approved for use in multiple myeloma patients by the US Food and Drug Administration (FDA) in 2003 and by the European Medicines Agency (EMEA) in 2004, and several new drugs with the same target and, sometimes, mechanism of action are currently under development. Interestingly, proteasome inhibitors have now also been tested in combination chemotherapy for the treatment of several solid tumors and it is likely that there will be more generalized use of these compounds in the near future. Despite its remarkable effectiveness, which led to it being rapidly approved for clinical use, some concern has been raised regarding the safety of bortezomib (and in general of proteasome inhibitors) since reduced degradation of damaged proteins has been postulated as being the basic mechanism of severe neurological diseases affecting the central nervous system. While this concern has not been confirmed by the clinical course of treated patients, from the first Phase I studies, it emerged that peripheral sensory neurotoxicity was one of the major dose-limiting toxicities. The main results from the use of proteasome inhibition in cancer chemotherapy and the implications for treatment on the nervous system will be reviewed.

Keywords: Protein degradation, ubiquitin-proteasome system, proteasome inhibition, protein aggregates, cancer, chemotherapy, neurotoxicity, neurodegenerative diseases