Neurotoxicity induced by antineoplastic proteasome inhibitors

• The protesome inhibitor bortezomib is first line treatment for multiple myeloma.
• Bortezomib induces a dose limiting sensory peripheral neuropathy.
• Neurotoxicity may be due to aggresome formation, oxidative stress or mitotoxicity.
• Neuroinflammation and DNA damage are also suggested neurotoxic mechanisms.
• New proteasome inhibitors have been developed to reduce their toxic profile.

In the last ten years, the proteasome has become one of the most attractive targets for the treatment of several cancer malignancies. Like other types of antineoplastic agents, proteasome inhibitors cause toxic peripheral neuropathy, which indeed is one of the limiting side effects of these treatments, and which thus curtails its potential effectiveness. Bortezomib was the first proteasome inhibitor approved for clinical use and is currently the first line treatment for multiple myeloma. The incidence of neuropathy induced by bortezomib is around 30–60%. Although the neurotoxic mechanisms are not completely understood, experimental studies suggest that aggresome formation, endoplasmic reticulum stress, mitotoxicity, inflammatory response, and DNA damage could contribute to this neurotoxicity. Additionally, the second generation of proteasome inhibitors, headed by carfilzomib, is currently being developed in order to reduce the toxic profile, with promising results. However, more extensive clinical experience and further experimental research are needed in order to determine the potential benefits of the second generation over bortezomib. The present review summarizes the main clinical features and mechanistic events related to the neuropathy induced by proteasome-inhibitors.