Neurotoxicity induced by antineoplastic proteasome inhibitors Albert Ale ´, Jordi Bruna, Xavier Navarro, Esther Udina * Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Auto `noma de Barcelona, and Centro de Investigacio ´n Biome ´dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain 1. Introduction Peripheral neuropathy induced by antineoplastic chemothera- py is a well-known dose-limiting adverse event, leading to reduction, discontinuation, or even withdrawal of the treatment. Therefore, it can impair survival and decrease the quality of life of patients (Argyriou et al., 2012; Mols et al., 2013). Moreover, neuropathy is not always reversible, and its management may have a negative socioeconomic impact on patients and the public health system (Lema et al., 2010; Hershman et al., 2011; Bennett et al., 2012; Pike et al., 2012). Chemotherapeutic drugs affect mainly the peripheral nervous system, more vulnerable to exogenous substances due to the permeability of the vasa nervorum, in contrast to the less permissive blood-brain barrier of the central nervous system (Windebank and Grisold, 2008). The type and severity of neuropathy is related to the drug, the dosage, and the cumulative dose administered. Depending on the drug used, a pure sensory neuropathy, sometimes painful, or a mixed sensorimotor neurop- athy, with or without involvement of the autonomic nervous system, can ensue. The most neurotoxic families of chemothera- peutic drugs are the Vinca alkaloids (e.g. vincristine, vinblastine), taxoid compounds (e.g. paclitaxel, docetaxel), epotilones (e.g. ixabepilones), platinum compounds (e.g. cisplatin, oxaliplatin, carboplatin), immunomodulators (thalidomide), and proteasome inhibitors. Vinca alkaloids, taxanes, and epotilones inhibit the mitotic spindle and microtubule assembly, arresting mitosis in metaphase. Since axonal transport (anterograde and retrograde) is microtubule-dependent, these drugs lead to distal axonopathy. Consequently, they affect sensory, autonomic, and motor fibers, predominantly in the distal segments of the nerves (Tanner et al., 1998; Topp et al., 2000; Bruna et al., 2011). Platinum compounds exert their effect by binding with DNA, impairing both DNA replication and transcription, and inducing apoptosis in prolifer- ative cells. However, these compounds can also affect sensory neurons by inducing re-entry into the cell cycle, mitochondrial dysfunction, and oxidative stress, leading to apoptosis and causing pure sensory neuronopathy (Russell et al., 1995; Gill and Wind- ebank, 1998; Lauren et al., 2006; Carozzi et al., 2010). The action of the immunomodulator thalidomide on malignant cells is not clear, but it is suggested that it inhibits angiogenesis and modulates cytokine expression. The neuropathy induced by thalidomide is mainly a sensory axonal polyneuropathy, but the underlying mechanisms are completely unknown (Mazumder and Jagannath, 2006; Argyriou et al., 2012; Grisold et al., 2012). NeuroToxicology xxx (2014) xxx–xxx A R T I C L E I N F O Article history: Received 31 October 2013 Received in revised form 3 February 2014 Accepted 3 February 2014 Available online xxx Keywords: Peripheral neurophathy Proteasome inhibitors Neurotoxicity Bortezomib Carfilzomib A B S T R A C T 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. ß 2014 Elsevier Inc. All rights reserved. * Corresponding author at: Faculty of Medicine, Universitat Auto ` noma de Barcelona, 08193 Bellaterra, Spain. Tel.: +34 935811348. E-mail address: esther.udina@uab.cat (E. Udina). G Model NEUTOX-1653; No. of Pages 8 Please cite this article in press as: Ale ´ A, et al. Neurotoxicity induced by antineoplastic proteasome inhibitors. Neurotoxicology (2014), http://dx.doi.org/10.1016/j.neuro.2014.02.001 Contents lists available at ScienceDirect NeuroToxicology http://dx.doi.org/10.1016/j.neuro.2014.02.001 0161-813X/ß 2014 Elsevier Inc. All rights reserved.