title: Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons.
abstract: Bortezomib is part of a newer class of chemotherapeutic agents whose mechanism of action is inhibition of the proteasome-ubiquitination system. Primarily used in multiple myeloma, bortezomib causes a sensory-predominant axonal peripheral neuropathy in approximately 30% of patients. There are no established useful preventative agents for bortezomib-induced peripheral neuropathy (BIPN), and the molecular mechanisms of BIPN are unknown. We have developed an in vitro model of BIPN using rat dorsal root ganglia neuronal cultures. At clinically-relevant dosages, bortezomib produces a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays. This sensory axonopathy is associated with alterations in tubulin and results in accumulation of somatic tubulin without changes in microtubule ultrastructure. Furthermore, we observed an increased proportion of polymerized tubulin, but not total or acetylated tubulin, in bortezomib-treated DRG neurons. Similar findings are observed with lactacystin, an unrelated proteasome-inhibitor, which argues for a class effect of proteasome inhibition on dorsal root ganglion neurons. Finally, there is a change in axonal transport of mitochondria induced by bortezomib in a time-dependent fashion. In summary, we have developed an in vitro model of BIPN that recapitulates the clinical sensory axonopathy; this model demonstrates that bortezomib induces an alteration in microtubules and axonal transport. This robust model will be used in future mechanistic studies of BIPN and its prevention.
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA. Electronic address: staff.nathan@mayo.edu.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Staff
authors.forename: Jewel L
authors.initials: JL
authors.lastname: Podratz
authors.forename: Lukas
authors.initials: L
authors.lastname: Grassner
authors.forename: Miranda
authors.initials: M
authors.lastname: Bader
authors.forename: Justin
authors.initials: J
authors.lastname: Paz
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Knight
authors.forename: Charles L
authors.initials: CL
authors.lastname: Loprinzi
authors.forename: Eugenia
authors.initials: E
authors.lastname: Trushina
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Windebank
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001370:Axonal Transport / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology*; D046529:Microscopy, Electron, Transmission; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D009924:Organ Culture Techniques; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D011719:Pyrazines; C067713:lactacystin; D000069286:Bortezomib; D000111:Acetylcysteine
keywords: Bortezomib; Chemotherapy-induced peripheral neuropathy; Dorsal root ganglia; Neurotoxicity; Peripheral neuropathy; Rat
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