Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons.
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.
['Staff|Nathan P|NP|', 'Podratz|Jewel L|JL|', 'Grassner|Lukas|L|', 'Bader|Miranda|M|', 'Paz|Justin|J|', 'Knight|Andrew M|AM|', 'Loprinzi|Charles L|CL|', 'Trushina|Eugenia|E|', 'Windebank|Anthony J|AJ|']
D000111:Acetylcysteine D000818:Animals D000970:Antineoplastic Agents D001370:Axonal Transport D001897:Boronic Acids D000069286:Bortezomib D016923:Cell Death D002478:Cells, Cultured D015853:Cysteine Proteinase Inhibitors D004305:Dose-Response Relationship, Drug D004622:Embryo, Mammalian D005727:Ganglia, Spinal D046529:Microscopy, Electron, Transmission D008870:Microtubules D009474:Neurons D009924:Organ Culture Techniques D011719:Pyrazines D051381:Rats D017207:Rats, Sprague-Dawley D018709:Statistics, Nonparametric D013997:Time Factors
Bortezomib Rat Peripheral neuropathy Dorsal root ganglia Chemotherapy-induced peripheral neuropathy Neurotoxicity