Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

• DOI: 10.4161/cc.27476
• Publication Date: 2014-01-20T12:31:38Z
• Authors: Cristina Meregalli; Alessia Chiorazzi; Valentina A Carozzi; Annalisa Canta; Barbara Sala; Matteo Colombo; Norberto Oggioni; Cecilia Ceresa; Dana Foudah; Federica La Russa; Mariarosaria Miloso; Gabriella Nicolini; Paola Marmiroli; David LH Bennett; Guido Cavaletti
• Keywords: Neurotoxicity

Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuropathy likely to be a class side effect of these drugs, although its severity largely variable, and it deserves further investigated, since mechanisms BTZ-induced peripheral neurotoxicity (BiPN) are still unknown. In our study, we investigated vivo vitro possible pathogenic events relevant BiPN using well-established rat model, with particular reference extent inhibition effects on α-tubulin polymerization sciatic nerves dorsal root ganglia specimens obtained from animals treated chronic regimens at dose 0.2 mg/kg intravenously. The same assessments were also performed after single injection. Moreover, studies replicated embryonic DRG neurons exposed 100 nM BTZ adult 10–50 for 24 h 48 h. A significant increase polymerized fraction prolonged observed treatment vivo. Recovery physiological levels was 4-week follow-up post-treatment period. Proteasome increased following both vitro. Our results suggest that alteration tubulin dynamics contribute BiPN. systems here described reliably replicate results, might therefore used mechanistic inhibitors neurons.