Shared and specific molecular mechanisms of proteasome inhibitors in chemotherapy-induced peripheral neurotoxicity

Background and Purpose Proteasome inhibitors have been approved for treatment of multiple myeloma but induce significant chemotherapy-related peripheral neurotoxicity in up to one third of patients. Crucial information about the several neurotoxicity mechanisms suggested in the literature and effective triggering events is either missing or controversial, due to heterogeneity of experimental models used to investigate such processes. To fill this knowledge gap, we compared the neurotoxicity of bortezomib (BTZ) and carfilzomib (CFZ), a less neurotoxic drug, by investigating preclinical models and dissecting the underlying molecular mechanisms using a multidimensional approach. Experimental Approach We developed a new mouse model of CFZ-induced neuropathy and compared it with an established BTZ model using behavioural, morphological/morphometric and proteomic analyses of dorsal root ganglia (DRG) tissues. Mitotoxicity and cytoskeleton alterations were compared in terms of onset of altered mitochondrial morphology, functionality and trafficking, alongside cytoskeletal protein expression and axonal degeneration in cultured mouse DRG neurons. Key Results BTZ's severe neurotoxicity in vivo correlated with severe loss of nerve fibres and extensive protein expression changes. In vitro, both compounds significantly altered mitochondrial network organization and energy production after 24 h of treatment. However, only BTZ induced accumulation of tubulin post-translational modifications and early axonal degeneration within the first 10 h, severely impacting mitochondrial trafficking after 24 h. Conclusions and Implications These results point to mitochondrial toxicity as a common downstream effect of both treatments, whereas BTZ-specific off-target activity on tubulin hyper-stability may initiate early mitochondrial trafficking alterations. This knowledge may inform future mitigation approaches.