Proteasome Inhibitors Bortezomib and Carfilzomib Induce CIPN through Different Molecular Mechanisms - Raw data

Here, 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. We developed a new mouse model of CFZ-induced neuropathy and compared it to an established BTZ model using behavioral, morphological/morphometric, and proteomic analyses showing that the more severe neurotoxicity correlated with loss of nerve fibers and protein expression changes.

Moreover, mitotoxicity and cytoskeleton alterations were comparatively investigated in terms of onset of altered mitochondrial morphology, functionality, and trafficking, alongside cytoskeletal proteins expression and axonal degeneration in cultured mouse dorsal root ganglion neurons. Both compounds significantly altered mitochondrial network organization and energy production after 24 hours of treatment. However, only BTZ increased microtubule hyper-stabilization by accumulation of tubulin post-translational modifications and induced early axonal degeneration within the first 10 hours, severely impacting mitochondrial trafficking after 24 hours.