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Abstract
<p class="first" id="d1186826e51">Vincristine and bortezomib are effective chemotherapeutics
widely used to treat hematological
cancers. Vincristine blocks tubulin polymerization, whereas bortezomib is a proteasome
inhibitor. Despite different mechanisms of action, the main non-hematological side
effect of both is peripheral neuropathy that can last long after treatment has ended
and cause permanent disability. Many different cellular and animal models of various
aspects of vincristine and bortezomib-induced neuropathies have been generated to
investigate underlying molecular mechanisms and serve as platforms to develop new
therapeutics. These models revealed that bortezomib induces several transcriptional
programs in dorsal root ganglia that result in the activation of different neuroinflammatory
pathways and secondary central sensitization. In contrast, vincristine has direct
toxic effects on the axon, which are accompanied by changes similar to those observed
after nerve cut. Axon degeneration following both vincristine and bortezomib is mediated
by a phylogenetically ancient, genetically encoded axon destruction program that leads
to the activation of the Toll-like receptor adaptor SARM1 (sterile alpha and TIR motif
containing protein 1) and local decrease of nicotinamide dinucleotide (NAD+). Here,
I describe current in vitro and in vivo models of vincristine- and bortezomib induced
neuropathies, present discoveries resulting from these models in the context of clinical
findings and discuss how increased understanding of molecular mechanisms underlying
different aspects of neuropathies can be translated to effective treatments to prevent,
attenuate or reverse vincristine- and bortezomib-induced neuropathies. Such treatments
could improve the quality of life of patients both during and after cancer therapy
and, accordingly, have enormous societal impact.
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