Vincristine- and bortezomib-induced neuropathies – from bedside to bench and back

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Abstract

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.

Original languageEnglish
Article number113519
JournalExperimental Neurology
Volume336
DOIs
StatePublished - Feb 2021

Keywords

  • Axon degeneration
  • Chemotherapy-induced neuropathy
  • Neuroinflammation
  • Pain
  • SARM1
  • Therapeutics

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