The paradox of paclitaxel neurotoxicity: Mechanisms and unanswered questions

• Microtubule stabilization underlies the chemotherapeutic value of paclitaxel.
• Paclitaxel-induced neurotoxicity entails axonal degeneration in vivo and in vitro.
• Normal axonal microtubules are relatively stable but still have dynamic instability.
• Axonal transport defects due to paclitaxel may be responsible for axonal degeneration.
• Secondary changes to hyperstable microtubules or off-target effects may be neurotoxic.

Paclitaxel is a microtubule-binding compound that is widely used as a chemotherapeutic in the treatment of common cancers, including breast and ovarian cancer. Paclitaxel binding along the length of microtubules stabilizes them and suppresses their dynamics, leading to mitotic arrest and apoptosis in dividing cells. Though they are not dividing cells, neurons are also susceptible to paclitaxel, and paclitaxel exposure results in axonal degeneration. Thus a frequent side effect of paclitaxel treatment in patients is peripheral neuropathy, which can necessitate dose reductions and have lasting symptoms. An understanding of the mechanisms underlying paclitaxel's neurotoxicity is important for development of therapeutics to prevent and alleviate the neuropathy. Here we will review approaches taken to investigate mechanisms of paclitaxel-induced neuropathy and evidence for potential mechanisms of the axonal degeneration downstream of or distinct from microtubule stabilization by paclitaxel.This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.