Differential Morphological and Biochemical Recovery from Chemotherapy-Induced Peripheral Neuropathy Following Paclitaxel, Ixabepilone, or Eribulin Treatment in Mouse Sciatic Nerves

Abstract

The reversibility of chemotherapy-induced peripheral neuropathy (CIPN), a disabling and potentially permanent side effect of microtubule-targeting agents (MTAs), is becoming an increasingly important issue as treatment outcomes improve. The molecular mechanisms regulating the variability in time to onset, severity, and time to recovery from CIPN between the common MTAs paclitaxel and eribulin are unknown. Previously (Benbow et al. in Neurotox Res 29:299-313, 2016), we found that after 2 weeks of a maximum tolerated dose (MTD) in mice, paclitaxel treatment resulted in severe reductions in axon area density, higher frequency of myelin abnormalities, and increased numbers of Schwann cell nuclei in sciatic nerves. Biochemically, eribulin induced greater microtubule-stabilizing effects than paclitaxel. Here, we extended these comparative MTD studies to assess the recovery from these short-term effects of paclitaxel, eribulin, and a third MTA, ixabepilone, over the course of 6 months. Paclitaxel induced a persistent reduction in axon area density over the entire 6-month recovery period, unlike ixabepilone- or eribulin-treated animals. The abundance of myelin abnormalities rapidly declined after cessation of all drugs but recovered most slowly after paclitaxel treatment. Paclitaxel- and ixabepilone- but not eribulin-treated animals exhibited increased Schwann cell numbers during the recovery period. Tubulin composition and biochemistry rapidly returned from MTD-induced levels of α-tubulin, acetylated α-tubulin, and end-binding protein 1 to control levels following cessation of drug treatment. Taken together, sciatic nerve axons recovered more rapidly from morphological effects in eribulin- and ixabepilone-treated animals than in paclitaxel-treated animals and drug-induced increases in protein expression levels following paclitaxel and eribulin treatment were relatively transient.

Signaling pathways and gene co-expression modules associated with cytoskeleton and axon morphology in breast cancer survivors with chronic paclitaxel-induced peripheral neuropathy

“…18,19 Microtubule hyper-stabilization primarily occurs on the most distal portion of the axon and may contribute to the “dying back” phenomenon associated with PIPN. 20–24 Recent preclinical evidence suggests that the neurotoxic effects associated with the stabilization of microtubules results in defects in axonal transport, 25,26 as well as morphological (e.g., increase in myelin abnormalities, 17,27 increase in number of Schwann cell nuclei 17,27 ), and biochemical (e.g., long-term retention of paclitaxel) changes in peripheral nerves. 17,27 The administration of paclitaxel results in the degradation of both peripheral and central branches of dorsal root ganglia (DRG) neurons.…”

“…13 The anti-tumor activity of paclitaxel occurs as a result of its ability to alter normal regulatory mechanisms that control microtubule dynamics and microtubule-based transport that are required for a cell's survival. 16,17 Preclinical evidence suggests that the administration of paclitaxel results in microtubule polymerization and stabilization in cancer cells. 18 Within peripheral neurons, paclitaxel binds to b-tubulin in polymerized microtubules, which causes a conformational change and renders these microtubules less dynamic.…”

Chemotherapy‐induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design

“…For example, only studies involving paclitaxel, vincristine, and bortezomib suggested microtubule stabilization as a mechanism for CIPN 38,43,46,57,87,91,95 . Table 2 23‐115 provides an overview of each type of mechanism studied categorized by the type of chemotherapy.…”

Tubulin-VDAC Interaction: Molecular Basis for Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy

“…It is worth mentioning that these studies employed different MTAs injection modes and administrated concentrations in which clinical relevance has been debated (Nakata and Yorifuji, 1999; Theiss and Meller, 2000; Gornstein and Schwarz, 2014). By contrast, recent studies employing cellular models of MTA-induced neurotoxicity have revealed alterations in microtubule dynamics parameters (Rovini et al., 2010; Shemesh and Spira, 2010) or tubulin biochemistry (Benbow et al., 2016; Cook et al., 2018; Wozniak et al., 2018), rather than massive ultrastructural changes of the microtubule network. Therefore, alteration of tubulin regulation of mitochondrial permeability to metabolic substrates remains to be explored as a possible mechanism by which MTAs would disrupt neuronal energy homeostasis.…”