Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: Implications for chemotherapy-induced peripheral neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious, painful and dose-limiting side effect of cancer drugs that target microtubules. The mechanisms underlying the neuronal damage are unknown, but may include disruption of fast axonal transport, an essential microtubule-based process that moves cellular components over long distances between neuronal cell bodies and nerve terminals. This idea is supported by the “dying back” pattern of degeneration observed in CIPN, and by the selective vulnerability of sensory neurons bearing the longest axonal projections. In this study, we test the hypothesis that microtubule-targeting drugs disrupt fast axonal transport using vesicle motility assays in isolated squid axoplasm and a cell-free microtubule gliding assay with defined components. We compare four clinically-used drugs, eribulin, vincristine, paclitaxel and ixabepilone. Of these, eribulin is associated with a relatively low incidence of severe neuropathy, while vincristine has a relatively high incidence. In vesicle motility assays, we found that all four drugs inhibited anterograde (conventional kinesin-dependent) fast axonal transport, with the potency being vincristine = ixabepilone > paclitaxel = eribulin. Interestingly, eribulin and paclitaxel did not inhibit retrograde (cytoplasmic dynein-dependent) fast axonal transport, in contrast to vincristine and ixabepilone. Similarly, vincristine and ixabepilone both exerted significant inhibitory effects in an in vitro microtubule gliding assay consisting of recombinant kinesin (kinesin-1) and microtubules composed of purified bovine brain tubulin, whereas paclitaxel and eribulin had negligible effects. Our results suggest that (i) inhibition of microtubule-based fast axonal transport may be a significant contributor to neurotoxicity induced by microtubule-targeting drugs, and (ii) that individual microtubule-targeting drugs affect fast axonal transport through different mechanisms.

Integrating Image-Based High-Content Screening with Mouse Models Identifies 5-Hydroxydecanoate as a Neuroprotective Drug for Paclitaxel-Induced Neuropathy

“…The incidence of paclitaxel-induced neuropathy ranges from 20% to 70% of patients (24,25). Mechanisms include disruption of axonal transport (26,27), mitochondrial damage (28)(29)(30), altered ion channel activities (31), and neuronal inflammation (32,33). Here we screened three compound libraries, including ion channel ligands, GABA and REDOX libraries, for the discovery of potential neuroprotective drugs.…”

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

“…33 Based on the reported evidence of changes in tubulin dynamics obtained in different cellular systems and on the relevance of tubulin interference in the pathogenesis of toxic peripheral neuropathies, 21,34,35 we focused on α-tubulin polymerization as a possible mechanism of neurotoxicity in BiPN. Despite the fact that the severity of nerve damage was more marked in the caudal nerve than the sciatic nerve, we selected the latter tissue to assay proteasome inhibition.…”

Taxane induced neuropathy in patients affected by breast cancer: Literature review

“…La Pointe et al have demonstrated an inhibition of microtubule-based fast axonal transport as significant contributor to neurotoxicity induced by microtubule-targeting drugs, including taxanes, through different mechanisms [23]. In this in vitro study, eribulin mesylate (a synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B) and paclitaxel both inhibit anterograde fast axonal transport but don't inhibit retrograde fast axonal transport (cytoplasmic dynein-dependent), in contrast to vincristine and ixabepilone (an epothilone that stabilizes the microtubules).…”