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.
Highlights
Microtubules are a major component of the cytoskeleton
Our results indicate that inhibition of fast axonal transport may contribute significantly to the neurotoxicity induced by microtubule-targeting drugs, and that eribulin's lower incidence of severe peripheral neuropathy may result, at least in part, from its milder effects on fast axonal transport relative to other microtubule-targeting drugs and from the low doses at which eribulin is clinically effective
Anterograde and retrograde fast axonal transport of vesicles depend upon the activities of conventional kinesin (Brady et al, 1990) and cytoplasmic dynein (DeGiorgis et al, 2011), respectively
Summary
Microtubules are a major component of the cytoskeleton. They are dynamic polymers composed of tubulin dimers arranged end to end in linear protofilaments that align to form a hollow cylinder. In addition to playing essential roles in migration and mitosis (Jordan and Wilson, 2004), microtubules are critical for intracellular transport, serving as tracks for “motor” proteins that carry vesicular cargo. The motor protein conventional kinesin transports various cargoes from the cell body toward distal terminals (anterograde fast axonal transport), supplying essential new materials for synapse function and maintenance (Morfini et al, 2011). Cytoplasmic dynein transports cargo in the opposite direction (retrograde fast axonal transport), clearing toxic components from nerve terminals (e.g., misfolded proteins, damaged organelles), and delivering survival factors to the cell body. The importance of fast axonal transport to neuronal function is highlighted by multiple lines of evidence linking deficits in this process to neurodegeneration (Millecamps and Julien, 2013; Morfini et al, 2009; Perlson et al, 2010)
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