title: Structural Basis for Induction of Peripheral Neuropathy by Microtubule-Targeting Cancer Drugs.
abstract: Peripheral neuropathy is a serious, dose-limiting side effect of cancer treatment with microtubule-targeting drugs. Symptoms present in a "stocking-glove" distribution, with longest nerves affected most acutely, suggesting a length-dependent component to the toxicity. Axonal transport of ATP-producing mitochondria along neuronal microtubules from cell body to synapse is crucial to neuronal function. We compared the effects of the drugs paclitaxel and ixabepilone that bind along the lengths of microtubules and the drugs eribulin and vincristine that bind at microtubule ends, on mitochondrial trafficking in cultured human neuronal SK-N-SH cells and on axonal transport in mouse sciatic nerves. Antiproliferative concentrations of paclitaxel and ixabepilone significantly inhibited the anterograde transport velocity of mitochondria in neuronal cells, whereas eribulin and vincristine inhibited transport only at significantly higher concentrations. Confirming these observations, anterogradely transported amyloid precursor protein accumulated in ligated sciatic nerves of control and eribulin-treated mice, but not in paclitaxel-treated mice, indicating that paclitaxel inhibited anterograde axonal transport, whereas eribulin did not. Electron microscopy of sciatic nerves of paclitaxel-treated mice showed reduced organelle accumulation proximal to the ligation consistent with inhibition of anterograde (kinesin based) transport by paclitaxel. In contrast, none of the drugs significantly affected retrograde (dynein based) transport in neuronal cells or mouse nerves. Collectively, these results suggest that paclitaxel and ixabepilone, which bind along the lengths and stabilize microtubules, inhibit kinesin-based axonal transport, but not dynein-based transport, whereas the microtubule-destabilizing drugs, eribulin and vincristine, which bind preferentially to microtubule ends, have significantly less effect on all microtubule-based axonal transport. Cancer Res; 76(17); 5115-23. ©2016 AACR.
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California. Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Wozniak
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Farah
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California. Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California.
authors.forename: Gregoriy
authors.initials: G
authors.lastname: Smiyun
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California. Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California. jordan@lifesci.ucsb.edu wilson@lifesci.ucsb.edu.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California. Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California.
authors.forename: Stuart
authors.initials: S
authors.lastname: Feinstein
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California. Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California. jordan@lifesci.ucsb.edu wilson@lifesci.ucsb.edu.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Jordan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001370:Axonal Transport / Q000187:drug effects*; D034261:Epothilones / Q000633:toxicity; D005663:Furans / Q000633:toxicity; D006801:Humans; D007659:Ketones / Q000633:toxicity; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D017239:Paclitaxel / Q000633:toxicity; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced*; D012584:Sciatic Nerve / Q000187:drug effects; D050257:Tubulin Modulators / Q000633:toxicity; D014750:Vincristine / Q000633:toxicity; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D005663:Furans; D007659:Ketones; D017239:Paclitaxel; D050257:Tubulin Modulators; D014750:Vincristine; C430592:ixabepilone; C490954:eribulin; D000095662:Polyether Polyketides