title: Microtubule-Targeting Agents Eribulin and Paclitaxel Differentially Affect Neuronal Cell Bodies in Chemotherapy-Induced Peripheral Neuropathy.
abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment with microtubule-targeted agents (MTAs). The frequency of severe CIPN, which can be dose limiting and even life threatening, varies widely among different MTAs. For example, paclitaxel induces a higher frequency of severe CIPN than does eribulin. Different MTAs also possess distinct mechanisms of microtubule-targeted action. Recently, we demonstrated that paclitaxel and eribulin differentially affect sciatic nerve axons, with paclitaxel inducing more pronounced neurodegenerative effects and eribulin inducing greater microtubule stabilizing biochemical effects. Here, we complement and extend these axonal studies by assessing the effects of paclitaxel and eribulin in the cell bodies of sciatic nerve axons, housed in the dorsal root ganglia (DRG). Importantly, the microtubule network in cell bodies is known to be significantly more dynamic than in axons. Paclitaxel induced activating transcription factor 3 expression, a marker of neuronal stress/injury. Paclitaxel also increased expression levels of acetylated tubulin and end binding protein 1, markers of microtubule stability and growth, respectively. These effects are hypothesized to be detrimental to the dynamic microtubule network within the cell bodies. In contrast, eribulin had no significant effect on any of these parameters in the cell bodies. Taken together, DRG cell bodies and their axons, two distinct neuronal cell compartments, contain functionally distinct microtubule networks that exhibit unique biochemical responses to different MTA treatments. We hypothesize that these distinct mechanistic actions may underlie the variability seen in the initiation, progression, persistence, and recovery from CIPN.
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, 93106, USA.|Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Benbow
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Wozniak
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, 93106, USA.|Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA, USA.
authors.forename: Bridget
authors.initials: B
authors.lastname: Kulesh
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, 93106, USA.|Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA, USA.
authors.forename: April
authors.initials: A
authors.lastname: Savage
authors.affiliation: Johns Hopkins Drug Discovery Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Departments of Neurology, Psychiatry, Neuroscience, Medicine and Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: Eisai Inc., Andover, MA, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Littlefield
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, 93106, USA.|Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Jordan
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, 93106, USA.|Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.affiliation: Neuroscience Research Institute, University of California, Santa Barbara, CA, 93106, USA. feinstei@lifesci.ucsb.edu.|Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA, USA. feinstei@lifesci.ucsb.edu.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Feinstein
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D066146:Cell Body; D004195:Disease Models, Animal; D005260:Female; D005663:Furans / Q000627:therapeutic use*; D005727:Ganglia, Spinal / Q000166:cytology; D007659:Ketones / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use*; D020426:Sciatic Neuropathy / Q000139:chemically induced* / Q000473:pathology*; D011984:Sensory Receptor Cells / Q000187:drug effects*; D014404:Tubulin / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; D017239:Paclitaxel; D014404:Tubulin; C103002:Atf3 protein, mouse; C490954:eribulin; D000095662:Polyether Polyketides
keywords: Chemotherapy-induced peripheral neuropathy; Dorsal root ganglia; Eribulin; Microtubules; Neuronal cell bodies; Paclitaxel