DOI: 10.1007/s12640-017-9729-6 Pages: 151-162
Article Type: ORIGINAL ARTICLE

Microtubule-Targeting Agents Eribulin and Paclitaxel Differentially Affect Neuronal Cell Bodies in Chemotherapy-Induced Peripheral Neuropathy

1. University of California, Neuroscience Research Institute

2. University of California, Department of Molecular, Cellular and Developmental Biology

3. Johns Hopkins School of Medicine, Johns Hopkins Drug Discovery Program

4. Johns Hopkins School of Medicine, Departments of Neurology, Psychiatry, Neuroscience, Medicine and Oncology

5. Eisai Inc.

Correspondence to:
Stuart C. Feinstein
Tel: 805-893-2659
Email: feinstei@lifesci.ucsb.edu

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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.

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  • Accepted: Mar 27, 2017
  • Online: Apr 8, 2017
  • Revised: Mar 21, 2017

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