Abstract
Microtubule targeting agents (MTAs) often lead to treatment limiting and life threatening side effects, including chemotherapy-induced peripheral neuropathy (CIPN). The frequency of severe CIPN varies among different MTAs. Since the microtubule binding interactions and mechanisms of action also vary among MTAs, we hypothesized that these distinct mechanisms may underlie the variability in frequency of severe CIPN. Using a two-week, maximum tolerated dose model, we morphologically and biochemically analyzed sciatic nerves from mice treated with either paclitaxel or eribulin. These drugs differ in their manner of microtubule binding and mechanisms of action and reports indicate paclitaxel also induces a higher frequency of severe CIPN than does eribulin. Morphologically, paclitaxel increased the frequency of observed signs of axon degeneration more significantly than did eribulin. Alternatively, eribulin but not paclitaxel induced occasional myelin “halo” structures. Biochemically, paclitaxel, and eribulin both induced α-tubulin expression (~1.9- and ~2.5-fold, respectively) and tubulin acetylation, a marker for microtubule stability, (~5- and ~11.7-fold, respectively). Eribulin but not paclitaxel-induced EB1 expression ~2.2-fold while paclitaxel but not eribulin mildly suppressed EB3 expression. Both EB proteins are associated with microtubule growth. Eribulin’s combination of relatively mild deleterious morphological effects coupled with more potent biochemical changes promoting microtubule stability and growth in mice correlate with lower frequencies of severe CIPN in humans. We suggest that these eribulin-induced effects create a relatively stable microtubule network that compensates, in part, for the toxic anti-cancer effects of the drug, leading to fewer reported incidences of CIPN than for paclitaxel.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Akhmanova A, Steinmetz MO (2008) Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nat Rev Mol Cell Biol 9:309–322. doi:10.1038/nrm2369
Almeida-Souza L, Timmerman V, Janssens S (2011) Microtubule dynamics in the peripheral nervous system: A matter of balance. Bioarchitecture 1:267–270. doi:10.4161/bioa.1.6.19198
Argyriou AA, Marmiroli P, Cavaletti G, Kalofonos HP (2011) Epothilone-induced peripheral neuropathy: a review of current knowledge. J Pain Symptom Manage 42:931–940. doi:10.1016/j.jpainsymman.2011.02.022
Argyriou AA, Bruna J, Marmiroli P, Cavaletti G (2012) Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol 82:51–77. doi:10.1016/j.critrevonc.2011.04.012
Avila J, Dominguez J, Diaz-Nido J (1994) Regulation of microtubule dynamics by microtubule-associated protein expression and phosphorylation during neuronal development. Int J Dev Biol 38:13–25
Banerjee A (2002) Increased levels of tyrosinated α-, βIII-, and βIV-tubulin isotypes in paclitaxel-resistant MCF-7 breast cancer cells. Biochem Biophys Res Commun 293:598–601. doi:10.1016/S0006-291X(02)00269-3
Boehmerle W, Huehnchen P, Peruzzaro S, Balkaya M, Endres M (2014) Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice. Sci Rep 4:6370. doi:10.1038/srep06370
Boyette-Davis J, Xin W, Zhang H, Dougherty PM (2011) Intraepidermal nerve fiber loss corresponds to the development of taxol-induced hyperalgesia and can be prevented by treatment with minocycline. Pain 152:308–313. doi:10.1016/j.pain.2010.10.030
Bunker JM, Wilson L, Jordan MA, Feinstein SC (2004) Modulation of microtubule dynamics by tau in living cells: implications for development and neurodegeneration. Mol Biol Cell 15:2720–2728. doi:10.1091/mbc.E04-01-0062
Carlson K, Ocean AJ (2011) Peripheral neuropathy with microtubule-targeting agents: occurrence and management approach. Clin Breast Cancer 11:73–81. doi:10.1016/j.clbc.2011.03.006
Choi YJ, Di Nardo A, Kramvis I, Meikle L, Kwiatkowski DJ, Sahin M, He X (2008) Tuberous sclerosis complex proteins control axon formation. Genes Dev 22:2485–2495
Cortes J, Montero AJ, Gluck S (2012) Eribulin mesylate, a novel microtubule inhibitor in the treatment of breast cancer. Cancer Treat Rev 38:143–151. doi:10.1016/j.ctrv.2011.03.006
Creppe C, Malinouskaya L, Volvert ML, Gillard M, Close P, Malaise O, Laguesse S, Cornez I, Rahmouni S, Ormenese S, Belachew S, Maigrange B, Chapelle JP, Siebenlist U, Moonen G, Chariot A, Nguyen L (2009) Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin. Cell 136:551–564. doi:10.1016/j.cell.2008.11.043
de Pennart H, Houliston E, Maro B (1988) Post-translational modifications of tubulin and the dynamics of microtubules in mouse oocytes and zygotes. Biol Cell 64:375–378
Derry WB, Wilson L, Jordan MA (1995) Substoichiometric binding of taxol suppresses microtubule dynamics. Biochemistry 34:2203–2211
Dompierre JP, Godin JD, Charrin BC, Cordelieres FP, King SJ, Humbert S, Saudou F (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J Neurosci 27:3571–3583. doi:10.1523/jneurosci.0037-07.2007
Field JJ, Kanakkanthara A, Miller JH (2014) Microtubule-targeting agents are clinically successful due to both mitotic and interphase impairment of microtubule function. Bioorg Med Chem 22:5050–5059. doi:10.1016/j.bmc.2014.02.035
Gay DA, Yen TJ, Lau JT, Cleveland DW (1987) Sequences that confer beta-tubulin autoregulation through modulated mRNA stability reside within exon 1 of a beta-tubulin mRNA. Cell 50:671–679
Geraldo S, Khanzada UK, Parsons M, Chilton JK, Gordon-Weeks PR (2008) Targeting of the F-actin-binding protein drebrin by the microtubule plus-tip protein EB3 is required for neuritogenesis. Nat Cell Biol 10:1181–1189. doi:10.1038/ncb1778
Godena VK, Brookes-Hocking N, Moller A, Shaw G, Oswald M, Sancho RM, Miller CC, Whitworth AJ, De Vos KJ (2014) Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat Commun 5:5245. doi:10.1038/ncomms6245
Gradishar WJ (2011) The place for eribulin in the treatment of metastatic breast cancer. Curr Oncol Rep 13:11–16. doi:10.1007/s11912-010-0145-9
Gu C, Zhou W, Puthenveedu MA, Xu M, Jan YN, Jan LY (2006) The microtubule plus-end tracking protein EB1 is required for Kv1 voltage-gated K+ channel axonal targeting. Neuron 52:803–816. doi:10.1016/j.neuron.2006.10.022
Heller BA, Ghidinelli M, Voelkl J, Einheber S, Smith R, Grund E, Morahan G, Chandler D, Kalaydjieva L, Giancotti F, King RH, Fejes-Toth AN, Fejes-Toth G, Feltri ML, Lang F, Salzer JL (2014) Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system. J Cell Biol 204:1219–1236. doi:10.1083/jcb.201307057
Janes K, Little JW, LI C, CBryant L, Chen C, Chen Z, Kamocki K, Doyle T, Snider A, Esposito E, Cuzzocrea S, Bieberich E, Obeid L, Petrache I, Nicol G, Neumann WL, Salvemini D (2014) The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1. J Biol Chem 289:21082–21097. doi:10.1074/jbc.M114.569574
Jaworski J, Kapitein LC, Gouveia SM, Dortland BR, Wulf PS, Grigoriev I, Camera P, Spangler SA, Di Stefano P, Demmers J, Krugers H, Defilippi P, Akhmanova A, Hoogenraad CC (2009) Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron 61:85–100. doi:10.1016/j.neuron.2008.11.013
Jiang K, Akhmanova A (2011) Microtubule tip-interacting proteins: a view from both ends. Curr Opin Cell Biol 23:94–101. doi:10.1016/j.ceb.2010.08.008
Jimenez-Mateos EM, Paglini G, Gonzalez-Billault C, Caceres A, Avila J (2005) End binding protein-1 (EB1) complements microtubule-associated protein-1B during axonogenesis. J Neurosci Res 80:350–359. doi:10.1002/jnr.20453
Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265. doi:10.1038/nrc1317
Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L (2005) The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 4:1086–1095. doi:10.1158/1535-7163.mct-04-0345
Kumar P, Wittmann T (2012) +TIPs: SxIPping along microtubule ends. Trends Cell Biol 22:418–428. doi:10.1016/j.tcb.2012.05.005
Lapointe NE, Morfini G, Brady ST, Feinstein SC, Wilson L, Jordan M (2013) Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: Implications for chemotherapy-induced peripheral neuropathy. Neurotoxicology. doi:10.1016/j.neuro.2013.05.008
Levy DB, Smith KJ, Beazer-Barclay Y, Hamilton SR, Vogelstein B, Kinzler KW (1994) Inactivation of both APC alleles in human and mouse tumors. Cancer Res 54:5953–5958
Matsuyama SS, Jarvik LF (1989) Hypothesis: microtubules, a key to Alzheimer disease. Proc Natl Acad Sci USA 86:8152–8156
Maurer SP, Fourniol FJ, Bohner G, Moores CA, Surrey T (2012) EBs recognize a nucleotide-dependent structural cap at growing microtubule ends. Cell 149:371–382. doi:10.1016/j.cell.2012.02.049
Morfini GA, Burns M, Binder LI, Kanaan NM, LaPointe N, Bosco DA, Brown RH Jr, Brown H, Tiwari A, Hayward L, Edgar J, Nave KA, Garberrn J, Atagi Y, Song Y, Pigino G, Brady ST (2009) Axonal transport defects in neurodegenerative diseases. J Neurosci 29:12776–12786. doi:10.1523/jneurosci.3463-09.2009
Moughamian AJ, Osborn GE, Lazarus JE, Maday S, Holzbaur EL (2013) Ordered recruitment of dynactin to the microtubule plus-end is required for efficient initiation of retrograde axonal transport. J Neurosci 33:13190–13203. doi:10.1523/jneurosci.0935-13.2013
Muguruma T, Sakura S, Kirihara Y, Saito Y (2006) Comparative somatic and visceral antinociception and neurotoxicity of intrathecal bupivacaine, levobupivacaine, and dextrobupivacaine in rats. Anesthesiology 104:1249–1256
Pachter JS, Yen TJ, Cleveland DW (1987) Autoregulation of tubulin expression is achieved through specific degradation of polysomal tubulin mRNAs. Cell 51:283–292
Peters CM, Jimenez-Andrade JM, Jonas BM, Sevcik MA, Koewler JN, Ghilardi JR, Wong GY, Mantyh PW (2007a) Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells. Exp Neurol 203:42–54. doi:10.1016/j.expneurol.2006.07.022
Peters CM, Jimenez-Andrade JM, Kuskowski MA, Ghilardi JR, Mantyh PW (2007b) An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. Brain Res 1168:46–59. doi:10.1016/j.brainres.2007.06.066
Piperno G, LeDizet M, Chang XJ (1987) Microtubules containing acetylated alpha-tubulin in mammalian cells in culture. J Cell Biol 104:289–302
Poruchynsky MS, Komlodi-Pasztor E, Trostel S, Wilkerson J, Regairaz M, Pommier Y, Zhang X, Kumar Maity T, Robey R, Burotto M, Sackett D, Guha U, Fojo AT (2015) Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins. Proc Natl Acad Sci USA 112:1571–1576. doi:10.1073/pnas.1416418112
Ranganathan S, Benetatos CA, Colarusso PJ, Dexter DW, Hudes GR (1998) Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells. Br J Cancer 77:562–566
Reed NA, Cai D, Blasius TL, Jih GT, Meyhofer E, Gaertig J, Verhey KJ (2006) Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol 16:2166–2172. doi:10.1016/j.cub.2006.09.014
Rotshenker S (2011) Wallerian degeneration: the innate-immune response to traumatic nerve injury. J Neuroinflammation 8:109. doi:10.1186/1742-2094-8-109
Schnaar RL, Gerardy-Schahn R, Hildebrandt H (2014) Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol Rev 94:461–518. doi:10.1152/physrev.00033.2013
Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA (2010) Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry 49:1331–1337. doi:10.1021/bi901810u
Steinberg M (2008) Ixabepilone: a novel microtubule inhibitor for the treatment of locally advanced or metastatic breast cancer. Clin Ther 30:1590–1617. doi:10.1016/j.clinthera.2008.09.015
Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (2001) In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 61:1013–1021
Vahdat LT, Garcia AA, Vogel C, Pellegrino C, Lindquist DL, Iannotti N, Gopalakrishna P, Sparano JsA (2013) Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropathy. Breast Cancer Res Treat 140:341–351. doi:10.1007/s10549-013-2574-2
Vitre B, Coquelle FM, Heichette C, Garnier C, Chretien D, Arnal I (2008) EB1 regulates microtubule dynamics and tubulin sheet closure in vitro. Nat Cell Biol 10:415–421. doi:10.1038/ncb1703
Walter WJ, Beranek V, Fischermeier E, Diez S (2012) Tubulin acetylation alone does not affect kinesin-1 velocity and run length in vitro. PLoS One 7:e42218. doi:10.1371/journal.pone.0042218
Windebank AJ, Grisold W (2008) Chemotherapy-induced neuropathy. J Peripher Nerv Syst 13:27–46. doi:10.1111/j.1529-8027.2008.00156.x
Wozniak KM, Nomoto K, Lapidus RG, Uw Y, Carozzi V, Cavaletti G, Hayakawa K, Hosokawa S, Towle MJ, Littlefield BA, Slusher BS (2011) Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice. Cancer Res 71:3952–3962. doi:10.1158/0008-5472.can-10-4184
Zhang T, Yao S, Wang P, Yin C, Xiao C, Qian M, Liu D, Zheng L, Meng W, Zhu H, Liu J, Xu H, Mo X (2011) ApoA-II directs morphogenetic movements of zebrafish embryo by preventing chromosome fusion during nuclear division in yolk syncytial layer. J Biol Chem 286:9514–9525. doi:10.1074/jbc.M110.134908
Acknowledgments
We are grateful to Nichole LaPointe, Jennifer Smith, Mary Raven, Mohamed Farah and Kenneth Rose for valuable discussions. We also acknowledge the use of instruments in the NRI-MCDB Microscopy Facility at UCSB (supported in part by the Office of The Director, National Institutes of Health of the NIH under Award # S10OD010610). This work was supported by grants from EISAI (to SCF, MAJ, BSS, and LW) and the NIH/NCI (R01CA161056) to,BSS.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Benbow, S.J., Cook, B.M., Reifert, J. et al. Effects of Paclitaxel and Eribulin in Mouse Sciatic Nerve: A Microtubule-Based Rationale for the Differential Induction of Chemotherapy-Induced Peripheral Neuropathy. Neurotox Res 29, 299–313 (2016). https://doi.org/10.1007/s12640-015-9580-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-015-9580-6