Vincristine and bortezomib cause axon outgrowth and behavioral defects in larval zebrafish
Tahsin M. Khan
Department of Biology, Williams College, Williamstown, MA, USA
Search for more papers by this authorNathan Benaich
Department of Biology, Williams College, Williamstown, MA, USA
Search for more papers by this authorClare F. Malone
Department of Biology, Williams College, Williamstown, MA, USA
Search for more papers by this authorRebecca L. Bernardos
Department of Biology, Smith College, Northampton, MA, USA
Search for more papers by this authorAmy R. Russell
Department of Biology, Williams College, Williamstown, MA, USA
Search for more papers by this authorGerald B. Downes
Department of Biology, University of Massachusetts, Amherst, MA, USA
Search for more papers by this authorMichael J. Barresi
Department of Biology, Smith College, Northampton, MA, USA
Search for more papers by this authorCorresponding Author
Lara D. Hutson
Department of Biology, Williams College, Williamstown, MA, USA
Program in Neuroscience, Williams College, Williamstown, MA, USA
Lara D. Hutson, Department of Biological Sciences, 109 Cooke Hall, University at Buffalo, State University of New York, Buffalo, NY 14260, USA. Tel: +1 716-645-4958; Fax: +1 716-645-2975; E-mail: [email protected]Search for more papers by this authorTahsin M. Khan
Department of Biology, Williams College, Williamstown, MA, USA
Search for more papers by this authorNathan Benaich
Department of Biology, Williams College, Williamstown, MA, USA
Search for more papers by this authorClare F. Malone
Department of Biology, Williams College, Williamstown, MA, USA
Search for more papers by this authorRebecca L. Bernardos
Department of Biology, Smith College, Northampton, MA, USA
Search for more papers by this authorAmy R. Russell
Department of Biology, Williams College, Williamstown, MA, USA
Search for more papers by this authorGerald B. Downes
Department of Biology, University of Massachusetts, Amherst, MA, USA
Search for more papers by this authorMichael J. Barresi
Department of Biology, Smith College, Northampton, MA, USA
Search for more papers by this authorCorresponding Author
Lara D. Hutson
Department of Biology, Williams College, Williamstown, MA, USA
Program in Neuroscience, Williams College, Williamstown, MA, USA
Lara D. Hutson, Department of Biological Sciences, 109 Cooke Hall, University at Buffalo, State University of New York, Buffalo, NY 14260, USA. Tel: +1 716-645-4958; Fax: +1 716-645-2975; E-mail: [email protected]Search for more papers by this authorAbstract
Peripheral neuropathy is a common side effect of a number of pharmaceutical compounds, including several chemotherapy drugs. Among these are vincristine sulfate, a mitotic inhibitor used to treat a variety of leukemias, lymphomas, and other cancers, and bortezomib, a 26S proteasome inhibitor used primarily to treat relapsed multiple myeloma and mantle cell lymphoma. To gain insight into the mechanisms by which these compounds act, we tested their effects in zebrafish. Vincristine or bortezomib given during late embryonic development caused significant defects at both behavioral and cellular levels. Intriguingly, the effects of the two drugs appear to be distinct. Vincristine causes uncoordinated swimming behavior, which is coupled with a reduction in the density of sensory innervation and overall size of motor axon arbors. Bortezomib, in contrast, increases the duration and amplitude of muscle contractions associated with escape swimming, which is coupled with a preferential reduction in fine processes and branches of sensory and motor axons. These results demonstrate that zebrafish is a convenient in vivo assay system for screening potential pharmaceutical compounds for neurotoxic side effects, and they provide an important step toward understanding how vincristine and bortezomib cause peripheral neuropathy.
Supporting Information
Supporting Information
Additional Supporting Information may be found in the online version of this article:
Movie S1 Normal zebrafish larval escape response. High-speed video recording of a typical control larva at approximately 50 hours post-fertilization exhibiting escape response to touch. Larva responds to touch with one or two high-amplitude body bends (C-bends), followed by low-amplitude left–right alternating contractions that propel the larva away from the site of stimulus. Video recorded at 500 frames per second (fps) and displayed at 30 fps, or approximately ×17 slower than real time.
Movie S2 Escape response of vincristine-treated larva. High-speed video recording of a typical larva treated with 50 µM vincristine. Larva responds to touch with an initial C-bend, but this is followed by irregular, uncoordinated contractions. Video recorded at 500 frames per second (fps) and displayed at 30 fps, or approximately ×17 slower than real time.
Movie S3 Escape response of bortezomib-treated larva. High-speed video recording of a typical larva treated with 25 µM bortezomib. The larva responds to touch by performing continuous C-bend-like contractions. Video recorded at 500 frames per second (fps) and displayed at 30 fps, or approximately ×17 slower than real time.
Figure S1 Variations in sensory axon density. Lateral views illustrating the range of sensory axon phenotypes within each treatment group. “High density” and “low density” refer to samples within each treatment group with the highest and lowest innervation density, respectively. “Reduced lateral line” shows an example within treatment group with reduced or absent lateral line. Note that overall density of sensory axons is often normal in larvae lacking the lateral line (E, H, K). VCR, vincristine. Bort, bortezomib.
| Filename | Description |
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| JNS5_371_sm_movie1.mov1.6 MB | Supporting info item |
| JNS5_371_sm_movie2.mov4.2 MB | Supporting info item |
| JNS5_371_sm_movie3.mov14.2 MB | Supporting info item |
| JNS5_371_sm_f1.eps10.3 MB | Supporting info item |
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References
- Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, Muchamuel T, Bennett MK, Driessen C, Ball AJ, Kirk CJ (2011). Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res 17: 2734–2743.
- Argyriou AA, Iconomou G, Kalofonos HP (2008). Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood 112: 1593–1599.
- Berger P, Young P, Suter U (2002). Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics 4: 1–15.
- Berman J, Hsu K, Look AT (2003). Zebrafish as a model organism for blood diseases. Br J Haematol 123: 568–576.
- Boon KL, Xiao S, McWhorter ML, Donn T, Wolf-Saxon E, Bohnsack MT, Moens CB, Beattie CE (2009). Zebrafish survival motor neuron mutants exhibit presynaptic neuromuscular junction defects. Hum Mol Genet 18: 3615–3625.
- Bradley WG, Lassman LP, Pearce GW, Walton JN (1970). The neuromyopathy of vincristine in man. Clinical, electrophysiological and pathological studies. J Neurol Sci 10: 107–131.
- Brustein E, Saint-Amant L, Buss RR, Chong M, McDearmid JR, Drapeau P (2003). Steps during the development of the zebrafish locomotor network. J Physiol Paris 97: 77–86.
- Burgess HA, Granato M (2007). Sensorimotor gating in larval zebrafish. J Neurosci 27: 4984–4994.
- Buss RR, Bourque CW, Drapeau P (2003). Membrane properties related to the firing behavior of zebrafish motoneurons. J Neurophysiol 89: 657–664.
- Cavaletti G, Nobile-Orazio E (2007). Bortezomib-induced peripheral neurotoxicity: still far from a painless gain. Haematologica 92: 1308–1310.
- Chaudhry V, Cornblath DR, Polydefkis M, Ferguson A, Borrello I (2008). Characteristics of bortezomib- and thalidomide-induced peripheral neuropathy. J Peripher Nerv Syst 13: 275–282.
- Chauhan D, Hideshima T, Anderson KC (2008). Targeting proteasomes as therapy in multiple myeloma. Adv Exp Med Biol 615: 251–260.
- Choi TY, Kim JH, Ko DH, Kim CH, Hwang JS, Ahn S, Kim SY, Kim CD, Lee JH, Yoon TJ (2007). Zebrafish as a new model for phenotype-based screening of melanogenic regulatory compounds. Pigment Cell Res 20: 120–127.
- Clarke JD, Hayes BP, Hunt SP, Roberts A (1984). Sensory physiology, anatomy and immunohistochemistry of Rohon-Beard neurones in embryos of Xenopus laevis. J Physiol 348: 511–525.
- Delforge M, Blade J, Dimopoulos MA, Facon T, Kropff M, Ludwig H, Palumbo A, Van Damme P, San-Miguel JF, Sonneveld P (2010). Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 11: 1086–1095.
- Drapeau P, Saint-Amant L, Buss RR, Chong M, McDearmid JR, Brustein E (2002). Development of the locomotor network in zebrafish. Prog Neurobiol 68: 85–111.
- Dyck PJ, Thomas D (2005). Peripheral Neuropathy, 4th Edn. Saunders, Philadelphia.
- Feitsma H, Cuppen E (2008). Zebrafish as a cancer model. Mol Cancer Res 6: 685–694.
- Flanagan-Steet H, Fox MA, Meyer D, Sanes JR (2005). Neuromuscular synapses can form in vivo by incorporation of initially aneural postsynaptic specializations. Development 132: 4471–4481.
- Frazer JK, Meeker ND, Rudner L, Bradley DF, Smith AC, Demarest B, Joshi D, Locke EE, Hutchinson SA, Tripp S, Perkins SL, Trede NS (2009). Heritable T-cell malignancy models established in a zebrafish phenotypic screen. Leukemia 23: 1825–1835.
- Gigant B, Wang C, Ravelli RB, Roussi F, Steinmetz MO, Curmi PA, Sobel A, Knossow M (2005). Structural basis for the regulation of tubulin by vinblastine. Nature 435: 519–522.
- Granato M, van Eeden FJ, Schach U, Trowe T, Brand M, Furutani-Seiki M, Haffter P, Hammerschmidt M, Heisenberg CP, Jiang YJ, Kane DA, Kelsh RN, Mullins MC, Odenthal J, Nusslein-Volhard C (1996). Genes controlling and mediating locomotion behavior of the zebrafish embryo and larva. Development 123: 399–413.
- Grider MH, Chen Q, Shine HD (2006). Semi-automated quantification of axonal densities in labeled CNS tissue. J Neurosci Methods 155: 172–179.
- Hallare A, Nagel K, Kohler HR, Triebskorn R (2006). Comparative embryotoxicity and proteotoxicity of three carrier solvents to zebrafish (Danio rerio) embryos. Ecotoxicol Environ Saf 63: 378–388.
- Haskins KM, Donoso JA, Himes RH (1981). Spirals and paracrystals induced by Vinca alkaloids: evidence that microtubule-associated proteins act as polycations. J Cell Sci 47: 237–247.
- Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J, Anderson KC (2002). NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277: 16639–16647.
- Hilkens PH, ven den Bent MJ (1997). Chemotherapy-induced peripheral neuropathy. J Peripher Nerv Syst 2: 350–361.
- Himes RH, Kersey RN, Heller-Bettinger I, Samson FE (1976). Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on microtubules in vitro. Cancer Res 36: 3798–3802.
- Hsu CH, Wen ZH, Lin CS, Chakraborty C (2007). The zebrafish model: use in studying cellular mechanisms for a spectrum of clinical disease entities. Curr Neurovasc Res 4: 111–120.
- Hutson LD, Chien CB (2002). Wiring the zebrafish: axon guidance and synaptogenesis. Curr Opin Neurobiol 12: 87–92.
- Kabashi E, Brustein E, Champagne N, Drapeau P (2011). Zebrafish models for the functional genomics of neurogenetic disorders. Biochim Biophys Acta 1812: 335–345.
- Kane RC, Dagher R, Farrell A, Ko CW, Sridhara R, Justice R, Pazdur R (2007). Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 13: 5291–5294.
- Kari G, Rodeck U, Dicker AP (2007). Zebrafish: an emerging model system for human disease and drug discovery. Clin Pharmacol Ther 82: 70–80.
- Kaufman CK, White RM, Zon L (2009). Chemical genetic screening in the zebrafish embryo. Nat Protoc 4: 1422–1432.
- Kempin S, Lee BJ III, Thaler HT, Koziner B, Hecht S, Gee T, Arlin Z, Little C, Straus D, Reich L, Phillips E, Al-Mondhiry H, Dowling M, Mayer K, Clarkson B (1982). Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristine, BCNU, cyclophosphamide, melphalan, and prednisone). Blood 60: 1110–1121.
- Khan ML, Stewart AK (2011). Carfilzomib: a novel second-generation proteasome inhibitor. Future Oncol 7: 607–612.
- Khersonsky SM, Jung DW, Kang TW, Walsh DP, Moon HS, Jo H, Jacobson EM, Shetty V, Neubert TA, Chang YT (2003). Facilitated forward chemical genetics using a tagged triazine library and zebrafish embryo screening. J Am Chem Soc 125: 11804–11805.
- Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF (1995). Stages of embryonic development of the zebrafish. Dev Dyn 203: 253–310.
- Langenau DM, Zon LI (2005). The zebrafish: a new model of T-cell and thymic development. Nat Rev Immunol 5: 307–317.
- Lefebvre JL, Ono F, Puglielli C, Seidner G, Franzini-Armstrong C, Brehm P, Granato M (2004). Increased neuromuscular activity causes axonal defects and muscular degeneration. Development 131: 2605–2618.
- Legha SS (1986). Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol 1: 421–427.
- Leonard JP, Furman RR, Coleman M (2006). Proteasome inhibition with bortezomib: a new therapeutic strategy for non-Hodgkin's lymphoma. Int J Cancer 119: 971–979.
- Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ (2000). Proteasome inhibition measurements: clinical application. Clin Chem 46: 673–683.
- Loeffler-Ragg J, Mueller D, Gamerith G, Auer T, Skvortsov S, Sarg B, Skvortsova I, Schmitz KJ, Martin HJ, Krugmann J, Alakus H, Maser E, Menzel J, Hilbe W, Lindner H, Schmid KW, Zwierzina H (2009). Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib. Mol Cancer Ther 8: 1995–2006.
- MacDonald BK, Cockerell OC, Sander JW, Shorvon SD (2000). The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 123: 665–676.
- Marques IJ, Weiss FU, Vlecken DH, Nitsche C, Bakkers J, Lagendijk AK, Partecke LI, Heidecke CD, Lerch MM, Bagowski CP (2009). Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model. BMC Cancer 9: 128.
- McKeown KA, Moreno R, Hall VL, Ribera AB, Downes GB (2012). Disruption of Eaat2b, a glutamate transporter, results in abnormal motor behaviors in developing zebrafish. Dev Biol 362: 162–171.
- McLeod JG, Penny R (1969). Vincristine neuropathy: an electrophysiological and histological study. J Neurol Neurosurg Psychiatry 32: 297–304.
- Mizgirev IV, Revskoy S (2010). A new zebrafish model for experimental leukemia therapy. Cancer Biol Ther 9: 895–902.
- Montagut C, Rovira A, Mellado B, Gascon P, Ross JS, Albanell J (2005). Preclinical and clinical development of the proteasome inhibitor bortezomib in cancer treatment. Drugs Today (Barc) 41: 299–315.
- Murphey RD, Stern HM, Straub CT, Zon LI (2006). A chemical genetic screen for cell cycle inhibitors in zebrafish embryos. Chem Biol Drug Des 68: 213–219.
- Myers PZ (1985). Spinal motoneurons of the larval zebrafish. J Comp Neurol 236: 555–561.
- Myers PZ, Eisen JS, Westerfield M (1986). Development and axonal outgrowth of identified motoneurons in the zebrafish. J Neurosci 6: 2278–2289.
- Oprea GE, Krober S, McWhorter ML, Rossoll W, Muller S, Krawczak M, Bassell GJ, Beattie CE, Wirth B (2008). Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 320: 524–527.
- Paulus JD, Willer GB, Willer JR, Gregg RG, Halloran MC (2009). Muscle contractions guide rohon-beard peripheral sensory axons. J Neurosci 29: 13190–13201.
- Peterson RT, Shaw SY, Peterson TA, Milan DJ, Zhong TP, Schreiber SL, MacRae CA, Fishman MC (2004). Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat Biotechnol 22: 595–599.
- Ribera AB, Nusslein-Volhard C (1998). Zebrafish touch-insensitive mutants reveal an essential role for the developmental regulation of sodium current. J Neurosci 18: 9181–9191.
- Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC (2003). A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348: 2609–2617.
- Rihel J, Prober DA, Arvanites A, Lam K, Zimmerman S, Jang S, Haggarty SJ, Kokel D, Rubin LL, Peterson RT, Schier AF (2010). Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation. Science 327: 348–351.
- Rosenthal S, Kaufman S (1974). Vincristine neurotoxicity. Ann Intern Med 80: 733–737.
- Sagasti A, Guido MR, Raible DW, Schier AF (2005). Repulsive interactions shape the morphologies and functional arrangement of zebrafish peripheral sensory arbors. Curr Biol 15: 804–814.
-
Saint-Amant L,
Drapeau P (1998). Time course of the development of motor behaviors in the zebrafish embryo.
J Neurobiol
37: 622–632.
10.1002/(SICI)1097-4695(199812)37:4<622::AID-NEU10>3.0.CO;2-S CAS PubMed Web of Science® Google Scholar
- San Miguel J, Blade J, Boccadoro M, Cavenagh J, Glasmacher A, Jagannath S, Lonial S, Orlowski RZ, Sonneveld P, Ludwig H (2006). A practical update on the use of bortezomib in the management of multiple myeloma. Oncologist 11: 51–61.
- Silva A, Wang Q, Wang M, Ravula SK, Glass JD (2006). Evidence for direct axonal toxicity in vincristine neuropathy. J Peripher Nerv Syst 11: 211–216.
- Smith AC, Raimondi AR, Salthouse CD, Ignatius MS, Blackburn JS, Mizgirev IV, Storer NY, de Jong JL, Chen AT, Zhou Y, Revskoy S, Zon LI, Langenau DM (2010). High-throughput cell transplantation establishes that tumor-initiating cells are abundant in zebrafish T-cell acute lymphoblastic leukemia. Blood 115: 3296–3303.
- Stoletov K, Klemke R (2008). Catch of the day: zebrafish as a human cancer model. Oncogene 27: 4509–4520.
- Taylor MR, Hurley JB, Van Epps HA, Brockerhoff SE (2004). A zebrafish model for pyruvate dehydrogenase deficiency: rescue of neurological dysfunction and embryonic lethality using a ketogenic diet. Proc Natl Acad Sci U S A 101: 4584–4589.
- Ton C, Parng C (2005). The use of zebrafish for assessing ototoxic and otoprotective agents. Hear Res 208: 79–88.
- Topp KS, Tanner KD, Levine JD (2000). Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat. J Comp Neurol 424: 563–576.
- Ubbels GA, Hara K, Koster CH, Kirschner MW (1983). Evidence for a functional role of the cytoskeleton in determination of the dorsoventral axis in Xenopus laevis eggs. J Embryol Exp Morphol 77: 15–37.
- Windebank AJ, Grisold W (2008). Chemotherapy-induced neuropathy. J Peripher Nerv Syst 13: 27–46.
- Yee NS, Pack M (2005). Zebrafish as a model for pancreatic cancer research. Methods Mol Med 103: 273–298.
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