title: Vinorelbine and epirubicin share common features with polysialic acid and modulate neuronal and glial functions.
abstract: Polysialic acid (PSA), a large, linear glycan composed of 8 to over 100 α2,8-linked sialic acid residues, modulates development of the nervous system by enhancing cell migration, axon pathfinding, and synaptic targeting and by regulating differentiation of progenitor cells. PSA also functions in developing and adult immune systems and is a signature of many cancers. In this study we identified vinorelbine, a semi-synthetic third generation vinca alkaloid, and epirubicin, an anthracycline and 4'-epimer of doxorubicin, as PSA mimetics. Similar to PSA, vinorelbine and epirubicin bind to the PSA-specific monoclonal antibody 735 and compete with the bacterial analog of PSA, colominic acid in binding to monoclonal antibody 735. Vinorelbine and epirubicin stimulate neurite outgrowth of cerebellar neurons via the neural cell adhesion molecule, via myristoylated alanine-rich C kinase substrate, and via fibroblast growth factor receptor, signaling through Erk pathways. Furthermore, the two compounds enhance process formation of Schwann cells and migration of cerebellar neurons in culture, and reduce migration of astrocytes after injury. These novel results show that the structure and function of PSA can be mimicked by the small organic compounds vinorelbine and epirubicin, thus raising the possibility to re-target drugs used in treatment of cancers to nervous system repair. Vinorelbine and epirubicin, identified as PSA mimetics, enhance, like PSA, neuronal migration, neuritogenesis, and formation of Schwann cell processes, and reduce astrocytic migration. Ablating NCAM, inhibiting fibroblast growth factor (FGFR) receptor, or adding the effector domain of myristoylated alanine-rich C kinase substrate (MARCKS) minimize the vinorelbine and epirubicin effects, indicating that they are true PSA mimetics triggering PSA-mediated functions.
authors.affiliation: Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, D-20251 Hamburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Loers
authors.affiliation: Department of Biotechnology, Guru Nanak Dev University, GT Road, 143005 Amritsar, India.
authors.forename: Vedangana
authors.initials: V
authors.lastname: Saini
authors.affiliation: Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, D-20251 Hamburg, Germany.
authors.forename: Bibhudatta
authors.initials: B
authors.lastname: Mishra
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology ScreeningPort (Fraunhofer-IME SP), Schnackenburgalle114, D-22525 Hamburg, Germany.
authors.forename: Sheraz
authors.initials: S
authors.lastname: Gul
authors.affiliation: DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, MD 21702 (USA).
authors.forename: Sidhartha
authors.initials: S
authors.lastname: Chaudhury
authors.affiliation: DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, MD 21702 (USA).
authors.forename: Anders
authors.initials: A
authors.lastname: Wallqvist
authors.affiliation: Department of Biotechnology, Guru Nanak Dev University, GT Road, 143005 Amritsar, India.
authors.forename: Gurcharan
authors.initials: G
authors.lastname: Kaur
authors.affiliation: Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Falkenried 94, D-20251 Hamburg, Germany.|Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ 08854, USA.|Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou, Guangdong 515041, China.
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D015251:Epirubicin / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D017434:Protein Structure, Tertiary; D012794:Sialic Acids / Q000737:chemistry / Q000494:pharmacology*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D012794:Sialic Acids; C021319:polysialic acid; D015251:Epirubicin; D014747:Vinblastine; D000077235:Vinorelbine
keywords: epirubicin; migration; neural cell adhesion molecule; neurite outgrowth; polysialic acid; vinorelbine