title: Inhibition of the neuronal NFκB pathway attenuates bortezomib-induced neuropathy in a mouse model.
abstract: Bortezomib is a proteasome inhibitor with a remarkable antitumor activity, used in the clinic as first line treatment for multiple myeloma. One hallmark of bortezomib mechanism of action in neoplastic cells is the inhibition of nuclear factor kappa B (NFκB), a transcription factor involved in cell survival and proliferation. Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity that often requires adjustment of treatment and affects patient's prognosis and quality of life. Since disruption of NFκB pathway can also affect neuronal survival, we assessed the role of NFκB in bortezomib-induced neuropathy by using a transgenic mouse that selectively provides blockage of the NFκB pathway in neurons. Interestingly, we observed that animals with impaired NFκB activation developed significantly less severe neuropathy than wild type animals, with particular preservation of large myelinated fibers, thus suggesting that neuronal NFκB activation plays a positive role in bortezomib induced neuropathy and that bortezomib treatment might induce neuropathy by inhibiting NFκΒ in non-neuronal cell types or by targeting other signaling pathways. Therefore, inhibition of NFκB might be a promising strategy for the cotreatment of cancer and neuropathy.
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Alé
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain; Neuro-Oncology Unit, Hospital Universitari de Bellvitge-Institut Català d́Oncologia-IDIBELL, ĹHospitalet, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruna
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Aina
authors.initials: A
authors.lastname: Calls
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Karamita
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Sylva
authors.initials: S
authors.lastname: Haralambous
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Lesley
authors.initials: L
authors.lastname: Probert
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Navarro
authors.affiliation: Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain. Electronic address: esther.udina@uab.cat.
authors.forename: Esther
authors.initials: E
authors.lastname: Udina
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000069286:Bortezomib; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009431:Neural Conduction / Q000187:drug effects / Q000235:genetics; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D010455:Peptides / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D016900:Neurofilament Proteins; D010455:Peptides; C118258:SN50 peptide; C044882:neurofilament protein L; D000069286:Bortezomib; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse
keywords: Bortezomib; Neurotoxicity; Nuclear factor kappa b; Peripheral neuropathy; Proteasome inhibition; Sensory neurons