title: Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response.
abstract: Neuropathic pain is a limiting factor of platinum-based chemotherapies. We sought to investigate the neuroprotective potential of niclosamide in peripheral neuropathies induced by oxaliplatin. Normal neuron-like and cancer cells were treated in vitro with oxaliplatin associated or not with an inhibitor of STAT3 and NF-κB, niclosamide. Cell production of reactive oxygen species and viability were measured by 2',7'-dichlorodihydrofluorescein diacetate and crystal violet. Peripheral neuropathies were induced in mice by oxaliplatin with or without niclosamide. Neurologic functions were assessed by behavioral and electrophysiologic tests, intraepidermal innervation, and myelination by immunohistochemical, histologic, and morphologic studies using confocal microscopy. Efficacy on tumor growth was assessed in mice grafted with CT26 colon cancer cells. In neuron-like cells, niclosamide downregulated the production of oxaliplatin-mediated H2O2, thereby preventing cell death. In colon cancer cells, niclosamide enhanced oxaliplatin-mediated cell death through increased H2O2production. These observations were explained by inherent lower basal levels of GSH in cancer cells compared with normal and neuron-like cells. In neuropathic mice, niclosamide prevented tactile hypoesthesia and thermal hyperalgesia and abrogated membrane hyperexcitability. The teniacide also prevented intraepidermal nerve fiber density reduction and demyelination in oxaliplatin mice in this mixed form of peripheral neuropathy. Niclosamide prevents oxaliplatin-induced increased levels of IL6, TNFα, and advanced oxidized protein products. Niclosamide displayed antitumor effects while not abrogating oxaliplatin efficacy. These results indicate that niclosamide exerts its neuroprotection both in vitro and in vivo by limiting oxaliplatin-induced oxidative stress and neuroinflammation. These findings identify niclosamide as a promising therapeutic adjunct to oxaliplatin chemotherapy. Mol Cancer Ther; 16(2); 300-11. ©2016 AACR.
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cerles
authors.affiliation: Institut des Neurosciences Paris-Saclay, UMR 9197, CNRS, Gif-sur-Yvette, France.|Molecular Engineering of Proteins Unit (DRF/iBiTec-S/SIMOPRO), CEA of Saclay, Gif-sur-Yvette, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Benoit
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chouzenoux
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.|Department of Immunology, Cochin Teaching Hospital, AP-HP, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Morin
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.|Department of Gastroenterology, Cochin Teaching Hospital, Paris Descartes University, Paris, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Guillaumot
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.|Department of Gastroenterology, Cochin Teaching Hospital, Paris Descartes University, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Coriat
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.|Department of Immunology, Cochin Teaching Hospital, AP-HP, Paris, France.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Loussier
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.|Department of Gynecology Obstetrics II and Reproductive Medicine, Cochin Teaching Hospital, Paris, France.
authors.forename: Pietro
authors.initials: P
authors.lastname: Santulli
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.|Department of Gynecology Obstetrics II and Reproductive Medicine, Cochin Teaching Hospital, Paris, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Marcellin
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.
authors.forename: Nathaniel E B
authors.initials: NE
authors.lastname: Saidu
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.|Department of Immunology, Cochin Teaching Hospital, AP-HP, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France. frederic.batteux@cch.aphp.fr.|Department of Immunology, Cochin Teaching Hospital, AP-HP, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.affiliation: Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009534:Niclosamide / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000633:toxicity; D000077150:Oxaliplatin; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects; D014110:Touch / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018696:Neuroprotective Agents; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin; D009534:Niclosamide; D005978:Glutathione