title: Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity.
abstract: Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin's ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols.
authors.affiliation: Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Experimental Neurology Unit, School of Medicine and Surgery, University of Milan-Bicocca, Monza MB, Italy.|Young Against Pain Group, Italy.
authors.forename: Valentina Alda
authors.initials: VA
authors.lastname: Carozzi
authors.affiliation: Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Reed
authors.affiliation: Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Ruifa
authors.initials: R
authors.lastname: Mi
authors.affiliation: Experimental Neurology Unit, School of Medicine and Surgery, University of Milan-Bicocca, Monza MB, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Marmiroli
authors.affiliation: Experimental Neurology Unit, School of Medicine and Surgery, University of Milan-Bicocca, Monza MB, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.affiliation: Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Hoke
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D000067698:Ataxin-2 / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D005015:Ethoxyquin / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D000072260:RNA Splicing Factors / Q000378:metabolism; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000067698:Ataxin-2; D018841:HSP90 Heat-Shock Proteins; D018696:Neuroprotective Agents; D000072260:RNA Splicing Factors; D005015:Ethoxyquin; D002945:Cisplatin