Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity

Sci Rep. 2016 Jun 28;6:28861. doi: 10.1038/srep28861.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / toxicity
  • Ataxin-2 / metabolism
  • Axons / drug effects
  • Axons / physiology
  • Cell Line
  • Cells, Cultured
  • Cisplatin / toxicity*
  • Ethoxyquin / pharmacology*
  • Female
  • Ganglia, Spinal / cytology
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Mice, Nude
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotection / drug effects*
  • Neuroprotective Agents / pharmacology
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / metabolism
  • Peripheral Nervous System Diseases / prevention & control
  • RNA Splicing Factors / metabolism
  • Rats
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Ataxin-2
  • HSP90 Heat-Shock Proteins
  • Neuroprotective Agents
  • RNA Splicing Factors
  • Ethoxyquin
  • Cisplatin