Ethoxyquin prevents chemotherapy-induced neurotoxicity via Hsp90 modulation

Jing Zhu, Weiran Chen, Ruifa Mi, Chunhua Zhou, Nicole Reed, Ahmet Hoke

Research output: Contribution to journalArticle

Abstract

Objective Peripheral neurotoxicity is a major dose-limiting side effect of many chemotherapeutic drugs. Currently there are no effective disease-modifying therapies for chemotherapy-induced peripheral neuropathies, but these side effects of chemotherapy are potentially ideal targets for development of neuroprotective therapies, because candidate drugs can be co- or preadministered before the injury to peripheral axons takes place. Methods We used a phenotypic drug screening approach to identify ethoxyquin as a potential neuroprotective drug and carried out additional biochemical experiments to identify its mechanism of action. Results We validated the screening results with ethoxyquin and its derivatives and showed that they prevented paclitaxel-induced peripheral neuropathy without blocking paclitaxel's ability to kill tumor cells. Furthermore, we demonstrated that ethoxyquin acts by modulating the chaperone activity of heat shock protein 90 (Hsp90) and blocking the binding of 2 of its client proteins, ataxin-2 and Sf3b2. Ethoxyquin-induced reduction in levels of both of these proteins resulted in prevention of axonal degeneration caused by paclitaxel. Interpretation Ethoxyquin and its novel derivatives as well as other classes of small molecules that act as Hsp90 modulators may offer a new opportunity for development of drugs to prevent chemotherapy-induced axonal degeneration. Ann Neurol 2013;74:893-904

Original languageEnglish (US)
Pages (from-to)893-904
Number of pages12
JournalAnnals of Neurology
Volume74
Issue number6
DOIs
StatePublished - Dec 2013

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Ethoxyquin
HSP90 Heat-Shock Proteins
Drug Therapy
Paclitaxel
Peripheral Nervous System Diseases
Pharmaceutical Preparations
Preclinical Drug Evaluations
Neuroprotective Agents
Axons
Wounds and Injuries
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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Ethoxyquin prevents chemotherapy-induced neurotoxicity via Hsp90 modulation. / Zhu, Jing; Chen, Weiran; Mi, Ruifa; Zhou, Chunhua; Reed, Nicole; Hoke, Ahmet.

In: Annals of Neurology, Vol. 74, No. 6, 12.2013, p. 893-904.

Research output: Contribution to journalArticle

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AU - Mi, Ruifa

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AU - Reed, Nicole

AU - Hoke, Ahmet

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AB - Objective Peripheral neurotoxicity is a major dose-limiting side effect of many chemotherapeutic drugs. Currently there are no effective disease-modifying therapies for chemotherapy-induced peripheral neuropathies, but these side effects of chemotherapy are potentially ideal targets for development of neuroprotective therapies, because candidate drugs can be co- or preadministered before the injury to peripheral axons takes place. Methods We used a phenotypic drug screening approach to identify ethoxyquin as a potential neuroprotective drug and carried out additional biochemical experiments to identify its mechanism of action. Results We validated the screening results with ethoxyquin and its derivatives and showed that they prevented paclitaxel-induced peripheral neuropathy without blocking paclitaxel's ability to kill tumor cells. Furthermore, we demonstrated that ethoxyquin acts by modulating the chaperone activity of heat shock protein 90 (Hsp90) and blocking the binding of 2 of its client proteins, ataxin-2 and Sf3b2. Ethoxyquin-induced reduction in levels of both of these proteins resulted in prevention of axonal degeneration caused by paclitaxel. Interpretation Ethoxyquin and its novel derivatives as well as other classes of small molecules that act as Hsp90 modulators may offer a new opportunity for development of drugs to prevent chemotherapy-induced axonal degeneration. Ann Neurol 2013;74:893-904

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