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.
Highlights
Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo
When we repeated the experiments using primary rat dorsal root ganglion (DRG) neuron-Schwann cell co-cultures, we found that ethoxyquin provided neuroprotection with a best efficacy range from 30 to 300 nM (Fig. 1C)
When we examined the levels of SF3B2 and ataxin-2 in DRGs isolated from mice treated with cisplatin and/or EQ, we found that cisplatin treatment alone resulted in lower expression of SF3B2 but higher expression of ataxin-2 levels similar to what we observed in vitro
Summary
Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. 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. We identified EQ as a neuroprotective compound against neurotoxicity of paclitaxel, another commonly used chemotherapy drug[6] In this previous study, identification of EQ as a neuroprotective compound was achieved through a phenotypic screen and followed by a mechanistic study, which showed that EQ acts as an inhibitor of chaperone activity of Hsp[90] reducing levels of two of its client proteins SF3B2 (a component of spliceosome complex) and ataxin-26. Since neurotoxicity of cisplatin is considered to be mediated through formation of DNA-platinum adducts[8,9], we examined the effect of EQ on DNA-platinum adduct formation with a new assay we developed
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