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EPO Attenuates Cisplatin-Induced Ototoxicity in HEI-OC1 Auditory Cell Via the Nrf2-ARE Signaling Pathway

Sun, Changling*; Yao, Ying; Zhang, Chenwei; Tong, Desheng§; Xie, Bingxue||,†

doi: 10.1097/MAO.0000000000002288
BASIC SCIENCE
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Hypothesis: Erythropoietin (EPO) may protect against cisplatin-induced ototoxicity in HEI-OC1 auditory cell line.

Background: Cisplatin is a widely used chemotherapeutic agent for the treatment of human solid tumors limited by its high incidence of ototoxicity. Currently, there are no clinical solutions. EPO has been reported to have varieties of neuroprotective effects. However, nothing has yet been reported on its potential to prevent cisplatin ototoxicity in auditory cell lines and possible mechanism.

Methods: HEI-OC1 cells were incubated with 20 μM of cisplatin for 48 hours, after application of various concentrations of EPO for 24 hours. Cell viability was determined using a Cell Counting Kit-8 (CCK-8) assay. Oxidative stress and apoptosis were assessed by reactive oxygen species (ROS) measurement, Hoechst 33258 staining, and flow cytometry (FC). Western blot (WB) and real-time quantitative PCR were used to detect nuclear factor erythroid 2-related factor 2 (Nrf2), NAD (P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), Bcl-2 and Bcl-xl protein and mRNA expression levels.

Results: Pretreatment with 40, 8, and 1.6 ng/mL of EPO for 24 hours before application of 20 μM cisplatin increased cell viability in HEI-OC1 cells. Besides, EPO enhanced the expression of Nrf-2, HO-1, and NQO1. Moreover, upregulation of the expression of Bcl-2 and bcl-xl were also observed.

Conclusion: Our results suggest that EPO alleviates cisplatin-induced ototoxicity by activating Nrf2-ARE signaling.

*Department of Otolaryngology–Head and Neck Surgery, Affiliated Hospital of Jiangnan University

Department of Pharmacy, Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University

Wuxi Hasen Biomedical Technology Co., LTD

§Jiangsu Institute of Parasitic Diseases

||Affiliated Hospital of Jiangnan University, Wuxi, China

Address correspondence and reprint requests to Bingxue Xie, M.S., Hui He Rd 200, Wuxi 214062, China; E-mail: xiebingxue_ok@126.com; Desheng Tong, B.S., Meiyuan Yangxiang 117, Wuxi, China; E-mail: tds419@163.com

C.S. and Y.Y. have contributed equally to this article.

This work was supported by the Natural Science Foundation of Jiangsu Province (BK20160195); Wuxi Young Medical Talents (QNRC054).

The authors declare no conflicts of interest.

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