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FDA-Approved Tedizolid Phosphate Prevents Cisplatin-Induced Hearing Loss Without Decreasing Its Anti-tumor Effect

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Abstract

Purpose

Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs.

Methods

Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin.

Results

Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs.

Conclusion

Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.

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Availability of Data and Material

The data sets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

Ted:

Tedizolid Phosphate

FDA:

Food and Drug Administration

HCs:

Hair cells

OHCs:

Outer hair cells

ROS:

Reactive oxygen species

CIHL:

Cisplatin-induced hearing loss

MET:

Mechanoelectrical transducer

BBB:

Blood-brain barrier

CCK8:

Cell Counting Kit-8

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Funding

This research was supported by grants from the National Natural Science Foundation of China (no. 82271175, 82192863, 82171162, 81900937, 82201296, 82201294, 82001204), the Natural Science Foundation from Shandong Province (no. ZR2021QH269 and ZR2022MC216), the Natural Science Foundation from Henan Province (no. 232300420259), and the Scientific and Technological Innovation Plan Project of Medical System Staff of Shandong Province (no. SDYWZGKCJHLH2023096) and Shandong Province medical health science and technology project (no. 202307010965).

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Author notes

  1. Zhiwei Yao, Yu Xiao and Wen Li contributed equallyto this work.

Authors and Affiliations

  1. Department of Pediatric Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, No. 154 Anshan Road, Heping District, Tianjin, 300052, China

    Zhiwei Yao, Lushun Ma, Song Wang, Xiaoxu Zhao, Yuan Zhang & Daqing Sun

  2. Medical Science and Technology Innovation Center, Shandong First Medical University, Jinan, 250117, China

    Zhiwei Yao, Yu Xiao, Wen Li, Hailong Tu, Ziyi Liu, Lushun Ma, Miao Chang & Xiaolong Fu

  3. School of Life Science, Shandong University, Qingdao, 266237, China

    Yu Xiao & Siwei Guo

  4. Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, 250000, China

    Shuhui Kong, Ruifeng Qiao & Lei Xu

Authors
  1. Zhiwei Yao
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  2. Yu Xiao
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  3. Wen Li
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  13. Yuan Zhang
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  15. Daqing Sun
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  16. Xiaolong Fu
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Contributions

Xiaolong Fu, Daqing Sun, Lei Xu, and Wen Li designed the research. Zhiwei Yao, Yu Xiao, Wen Li, Hailong Tu, Shuhui Kong, Ruifeng Qiao, Lushun Ma, and Siwei Guo conducted experiments and analyzed data. Song Wang and Miao Chang contributed to writing the manuscript. Zhiwei Yao, Xiaolong Fu, Wen Li, and Daqing Sun wrote the manuscript and interpreted the data. Xiaoxu Zhao and Yuan Zhang revised the article.

Corresponding authors

Correspondence to Wen Li, Lei Xu, Daqing Sun or Xiaolong Fu.

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All experimental procedures involving animals were approved by the Tianjin Medical University General Hospital Experimental Animal Administrative Committee and were in accordance with animal welfare principles.

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Yao, Z., Xiao, Y., Li, W. et al. FDA-Approved Tedizolid Phosphate Prevents Cisplatin-Induced Hearing Loss Without Decreasing Its Anti-tumor Effect. JARO (2024). https://doi.org/10.1007/s10162-024-00945-2

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  • DOI: https://doi.org/10.1007/s10162-024-00945-2

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