Drug screening identifies aldose reductase as a novel target for treating cisplatin-induced hearing loss
Copyright © 2023 Elsevier Inc. All rights reserved..
Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss.
| Errataetall: |
ErratumIn: Free Radic Biol Med. 2024 Feb 17;214:114. - PMID 38368776 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:210 |
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| Enthalten in: |
Free radical biology & medicine - 210(2024) vom: 19. Jan., Seite 430-447 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liao, Yaqi [VerfasserIn] |
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| Links: |
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| Themen: |
Aldehyde Reductase |
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| Anmerkungen: |
Date Completed 22.12.2023 Date Revised 19.02.2024 published: Print-Electronic ErratumIn: Free Radic Biol Med. 2024 Feb 17;214:114. - PMID 38368776 Citation Status MEDLINE |
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| doi: |
10.1016/j.freeradbiomed.2023.11.025 |
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| 520 | |a Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss | ||
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| 700 | 1 | |a Li, Wenyan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Huawei |e verfasserin |4 aut | |
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