PDF(Pubmed)
Abstract：
OBJECTIVE: 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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
目的：顺铂是一种廉价的临床抗肿瘤药物，广泛用于治疗实体肿瘤。然而,它的使用可能会损害耳蜗毛细胞，导致不可逆转的听力损失。目前,有一种药物在临床上被批准仅用于减少儿科患者与顺铂相关的耳毒性，这需要进一步探索其他候选药物。
方法：这里，通过筛选1967年FDA批准的药物来保护耳蜗毛细胞系（HEI-OC1）免受顺铂损伤，我们发现磷酸泰迪唑(Ted)，一种用于治疗急性感染的药物，保护效果最好。Further,我们评估了Ted对小鼠耳蜗外植体耳毒性的保护作用，斑马鱼,成年老鼠使用RNA测序分析进一步探索并验证了Ted的作用机制。同时,我们还观察了Ted对顺铂抗肿瘤作用的影响。
结果：Ted对斑马鱼和小鼠耳蜗外植体中顺铂诱导的毛细胞（HC）损失具有很强的保护作用。此外,当全身给药时，它保护小鼠免受顺铂引起的听力损失。此外，抗肿瘤研究表明，Ted对顺铂的体内外抗肿瘤活性没有影响。RNA测序分析表明，Ted的耳保护作用主要是通过抑制ERK的磷酸化来实现的。始终如一，ERK激活剂加重了顺铂对HCs的损伤。
结论：总的来说，这些结果表明，FDA批准的Ted通过抑制ERK磷酸化来保护HC免受顺铂诱导的HC损失，表明其作为预防临床环境中顺铂耳毒性的候选药物的潜力。
方法：这里，通过筛选1967年FDA批准的药物来保护耳蜗毛细胞系（HEI-OC1）免受顺铂损伤，我们发现磷酸泰迪唑(Ted)，一种用于治疗急性感染的药物，保护效果最好。Further,我们评估了Ted对小鼠耳蜗外植体耳毒性的保护作用，斑马鱼,成年老鼠使用RNA测序分析进一步探索并验证了Ted的作用机制。同时,我们还观察了Ted对顺铂抗肿瘤作用的影响。
结果：Ted对斑马鱼和小鼠耳蜗外植体中顺铂诱导的毛细胞（HC）损失具有很强的保护作用。此外,当全身给药时，它保护小鼠免受顺铂引起的听力损失。此外，抗肿瘤研究表明，Ted对顺铂的体内外抗肿瘤活性没有影响。RNA测序分析表明，Ted的耳保护作用主要是通过抑制ERK的磷酸化来实现的。始终如一，ERK激活剂加重了顺铂对HCs的损伤。
结论：总的来说，这些结果表明，FDA批准的Ted通过抑制ERK磷酸化来保护HC免受顺铂诱导的HC损失，表明其作为预防临床环境中顺铂耳毒性的候选药物的潜力。
