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用ISRIB调节未折叠的蛋白质反应可以减轻西斯的毒性
Jiang Li1, Stephanie L Rouse2,3, Ian R Matthews2
1Department of Neurology, UCSF, San Francisco, USA.
Scientific reports
|September 27, 2024
概括
西斯普拉丁化疗导致听力损失. 用ISRIB针对小鼠的未折叠蛋白响应 (UPR) 进行药物保护听力,而不会影响化疗.
科学领域:
- 耳毒性研究研究
- 癌症化疗机制 癌症化疗机制
- 细胞应激反应路径的细胞应激反应路径.
背景情况:
- 西斯普拉丁化疗经常导致感觉神经听力损失,这是一个副作用,机制不太清楚.
- 目前预防耳毒性的策略集中在氧化应激和亡上,但硫酸盐 (STS) 在一些儿科癌症中显示生存率降低.
- 细胞内膜网膜 (ER) 应激和未折叠蛋白质反应 (UPR) 与听力损失和西斯普拉丁细胞毒性有关,这表明UPR是治疗点.
研究的目的:
- 调查是否针对UPR可以预防西斯胺诱导的耳毒性.
- 评估ISRIB (综合应激反应抑制剂) 药物对其对西斯的耳毒性保护作用的评价.
- 评估ISRIB是否干扰着西斯普拉丁对癌细胞的有效性.
主要方法:
- 暴露于新生儿耳培养物和HEK细胞的西斯普拉丁,测量UPR标记物和细胞死亡.
- 用ISRIB治疗小鼠,以评估对西斯普拉丁诱导的听力损失和毛细胞死亡的保护.
- 评估ISRIB对头部和部状细胞癌 (HNSCC) 细胞系中西斯丁细胞毒性的影响.
主要成果:
- 西斯普拉丁诱导了剂量依赖的细胞死亡和细胞亡,与UPR标记物表达相关.
- 在体内和体外,ISRIB治疗显著保护了对西斯普拉丁诱导的听力损失和头发细胞死亡.
- 与STS.不同的是,ISRIB并没有降低西斯普拉丁对HNSCC细胞的细胞毒性作用.
结论:
- 通过ISRIB准UPR的亲细胞亡PERK/CHOP通路,可以减轻西斯的耳毒性.
- ISRIB提供了一种潜在的治疗策略,可以在不损害抗癌疗效的前提下,在西斯普拉丁化疗期间预防听力损失.
- 这种方法为STS提供了一个更具体的替代方案,用于控制西斯产生的耳毒性.
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