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重新使用AZD5438和达布拉费尼布治疗西斯胺诱导的AKI
Chithra K Pushpan1, Daniel F Kresock1, Matthew A Ingersoll1
1Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, Nebraska.
Journal of the American Society of Nephrology : JASN
|November 14, 2023
概括
两种口服抗癌药物,AZD5438和dabrafenib,在保护对甲诱导的损伤 (AKI) 和听力损失方面表现有前途. 这些药物降低了损伤标志物和细胞死亡,改善了接受西斯丁治疗的小鼠的生存率.
科学领域:
- 药理学 药理学是指药理学的学科.
- 腎臟病學 (nephrology) 是一種醫學專業.
- 耳部毒理学 耳部毒理学
背景情况:
- 西斯是一种重要的化疗药物,但会导致剂量限制性毒性和耳毒性.
- 目前没有FDA批准的药物可以治疗西斯普拉丁诱导的损伤和听力损失.
- AZD5438 (CDK2抑制剂) 和达布拉费尼布 (BRAF抑制剂) 已先前对小鼠的西斯普拉丁诱导的听力损失进行了保护.
研究的目的:
- 调查AZD5438和达布拉费尼布在减轻西斯普拉丁诱导的急性损伤 (AKI) 的潜力.
- 为了确定共享的细胞通路是否参与西斯胺诱导的脏和内耳损伤.
- 为了评估这些药物的疗效,在小鼠模型中使用西斯诱导的AKI.
主要方法:
- 利用HK-2细胞系和FVB小鼠评估药物保护对西斯普拉丁诱导的细胞死亡和AKI.
- 分析了血清生物标志物 (BUN,肌素,NGAL) 和细胞病理学.
- 检查细胞死亡的标志物 (亡,烧亡) 和通过西式斑点和免疫光的扩散 (pERK,PCNA).
- 使用CDK2敲除小鼠来确认AZD5438的作用机制.
主要成果:
- AZD5438和达布拉芬尼减少了HK-2细胞中西斯普拉丁诱导的细胞死亡,并在小鼠中减弱了AKI.
- 这两种药物都降低了血清损伤标志物,并抑制了细胞死亡途径.
- 降低pERK和PCNA水平与改善动物生存率相关.
- CDK2淘汰赛小鼠对西斯胺诱导的AKI表现出耐药性,而AZD5438没有提供额外的益处.
结论:
- 西斯胺诱导的脏和内耳损伤对AZD5438和dabrafenib表现出类似的细胞反应.
- 这些发现凸显了AZD5438和达布拉费尼布在治疗西斯产生的毒性和耳毒性方面的潜在治疗效用.
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