氨酸激酶抑制剂Nintedanib诱导了溶酶体功能障碍: 质子依赖结晶过程的作用
Elena Mosca1, Anja Federa2, Christine Pirker1
1Center of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria.
Chemico-biological interactions
|September 16, 2024
概括
宁达达尼布 (NIN) 在酸性溶解体中形成晶体结构,独立于激酶抑制,影响细胞功能. 这种溶解体微结晶有助于NIN.
科学领域:
- 细胞生物学 细胞生物学
- 药理学 药理学是指药理学的学科.
- 生物物理学的生物物理.
背景情况:
- 丁丁达尼布 (NIN) 是一种多氨酸激酶抑制剂,用于治疗异常性肺纤维化和肺癌.
- 尼恩表现出依赖于质子化的 lysosomotropic 行为和独特的 lysosome 特定的光.
- 这些性质的潜在机制及其对 lysosome 功能的影响仍然不清楚.
研究的目的:
- 研究Nintedanib物质在酸性细胞区内自发形成的过程.
- 为了确定这种物质形成是否是NIN的发射性质的基础,并影响 lysosome 的功能.
- 探索NIN诱导的溶酶体变化对细胞过程和潜在不良影响的后果.
主要方法:
- 使用Nintedanib和非质子化衍生物的细胞实验.
- 对 lysosomal 双断裂,光发射和vATPase 抑制剂敏感性的分析.
- 在不同的pH条件下NIN的体外结晶,加上光谱和显微镜分析.
- 在受治疗的细胞中评估溶酶体功能,自,脂质代谢和脂化.
- 在体内对小鼠进行的体内研究,小鼠口服接受了Nintedanib的治疗.
主要成果:
- 用NIN处理的溶解体,但不是其衍生物,显示pH取决于晶体NIN结构的自发形成.
- 这些晶体结构表现出光和双折光,在溶酶体内共同定位.
- 宁达达尼布诱导的溶酶体结晶损害了溶酶体功能,引起了真空化,增强了自,放松了脂质代谢的调节,并诱导了脂症.
- 丁丁达尼布还诱导了依赖于溶酶体微结晶的光毒性.
- 在接受治疗的小鼠的肠道粘膜中观察到9个晶体结构.
结论:
- 宁泰达尼布在酸性溶解体内自发地形成晶体物质,从而产生独特的发射性质.
- 这种酶抑制对 lysosomal 功能的独立影响驱动了 NIN 的几个细胞生物活动.
- 丁丁达尼布的溶解体微结晶可能导致其观察到的不良影响和光毒性.
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