通过抑制P-葡萄糖蛋白来克服拉帕蛋白抗性
bioRxiv : the preprint server for biology
|November 19, 2025
概括
拉帕蛋白是一种蛋白酶体抑制剂,在固体瘤中由于P-糖蛋白 (P-gp) 而表现出耐药性. 抑制P-gp可以恢复Rapaprotin.
科学领域:
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
- 药物耐药性 药物耐药性 药物耐药性
背景情况:
- 26S蛋白酶调节蛋白质稳态,是多发性骨髓瘤的治疗点.
- 拉帕蛋白是一种新型的宏循环,通过分解其19S调节粒子来抑制26S蛋白质体,从而诱导癌细胞的亡.
- 拉帕蛋白需要通过prolyl endopeptidase (PREP) 生物激活为拉帕蛋白-L,这是一个强大的线性代谢物.
研究的目的:
- 研究固体瘤细胞系中拉帕蛋白抗性的机制.
- 通过使用PRISM癌症细胞系分析平台,确定拉帕蛋白耐药性的决定因素.
- 评估克服Rapaprotin耐药性的治疗潜力.
主要方法:
- 利用PRISM癌症细胞系分析平台来识别抵抗机制.
- 进行了排泄试验,以确定基质对P-糖蛋白的亲和力 (P-gp/ABCB1).
- 在细胞系和3D球形模型中评估了与Rapaprotin和P-gp抑制剂tariquidar联合治疗的疗效.
主要成果:
- 高P-糖蛋白 (P-gp/ABCB1) 表达被确定为固体瘤中Rapaprotin耐药性的关键决定因素.
- 活性代谢物Rapaprotin-L被证实是高亲和度P-gp基质,而基因化合物没有.
- 与tariquidar同时治疗恢复了细胞内Rapaprotin-L的积累,导致抗性细胞系中的蛋白质酶抑制和细胞亡.
- 在3D球形模型中观察到Rapaprotin和tariquidar之间的协同效应.
结论:
- P-glycoprotein (P-gp) 是对Rapaprotin治疗耐药性的关键调解者.
- 拉帕蛋白-L 是一种罕见的负电荷P-gp基质的例子.
- 将Rapaprotin与Tariquidar等P-gp抑制剂相结合可以克服耐药性,将其治疗应用扩展到除了血液恶性瘤之外的固体瘤.
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