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通过受体介导的L-阿斯巴拉金酶进入瘤细胞的内化被多氨酸抑制

Igor D Zlotnikov¹, Alexander A Ezhov², Elena V Kudryashova¹

¹Faculty of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1/3, 119991 Moscow, Russia.

International journal of molecular sciences

|July 29, 2025

概括

将L-阿斯巴拉金酶 (L-ASNase) 与聚氨酸结合,通过向聚氨酸运输系统 (PTS) 来增强其对白血病细胞的吸收和有效性. PTS受体的抑制剂可以阻止这种增强的吸收,揭示了对L-ASNase治疗至关重要的复杂相互作用.

科学领域:

生物化学生物化学
药理学药理学是指药理学的学科.
在瘤学瘤学.

背景情况:

通过耗尽阿斯巴拉金,L-asparaginase (L-ASNase) 对急性淋巴细胞白血病 (ALL) 的治疗至关重要.
现有的L-ASNase配方具有免疫性和快速清除等局限性.
聚氨酸通过促进瘤细胞的积累来增强L-ASNase的抗增殖活性,很可能是通过聚氨酸运输系统 (PTS) 受体.

研究的目的:

研究竞争性PTS受体抑制剂对L-ASNase与癌细胞相互作用的影响.
评估PTS在L-ASNase吸收和聚胺合物的细胞毒性中的作用.

主要方法:

来自不同来源的L-ASNase (RrA,EwA,EcA) 与天然的多氨酸 (精子胺,精子胺,氨酸) 和多乙烯胺 (PEI2) 结合使用碳胺化学.
细胞结合和摄取量使用度计和共聚焦显微镜量化.
评估了PTS受体竞争性配体对原生和结合L-ASNase的吸收和细胞毒性的影响.

主要成果:

聚胺结合显著增加了L-ASNase结合,细胞吸收和细胞毒性.
竞争性PTS配体,特别是聚胺的脂肪酸衍生物,降低了聚胺结合L-ASNase的吸收.
一些PTS配体也增强了本地L-ASNase的吸收,使本地和结合形式之间的吸收相等.
鉴定出精氨酸和酸/酸衍生物是PTS受体介导的内细胞酶的强有力的抑制剂,降低了聚胺结合L-ASNase的疗效.

结论:

聚胺运输系统 (PTS) 在L-ASNase内部化和细胞毒性活动中起着重要作用.
聚胺结合是一种可行的策略,通过向PTS来增强L-ASNase的输送和有效性.
相互作用是复杂的,取决于细胞类型和抑制剂特异性的,突出显示了需要量身定制的治疗方法.

关键词:

竞争性抑制剂竞争性抑制剂结合在一起的结合物.这种白血病是白血病.聚胺运输系统的运输系统.聚氨酸是多氨基的有针对性的L-酸酶.

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