Polyamine-Based Nanostructures Share Polyamine Transport Mechanisms with Native Polyamines and Their Analogues: Significance for Polyamine-Targeted Therapy.
Polyamine-Based Nanostructures Share Polyamine Transport Mechanisms with Native Polyamines and Their Analogues: Significance for Polyamine-Targeted Therapy.
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DOI：
10.3390/medsci10030044
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发表时间：
2022-08-22
期刊：
影响因子：
--
通讯作者：
Casero, Robert A.
中科院分区：
文献类型：
--
作者：
Holbert, Cassandra E.;Foley, Jackson R.;Yu, Ao;Stewart, Tracy Murray;Phanstiel, Otto;Oupicky, David;Casero, Robert A.
关键词：
多胺是一种小分子多阳离子烷基胺，参与许多基本细胞过程，包括细胞增殖、生存和氧化应激保护。多胺稳态通过协调的生物合成、催化和运输而被严格调节。由于癌细胞的持续增殖，其细胞内多胺库维持升高。多胺代谢和转运通常在癌症中失调，因此，多胺类似物是利用癌细胞增加的多胺需求的有前途的策略。一种潜在的多胺类似物抗性机制是不明确的多胺转运系统的下调。纳米医学的最新进展已经产生了具有基于聚胺类似物的主链（纳米聚胺）的纳米结构。具有非聚胺主链的类似纳米结构已显示通过胞吞作用转运。由于这些基于多胺的纳米颗粒可能是绕过多胺转运的多胺类似物递送的方法，我们设计了当前的研究以确定基于多胺的纳米颗粒在缺乏完整多胺转运的细胞中的功效。利用肺腺癌细胞系的多胺转运缺陷衍生物，我们证明了不能转运天然多胺的细胞也能抵抗纳米多胺诱导的细胞毒性。这种耐药性是运输缺陷细胞无法输入和积累纳米多胺的结果。多胺转运的药理学调节证实了多胺转运感受态细胞中的这些结果。这些研究提供了更多的了解多胺运输途径，并表明受体介导的内吞作用是一个可能的机制，运输高阶多胺，多胺类似物和纳米多胺。
Polyamines are small polycationic alkylamines involved in many fundamental cellular processes, including cell proliferation, survival, and protection from oxidative stress. Polyamine homeostasis is tightly regulated through coordinated biosynthesis, catabolism, and transport. Due to their continual proliferation, cancer cells maintain elevated intracellular polyamine pools. Both polyamine metabolism and transport are commonly dysregulated in cancer, and as such, polyamine analogues are a promising strategy for exploiting the increased polyamine requirement of cancer cells. One potential polyamine analogue resistance mechanism is the downregulation of the poorly defined polyamine transport system. Recent advances in nanomedicine have produced nanostructures with polyamine analogue-based backbones (nanopolyamines). Similar nanostructures with non-polyamine backbones have been shown to be transported by endocytosis. As these polyamine-based nanoparticles could be a method for polyamine analogue delivery that bypasses polyamine transport, we designed the current studies to determine the efficacy of polyamine-based nanoparticles in cells lacking intact polyamine transport. Utilizing polyamine transport-deficient derivatives of lung adenocarcinoma lines, we demonstrated that cells unable to transport natural polyamines were also resistant to nanopolyamine-induced cytotoxicity. This resistance was a result of transport-deficient cells being incapable of importing and accumulating nanopolyamines. Pharmacological modulation of polyamine transport confirmed these results in polyamine transport competent cells. These studies provide additional insight into the polyamine transport pathway and suggest that receptor-mediated endocytosis is a likely mechanism of transport for higher-order polyamines, polyamine analogues and the nanopolyamines.
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影响因子：
5.6
作者：
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通讯作者：
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影响因子：
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5.5
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46.2
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