Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA.
Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Cancer Center, Omaha, NE 68105, USA.
Med Sci (Basel). 2022 Aug 22;10(3):44. doi: 10.3390/medsci10030044.
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.
多胺是参与许多基本细胞过程的小分子多阳离子烷基胺，包括细胞增殖、存活和抵抗氧化应激。多胺稳态通过协调的生物合成、分解代谢和运输来严格调节。由于癌细胞持续增殖，细胞内多胺池保持升高。多胺代谢和运输在癌症中通常失调，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耐药机制是下调定义不明确的多胺转运系统。纳米医学的最新进展产生了具有多胺类似物骨架的纳米结构（纳米多胺）。具有非多胺骨架的类似纳米结构已被证明通过内吞作用进行转运。由于这些基于多胺的纳米颗粒可能是一种绕过多胺转运的多胺类似物递送方法，我们设计了当前的研究来确定缺乏完整多胺转运的细胞中基于多胺的纳米颗粒的功效。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对纳米多胺诱导的细胞毒性具有抗性。这种抗性是由于转运缺陷细胞无法导入和积累纳米多胺。多胺转运的药理学调节在多胺转运能力细胞中证实了这些结果。这些研究为多胺转运途径提供了更多的见解，并表明受体介导的内吞作用是较高阶多胺、多胺类似物和纳米多胺的可能转运机制。
