一种基于荧光的检测方法来探测果糖模拟物对乳腺癌细胞中 GLUT5 转运的抑制作用,ACS Bio & Med Chem Au

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一种基于荧光的检测方法来探测果糖模拟物对乳腺癌细胞中 GLUT5 转运的抑制作用
ACS Bio & Med Chem Au ( IF 3.8 ) Pub Date : 2022-11-07 , DOI: 10.1021/acsbiomedchemau.2c00056
Natasha Rana _{1,

2,

3} , Marwa A Aziz _{1,

4} , Rabah A T Serya ₄ , Deena S Lasheen ₄ , Nermin Samir ₄ , Frank Wuest _{1,

2} , Khaled A M Abouzid ₄ , F G West _{1,

2,

3}

Affiliation

快速的细胞分裂和能量代谢的重新编程是癌细胞的两个重要标志。在人类中，己糖转运至癌细胞主要是通过葡萄糖转运蛋白 (GLUT) 家族介导的，这些葡萄糖转运蛋白是促进性跨膜己糖转运蛋白。在几种乳腺癌中，果糖可以在功能上替代葡萄糖作为支持快速增殖的替代能源。GLUT5 是主要的果糖转运蛋白，在人类乳腺癌细胞中过度表达，为乳腺癌检测以及使用结构修饰的果糖模拟物选择性靶向抗癌药物提供了有价值的靶点。在此，设计了一种新型荧光测定法，旨在筛选一系列 C-3 修饰的 2,5-脱水甘露醇 (2,5-AM) 化合物作为d- 用于探索 GLUT5 结合位点要求的果糖类似物。评估了合成探针抑制荧光标记的d-果糖衍生物 6-NBDF 摄取到 EMT6 小鼠乳腺癌细胞中的能力。筛选出的一些化合物显示出对 6-NBDF 细胞摄取的高度个位数微摩尔抑制，这在 100 倍或更多的水平上比天然底物d -果糖更有效。^{该测定的结果与之前对某些选定化合物针对18} F-标记的基于d -果糖的探针 6-[ ¹⁸进行的研究获得的结果一致。F]FDF，表明当前非放射性标记测定的可重复性。这些针对 6-NBDF 进行评估的高效化合物为开发针对表达 GLUT5 的癌细胞的更有效探针开辟了道路。

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A Fluorescence-Based Assay to Probe Inhibitory Effect of Fructose Mimics on GLUT5 Transport in Breast Cancer Cells

Rapid cell division and reprogramming of energy metabolism are two crucial hallmarks of cancer cells. In humans, hexose trafficking into cancer cells is mainly mediated through a family of glucose transporters (GLUTs), which are facilitative transmembrane hexose transporter proteins. In several breast cancers, fructose can functionally substitute glucose as an alternative energy supply supporting rapid proliferation. GLUT5, the principal fructose transporter, is overexpressed in human breast cancer cells, providing valuable targets for breast cancer detection as well as selective targeting of anticancer drugs using structurally modified fructose mimics. Herein, a novel fluorescence assay was designed aiming to screen a series of C-3 modified 2,5-anhydromannitol (2,5-AM) compounds as d-fructose analogues to explore GLUT5 binding site requirements. The synthesized probes were evaluated for their ability to inhibit the uptake of the fluorescently labeled d-fructose derivative 6-NBDF into EMT6 murine breast cancer cells. A few of the compounds screened demonstrated highly potent single-digit micromolar inhibition of 6-NBDF cellular uptake, which was substantially more potent than the natural substrate d-fructose, at a level of 100-fold or more. The results of this assay are consistent with those obtained from a previous study conducted for some selected compounds against ¹⁸F-labeled d-fructose-based probe 6-[¹⁸F]FDF, indicating the reproducibility of the current non-radiolabeled assay. These highly potent compounds assessed against 6-NBDF open avenues for the development of more potent probes targeting GLUT5-expressing cancerous cells.

更新日期：2022-11-07

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