文章：

靶向胶质母细胞瘤中基于半乳糖的抗代谢物：聚焦Leloir通路

Targeting the Leloir Pathway with Galactose-Based Antimetabolites in Glioblastoma

原文发布日期：17 October 2024

DOI: 10.3390/cancers16203510

类型: Article

开放获取: 是

英文摘要：

Background: Glioblastoma (GBM) uses Glut3 and/or Glut14 and the Leloir pathway to catabolize D-Galactose (Gal). UDP-4-deoxy-4-fluorogalactose (UDP-4DFG) is a potent inhibitor of the two key enzymes, UDP-galactose-4-epimerase (GALE) and UDP-Glucose 6-dehydrogenase (UGDH), involved in Gal metabolism and in glycan synthesis. The Gal antimetabolite 4-deoxy-4-fluorogalactose (4DFG) is a good substrate for Glut3/Glut14 and acts as a potent glioma chemotherapeutic. Methods: Primary GBM cell cultures were used to examine toxicity and alterations in glycan composition via lectin binding in fixed cells and by Western blots. Toxicity/efficacy in vivo data was performed in mouse flank and intracranial models. The effect of 4DFG on D-glucose (Glc) metabolism in GBM cells was assessed by using13C NMR-based tracer studies. Results: 4DFG is moderately potent against GBM cells (IC50: 125–300 µM). GBM glycosylation is disrupted by 4DFG. Survival analysis in an intracranial mouse model showed that treatment with 4DFG (6 × 25 mg/kg of 4DFG, intravenously) improved outcomes by three-fold (p< 0.01). Metabolic flux analysis revealed that both glycolytic and mitochondrial metabolic fluxes of [U-13C]Glc were significantly decreased in the presence of 4DFG in GBM cells. Conclusion: A functional Gal-scavenging pathway in GBM allows Gal-based antimetabolites to act as chemotherapeutics. 4DFG is metabolized by GBM in vitro and in vivo, is lethal to GBM tumors, and is well tolerated in mice.

摘要翻译： 

背景：胶质母细胞瘤（GBM）利用Glut3和/或Glut14以及Leloir途径分解代谢D-半乳糖（Gal）。UDP-4-脱氧-4-氟半乳糖（UDP-4DFG）是参与Gal代谢及聚糖合成的两种关键酶——UDP-半乳糖-4-差向异构酶（GALE）和UDP-葡萄糖-6-脱氢酶（UGDH）的有效抑制剂。Gal抗代谢物4-脱氧-4-氟半乳糖（4DFG）是Glut3/Glut14的良好底物，可作为有效的胶质瘤化疗药物。 方法：采用原代GBM细胞培养，通过固定细胞凝集素结合实验及蛋白质印迹法检测毒性及聚糖组成变化。体内毒性/疗效数据通过小鼠侧腹及颅内模型获得。利用基于13C NMR的示踪研究评估4DFG对GBM细胞D-葡萄糖（Glc）代谢的影响。 结果：4DFG对GBM细胞具有中等效力（IC50：125–300 µM）。4DFG可破坏GBM糖基化过程。颅内小鼠模型生存分析显示，4DFG治疗（静脉注射6×25 mg/kg 4DFG）使生存结局改善三倍（p<0.01）。代谢通量分析表明，在GBM细胞中，[U-13C]Glc的糖酵解和线粒体代谢通量在4DFG存在下均显著降低。 结论：GBM中功能性Gal清除途径使基于Gal的抗代谢物能够发挥化疗作用。4DFG在体外和体内均可被GBM代谢，对GBM肿瘤具有致死性，且在小鼠体内耐受性良好。

原文链接：

Targeting the Leloir Pathway with Galactose-Based Antimetabolites in Glioblastoma