Laussel Clotilde, Léon Sébastien
Université de Paris, CNRS, Institut Jacques Monod, F-75006 Paris, France.
Université de Paris, CNRS, Institut Jacques Monod, F-75006 Paris, France.
Biochem Pharmacol. 2020 Dec;182:114213. doi: 10.1016/j.bcp.2020.114213. Epub 2020 Sep 3.
Most malignant cells display increased glucose absorption and metabolism compared to surrounding tissues. This well-described phenomenon results from a metabolic reprogramming occurring during transformation, that provides the building blocks and supports the high energetic cost of proliferation by increasing glycolysis. These features led to the idea that drugs targeting glycolysis might prove efficient in the context of cancer treatment. One of these drugs, 2-deoxyglucose (2-DG), is a synthetic glucose analog that can be imported into cells and interfere with glycolysis and ATP generation. Its preferential targeting to sites of cell proliferation is supported by the observation that a derived molecule, 2-fluoro-2-deoxyglucose (FDG) accumulates in tumors and is used for cancer imaging. Here, we review the toxicity mechanisms of this drug, from the early-described effects on glycolysis to its other cellular consequences, including inhibition of protein glycosylation and endoplasmic reticulum stress, and its interference with signaling pathways. Then, we summarize the current data on the use of 2-DG as an anti-cancer agent, especially in the context of combination therapies, as novel 2-DG-derived drugs are being developed. We also show how the use of 2-DG helped to decipher glucose-signaling pathways in yeast and favored their engineering for biotechnologies. Finally, we discuss the resistance strategies to this inhibitor that have been identified in the course of these studies and which may have important implications regarding a medical use of this drug.
与周围组织相比，大多数恶性细胞表现出葡萄糖摄取和代谢增加。这种已被充分描述的现象源于细胞转化过程中发生的代谢重编程，该过程通过增加糖酵解提供了增殖所需的构建模块并支持其高能量消耗。这些特征促使人们认为，靶向糖酵解的药物在癌症治疗中可能被证明是有效的。其中一种药物2-脱氧葡萄糖（2-DG）是一种合成葡萄糖类似物，可被导入细胞并干扰糖酵解和ATP生成。一种衍生分子2-氟-2-脱氧葡萄糖（FDG）在肿瘤中积累并用于癌症成像，这一观察结果支持了2-DG对细胞增殖部位的优先靶向作用。在此，我们综述了这种药物的毒性机制，从早期描述的对糖酵解的影响到其其他细胞后果，包括抑制蛋白质糖基化和内质网应激，以及其对信号通路的干扰。然后，我们总结了目前关于使用2-DG作为抗癌药物的数据，特别是在联合治疗的背景下，因为新型2-DG衍生药物正在研发中。我们还展示了2-DG的使用如何帮助破译酵母中的葡萄糖信号通路，并有利于对其进行生物技术工程改造。最后，我们讨论了在这些研究过程中确定的对这种抑制剂的耐药策略，这些策略可能对该药物的医学应用具有重要意义。
