Research Laboratory in Applied Metabolic Engineering, Department of Chemical Engineering, École Polytechnique de Montréal, P.O. Box 6079, Centre-ville Station, Montréal, Québec, Canada.
Institut Cochin, Université Paris- Descartes, 75014, Paris, France.
Sci Rep. 2019 Feb 28;9(1):3153. doi: 10.1038/s41598-019-39109-1.
In the recent years, cancer research succeeded with sensitive detection methods, targeted drug delivery systems, and the identification of a large set of genes differently expressed. However, although most therapies are still based on antimitotic agents, which are causing wide secondary effects, there is an increasing interest for metabolic therapies that can minimize side effects. In the early 20 century, Otto Warburg revealed that cancer cells rely on the cytoplasmic fermentation of glucose to lactic acid for energy synthesis (called "Warburg effect"). Our investigations aim to reverse this effect in reprogramming cancer cells' metabolism. In this work, we present a metabolic therapy specifically targeting the activity of specific enzymes of central carbon metabolism, combining the METABLOC bi-therapeutic drugs combination (Alpha Lipoic Acid and Hydroxycitrate) to Metformin and Diclofenac, for treating tumors implanted in mice. Furthermore, a dynamic metabolic model describing central carbon metabolism as well as fluxes targeted by the drugs allowed to simulate tumors progression in both treated and non-treated mice, in addition to draw hypotheses on the effects of the drugs on tumor cells metabolism. Our model predicts metabolic therapies-induced reversed Warburg effect on tumor cells.
近年来，癌症研究在敏感检测方法、靶向药物输送系统和大量差异表达基因的鉴定方面取得了成功。然而，尽管大多数治疗方法仍基于抗有丝分裂药物，这些药物会引起广泛的副作用，但人们对代谢疗法的兴趣越来越大，因为代谢疗法可以最大限度地减少副作用。20 世纪初，奥托·瓦伯格（Otto Warburg）揭示了癌细胞依赖细胞质发酵葡萄糖产生乳酸来合成能量（称为“瓦伯格效应”）。我们的研究旨在通过重新编程癌细胞的代谢来逆转这种效应。在这项工作中，我们提出了一种代谢疗法，专门针对中央碳代谢的特定酶的活性，将 METABLOC 双治疗药物组合（α-硫辛酸和羟基柠檬酸）与二甲双胍和双氯芬酸结合起来，用于治疗植入小鼠的肿瘤。此外，一个描述中央碳代谢以及药物靶向通量的动态代谢模型，允许模拟治疗和未治疗小鼠中的肿瘤进展，此外还可以对药物对肿瘤细胞代谢的影响提出假设。我们的模型预测代谢疗法会诱导肿瘤细胞的“反向瓦伯格效应”。
