National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
Cancer Center & Research Institute, Department of Pharmacology & Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Int J Mol Sci. 2023 Apr 23;24(9):7741. doi: 10.3390/ijms24097741.
Since aerobic glycolysis was first observed in tumors almost a century ago by Otto Warburg, the field of cancer cell metabolism has sparked the interest of scientists around the world as it might offer new avenues of treatment for malignant cells. Our current study claims the discovery of gnetin H (GH) as a novel glycolysis inhibitor that can decrease metabolic activity and lactic acid synthesis and displays a strong cytostatic effect in melanoma and glioblastoma cells. Compared to most of the other glycolysis inhibitors used in combination with the complex-1 mitochondrial inhibitor phenformin (Phen), GH more potently inhibited cell growth. RNA-Seq with the T98G glioblastoma cell line treated with GH showed more than an 80-fold reduction in thioredoxin interacting protein (TXNIP) expression, indicating that GH has a direct effect on regulating a key gene involved in the homeostasis of cellular glucose. GH in combination with phenformin also substantially enhances the levels of p-AMPK, a marker of metabolic catastrophe. These findings suggest that the concurrent use of the glycolytic inhibitor GH with a complex-1 mitochondrial inhibitor could be used as a powerful tool for inducing metabolic catastrophe in cancer cells and reducing their growth.
自一个世纪前奥托·瓦尔堡（Otto Warburg）首次在肿瘤中观察到有氧糖酵解以来，癌细胞代谢领域引起了全世界科学家的兴趣，因为它可能为恶性细胞提供新的治疗途径。我们目前的研究声称发现了具有 novel glycolysis inhibitor 特性的染料木素 H（GH），它可以降低代谢活性和乳酸合成，并在黑色素瘤和神经胶质瘤细胞中显示出强烈的细胞生长抑制作用。与大多数与线粒体复合物 1 抑制剂苯乙双胍（Phen）联合使用的其他糖酵解抑制剂相比，GH 更能强烈抑制细胞生长。用 GH 处理 T98G 神经胶质瘤细胞系的 RNA-Seq 显示，硫氧还蛋白相互作用蛋白（TXNIP）的表达减少了 80 多倍，表明 GH 对调节与细胞葡萄糖内稳态相关的关键基因有直接作用。GH 与苯乙双胍联合使用还显著增加了 p-AMPK 的水平，这是代谢灾难的一个标志。这些发现表明，同时使用糖酵解抑制剂 GH 和线粒体复合物 1 抑制剂可以作为一种在癌细胞中诱导代谢灾难并减少其生长的强大工具。
