Glyceraldehyde (GA) is a three-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits neuroblastoma cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and13C-labeling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in neuroblastoma cells. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. Analysis of nucleotide pools in L-GA-treated cells depicted a previously unreported observation, in which nucleotide biosynthesis is significantly inhibited. The inhibitory action of L-GA was partially relieved with the co-application of the antioxidant N-acetyl-cysteine. We present novel evidence for a simple sugar that inhibits cancer cell proliferation via dysregulating its fragile homeostatic environment.
甘油醛是一种三碳单糖，可作为果糖代谢副产物存在于细胞中。布鲁诺·门德尔与奥托·瓦尔堡的研究表明，甘油醛作用于癌细胞可抑制糖酵解及其生长，但其分子机制尚未阐明。本研究揭示了L-甘油醛异构体抑制神经母细胞瘤生长的多模态新机制：L-甘油醛可诱导代谢谱显著改变，促进氧化应激并阻碍核苷酸生物合成。通过气相色谱-质谱联用及13C标记技术检测发现，L-甘油醛通过靶向NAD(H)依赖性反应成为糖酵解的有效抑制剂，导致神经母细胞瘤细胞生长抑制、细胞凋亡及氧化还原危机。蛋白质组学分析证实L-甘油醛可调控氧化还原机制。对L-甘油醛处理细胞的核苷酸库分析发现，核苷酸生物合成显著受抑制，此现象尚未见报道。联合应用抗氧化剂N-乙酰半胱氨酸可部分逆转L-甘油醛的抑制作用。本研究首次证明单糖可通过破坏癌细胞脆弱的稳态环境抑制其增殖。
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