School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
Toxins (Basel). 2019 Aug 26;11(9):492. doi: 10.3390/toxins11090492.
Gallic acid (GA) is a natural anti-cancer compound that can be found in many food sources, including edible mushrooms, fruits, and vegetables. Studies generally attribute the anti-cancer activity of GA to the induction of apoptosis. Here, we reported that GA activated iron-dependent cell death mechanisms with apoptotic, ferroptotic, and necroptotic features. Our time-lapse live-cell microscopy study demonstrated that GA could induce coexistence of multiple types of cell death pathways, including apoptosis characterized by mitochondrial cytochrome release and caspase-3 activation, ferroptosis characterized by lipid peroxidation, and necroptosis characterized by the loss of plasma membrane integrity. This GA-induced cell death could be completely suppressed by exposure to an iron chelator deferoxamine, indicating that it is an iron-dependent cell death process. Importantly, MLKL (mixed lineage kinase domain-like protein) inhibitor necrosulfonamide exerted a synergistic effect by increasing the sensitivity of cancer cells to GA. Taken together, our results provide new mechanistic insights, and also suggest new strategies to enhance the efficacy of this natural anti-cancer compound by identifying the agents that can promote or suppress the GA-induced cell death process.
没食子酸（GA）是一种天然的抗癌化合物，存在于许多食物来源中，包括食用菌、水果和蔬菜。研究普遍认为 GA 的抗癌活性归因于诱导细胞凋亡。在这里，我们报告 GA 通过具有凋亡、铁死亡和坏死样特征的铁依赖性细胞死亡机制被激活。我们的延时活细胞显微镜研究表明，GA 可以诱导多种类型的细胞死亡途径共存，包括线粒体细胞色素 c 释放和 caspase-3 激活特征的凋亡、脂质过氧化特征的铁死亡和质膜完整性丧失特征的坏死样。这种 GA 诱导的细胞死亡可以通过暴露于铁螯合剂去铁胺完全抑制，表明这是一种铁依赖性细胞死亡过程。重要的是，混合谱系激酶结构域样蛋白（MLKL）抑制剂坏死磺胺通过增加癌细胞对 GA 的敏感性发挥协同作用。总之，我们的研究结果提供了新的机制见解，并提出了通过确定可以促进或抑制 GA 诱导的细胞死亡过程的药物来增强这种天然抗癌化合物疗效的新策略。
