PDF(Pubmed)
Abstract：
The recently defined type of cell death ferroptosis has garnered significant attention as a potential new approach to cancer treatment owing to its more immunogenic nature when compared with apoptosis. Ferroptosis is characterized by the depletion of glutathione (GSH)/glutathione peroxidase-4 (GPx4) and iron-dependent lipid peroxidation. Diplacone (DP), a geranylated flavonoid compound found in Paulownia tomentosa fruit, has been identified to have anti-inflammatory and anti-radical activity. In this study, the potential anticancer activity of DP was explored against A549 human lung cancer cells. It was found that DP induced a form of cytotoxicity distinct from apoptosis, which was accompanied by extensive mitochondrial-derived cytoplasmic vacuoles. DP was also shown to increase mitochondrial Ca2+ influx, reactive oxygen species (ROS) production, and mitochondrial permeability transition (MPT) pore-opening. These changes led to decreases in mitochondrial membrane potential and DP-induced cell death. DP also induced lipid peroxidation and ATF3 expression, which are hallmarks of ferroptosis. The ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 were effective in counteracting the DP-mediated ferroptosis-related features. Our results could contribute to the use of DP as a ferroptosis-inducing agent, enabling studies focusing on the relationship between ferroptosis and the immunogenic cell death of cancer cells.
摘要：
由于与细胞凋亡相比具有更高的免疫原性，最近定义的细胞死亡类型已成为癌症治疗的潜在新方法，因此引起了广泛关注。铁凋亡的特征是谷胱甘肽（GSH）/谷胱甘肽过氧化物酶-4（GPx4）的消耗和铁依赖性脂质过氧化。Diplacone(DP),一种在泡桐果实中发现的香叶化类黄酮化合物，已被确定具有抗炎和抗自由基活性。在这项研究中,研究了DP对A549人肺癌细胞的潜在抗癌活性。发现DP诱导了一种不同于细胞凋亡的细胞毒性，伴有广泛的线粒体来源的细胞质液泡。DP也显示增加线粒体Ca2+流入，活性氧（ROS）的产生，和线粒体通透性转换（MPT）孔开放。这些变化导致线粒体膜电位降低和DP诱导的细胞死亡。DP还诱导脂质过氧化和ATF3表达，这是铁性死亡的标志。铁凋亡抑制剂铁抑制素-1和利丙他汀-1可有效抵消DP介导的铁凋亡相关特征。我们的结果可能有助于使用DP作为铁凋亡诱导剂，使研究集中在铁死亡和癌症细胞的免疫原性细胞死亡之间的关系。
