Department of Gastroenterology, PLA Naval Medical Center, Shanghai, China.
Chem Biol Drug Des. 2024 Jan;103(1):e14417. doi: 10.1111/cbdd.14417.
Programmed cell death (PCD) induction is a promising strategy for killing gastric cancer cells. In this study, we investigated the effects of chrysophanol on apoptosis and ferroptosis in gastric cancer cells. Chrysophanol in concentrations ranging from 0 to 100 μM were used to treat GES-1, HGC-27 and AGS cells. Cell counting kit-8 assay, colony formation assay, 5-ethynyl-2'-deoxyuridine staining, flow cytometry, JC-1 probe insertion, dihydroethidium staining and western blotting were performed. The effects of chrysophanol on gastric cancer cells were evaluated in vivo using a xenograft mouse model. Chrysophanol had no cytotoxic effects on GES-1 cells. Chrysophanol with concentrations higher than 25 μM inhibited gastric cancer cell colony formation and proliferation. Chrysophanol induces gastric cancer cell apoptosis in a dose-dependent manner, accompanied by mitochondrial membrane potential dysfunction and cytochrome c release. Additionally, chrysophanol increased the levels of reactive oxygen species, total iron, and Fe in HGC-27 and AGS cells, in a dose-dependent manner. Treatment of cells with the ferroptosis inhibitor ferrostatin-1 attenuated the effects of chrysophanol on cell survival and the expression of ferroptosis markers SLC7A11 and GPX4. Screening by GEO software indicated that the mTOR signalling pathway is possibly regulated by chrysophanol. Furthermore, mTOR overexpression significantly reversed the inhibitory effects of chrysophanol on gastric cancer cells. In gastric cancer xenograft mouse models, chrysophanol treatment inhibited tumour growth and downregulated SLC7A11 and GPX4. Chrysophanol induces apoptosis and ferroptosis, making it a potential candidate for killing gastric cancer cells. The beneficial effects of chrysophanol may be attribute to the targeted regulation of mTOR.
程序性细胞死亡（PCD）诱导是杀死胃癌细胞的一种有前途的策略。在这项研究中，我们研究了大黄素对胃癌细胞凋亡和铁死亡的影响。用浓度范围为 0 至 100 μM 的大黄素处理 GES-1、HGC-27 和 AGS 细胞。进行细胞计数试剂盒-8 测定、集落形成测定、5-乙炔基-2'-脱氧尿苷染色、流式细胞术、JC-1 探针插入、二氢乙啶染色和蛋白质印迹。使用异种移植小鼠模型评估大黄素对胃癌细胞的影响。大黄素对 GES-1 细胞没有细胞毒性作用。浓度高于 25 μM 的大黄素抑制胃癌细胞集落形成和增殖。大黄素以剂量依赖性方式诱导胃癌细胞凋亡，伴有线粒体膜电位功能障碍和细胞色素 c 释放。此外，大黄素以剂量依赖性方式增加 HGC-27 和 AGS 细胞中活性氧、总铁和 Fe 的水平。用铁死亡抑制剂 ferrostatin-1 处理细胞可减弱大黄素对细胞存活和铁死亡标志物 SLC7A11 和 GPX4 表达的影响。GEO 软件筛选表明，mTOR 信号通路可能受大黄素调节。此外，mTOR 过表达显著逆转了大黄素对胃癌细胞的抑制作用。在胃癌异种移植小鼠模型中，大黄素处理抑制肿瘤生长并下调 SLC7A11 和 GPX4。大黄素诱导细胞凋亡和铁死亡，使其成为杀死胃癌细胞的潜在候选药物。大黄素的有益作用可能归因于对 mTOR 的靶向调节。
