Sujuan Xi, Wei Ding, Danping Weng, Yue Zeng, Kewei Gao, Qiuye Wu, Guoping Huang, Yufang Li, Haiyan Yue

Chrysophanol induces apoptosis and ferroptosis of gastric cancer cells by targeted regulation of mTOR

  • Molecular Medicine
  • Biochemistry
  • Drug Discovery
  • Pharmacology
  • Organic Chemistry

AbstractProgrammed 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 Fe2+ 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.

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