Ophiopogonin B induces gastric cancer cell death by blocking the GPX4/xCT-dependent ferroptosis pathway

Ophiopogonin B (OP-B) is extensively applied as a treatment for pulmonary disease and is reported to suppress lung cancer. However, further study is needed to determine whether OP-B suppresses gastric cancer (GC). The mRNA levels of prostaglandin-endoperoxide synthase 2 (Ptgs2) and ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (Chac1) were determined using quantitative PCR. Ptgs2 and Chac1 mRNA levels were significantly increased in GC cancer tissues compared with those of adjacent normal controls. The CCK-8 assay revealed that OP-B suppressed GC cell viability in a time- and dose-dependent manner. The administration of OP-B in combination with different cell death inhibitors showed that only the ferroptosis inhibitor, ferrostatin-1 (Fer-1), abolished the OP-B-induced death of both AGS and NCI-N87 cells, but not other inhibitors. Western blot analysis indicated that OP-B reduced the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11, xCT) but had no effects on the expression of nuclear receptor coactivator 4 (NCOA4) and ferritin heavy chain 1 (FTH1) in AGS and NCI-N87 cells. In vivo administration of OP-B reduced the volume and weight of AGS tumors. In addition, the expression of GPX4 and xCT was reduced in nude mice treated with OP-B compared with control mice. In summary, results of the present study suggest that OP-B induces ferroptosis in gastric cancer cells by blocking the GPX4/xCT system.