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

Abstract

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.

Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance

“…[ 101 ] Ophiopogon B was capable of provoking ferroptosis in GC cells by preventing the GPX4/xCT system. [ 102 ] Self‐assembled nanoparticles accelerated the process of lipid peroxidation by increasing the depletion of GSH and stimulating SO2 production. Additionally, they hampered the malignant development of GC by suppressing GPX4 expression and allowing ferroptosis to occur.…”

System Xc−/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy

“…A number of studies have proved that some natural compounds ( Table 1 ) such as dihydroartemisinin ( Yuan et al, 2020 ), artesunate ( Zhang Q. et al, 2021 ),sulforaphane ( Iida et al, 2021 ), curcumin ( Tang X. et al, 2021 ), bufotalin ( Zhang W. et al, 2022 ), sanguinarine ( Xu R. et al, 2022 ), sinapine ( Shao et al, 2022 ), solasonine ( Zeng et al, 2022 ), ophiopogonin B ( Zhang L. et al, 2022 ), red ginseng polysaccharide ( Zhai et al, 2022 ) Dihydroisotanshinone I ( Wu et al, 2021 ).inhibits the proliferation, colony formation and induces ferroptosis of lung cancer cells by the interfering mRNA and/or protein expression and/or degradation of SLC7A11 or GPX4. Apart from natural compounds, some drugs that have been marketed ( Table 1 ) such as Vorinostat ( Zhang T. et al, 2021 ), Orlistat ( Zhou W. et al, 2021 ) have also been found to act as ferroptosis inducers in lung cancer cells via inhibiting System X c − /GSH/GPX4 axis.…”

Natural products targeting signaling pathways associated with regulated cell death in gastric cancer: Recent advances and perspectives

“…Ophiopogonin B is an active compound extracted from Radix Ophiopogon japonicus with anticancer activity. Recently, Ophiopogonin B was demonstrated to decrease GPX4/xCT expression in AGS and NCI‐N87 cells, leading to ferroptosis (Zhang, Li, et al, 2022b). Moreover, a recent study has shown that nanoparticles loaded with sulfur dioxide polymer predrugs were able to promote ferroptosis in GC cells by accelerating lipid oxidation and reducing GPX4 (Xia et al, 2022).…”