Polyphyllin B Suppresses Gastric Tumor Growth by Modulating Iron Metabolism and Inducing Ferroptosis

Abstract

Gastric cancer (GC) is one of the most common malignant tumors in the world. GPx4, as the core regulator of ferroptosis, has become a potential molecular target for developing anticancer agents. In the present study, we found that GPx4 was overexpressed and negatively correlated with poor prognosis in GC, while it was associated with the GC development. Molecular docking and structure-based virtual screening assays were used to screen potential GPx4 inhibitors, and we identified a novel GPx4 inhibitor, polyphyllin B (PB), which can induce ferroptosis by down-regulating GPx4 expression in GC cells. It has also been shown to inhibit cell proliferation, suppress invasion and migration, induce apoptosis, and block the cell cycle progression in GC cells in vitro. Then, immunofluorescence and western blotting assay confirmed that PB can regulate the expression of LC3B, TFR1, NOCA4 and FTH1 in vitro, which suggested that suggest that PB may increase the level of Fe 2+ by transporting Fe 3+ into the cell by TFR1 and promoting NCOA4-dependent iron autophagy. In addition, PB can also suppresses tumor growth in an orthotopic mouse model of GC via regulating the expression of GPx4, TFR1, NOCA4 and FTH1 in vivo. In summary, we confirmed that GPx4 may be a potential target for GC treatment, PB may be a novel and promising drug for the treatment of GC, which shows good antitumor efficacy without causing significant host toxicity via inducing ferroptosis in both gastric cancer cells and mouse models.

Steroidal Saponins: Naturally Occurring Compounds as Inhibitors of the Hallmarks of Cancer

“…It induced ferroptosis by directly binding to GPX4. This was confirmed by molecular docking, Western blot, and immunofluorescence analyses [55]. Another Paris polyphylla-derived steroidal saponin, polyphyllin III, induced the ferroptotic death of MDA-MB-231 triple-negative cancer cells via the ACSL4-dependant peroxidation of lipids.…”

Blocking Ubiquitin‐Specific Protease 7 Induces Ferroptosis in Gastric Cancer via Targeting Stearoyl‐CoA Desaturase

“…[ 36 ] Polyphyllin B demonstrated the ability to induce ferroptosis in GC cells by modulating GPX4, TFR1, NOCA4, and FTH1 expression. [ 37 ] Amentoflavone, a multifunctional biflavonoid, suppresses proliferation and induces ferroptotic cell death in GC cells via the miR‐496/ATF2 axis. [ 38 ] Despite notable progress, there remain unknown aspects of the specific mechanisms of ferroptosis in GC, warranting further research.…”

Targeting ferroptosis in gastric cancer: Strategies and opportunities

“…Additionally, PB demonstrated the potential to impede the growth of GC cells, suppress migration and invasion, induce apoptosis, and arrest cell cycle progression. 145 Similarly, Jiyuan oridonin A (JDA), a natural compound derived from Jiyuan Rabdosia rubescens, and its derivatives have been found to induce the accumulation of Fe 2+ through the autophagic pathway, leading to iron-mediated cell death and effectively inhibiting the growth of GC cells. This highlights the significant antitumor activity of JDA and its potential as a therapeutic agent.…”

“…PB could regulate the expression of LC3B, TFR1, NOCA4, and FTH1 in vitro, indicating that PB may facilitate the transport of Fe 3+ into cells through TFR1 and enhance NCOA4‐dependent ferritinophagy, consequently elevating Fe 2+ levels. Additionally, PB demonstrated the potential to impede the growth of GC cells, suppress migration and invasion, induce apoptosis, and arrest cell cycle progression 145 . Similarly, Jiyuan oridonin A (JDA), a natural compound derived from Jiyuan Rabdosia rubescens , and its derivatives have been found to induce the accumulation of Fe 2+ through the autophagic pathway, leading to iron‐mediated cell death and effectively inhibiting the growth of GC cells.…”