Pomiferin Induces Antiproliferative and Pro-Death Effects in High-Risk Neuroblastoma Cells by Modulating Multiple Cell Death Pathways

Resistance to chemotherapy-induced apoptosis significantly hinders the successful treatment of high-risk neuroblastoma (NB). Natural compounds, such as osajin and pomiferin-isoflavones extracted from Osage orange (<i>Maclura pomifera</i> [Raf.] Schneid.)-have known anti-inflammatory and anticancer properties and may have the potential as a therapeutic agent to target conventional drug resistance in NB. In this study, we investigated the antiproliferative and cytotoxic potential of osajin and pomiferin in NB cell lines. Both compounds reduced proliferation and induced cytotoxicity, with pomiferin showing a lower IC50 than osajin. Using multiple techniques, we show that pomiferin induced a dose-dependent increase in apoptosis. In addition to apoptosis, we identified the activation of multiple cell death pathways. Pomiferin induced ferroptosis by inhibiting GPX4 and increasing lipid peroxidation. In addition, pomiferin treatment significantly impaired autophagic machinery. LAN5, a <i>MYCN</i>-amplified cell line, showed increased gasdermin E cleavage in response to pomiferin, suggesting pyroptosis. No changes were observed in phosphorylated MLKL, indicating the absence of necroptosis. In conclusion, our comprehensive evaluation demonstrates that pomiferin activates multiple cell death pathways in high-risk NB cells, potentially offering a valuable strategy to overcome drug resistance to conventional chemotherapy.