Pomiferin induces anti-proliferative and pro-death effects in high-risk Neuroblastoma cells by modulating multiple cell death pathways

Authors: GNANAMONY, MANU - University Of Illinois; THOMAS, MARIA - University Of Illinois; NGUYEN, THU HIEN - University Of Illinois; Brownstein, Korey; DE ALARCON, PEDRO - University Of Illinois

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/8/2025
Publication Date: 4/11/2025
Citation: Gnanamony, M., Thomas, M., Nguyen, T., Brownstein, K.J., De Alarcon, P. 2025. Pomiferin induces anti-proliferative and pro-death effects in high-risk Neuroblastoma cells by modulating multiple cell death pathways. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms26083600.
DOI: https://doi.org/10.3390/ijms26083600

Interpretive Summary: Treating high-risk Neuroblastoma (NB), a type of pediatric cancer, is challenging due to disease relapse and drug resistance. In this study, we explored natural compounds osajin and pomiferin, found in Osage orange, as potential solutions. We found that both compounds reduced cancer cell growth and were toxic to the cells, with pomiferin being more effective. Pomiferin caused cancer cells to die through several mechanisms, including apoptosis, ferroptosis (iron-dependent cell death), and pyroptosis (inflammatory cell death). Overall, the research suggests that pomiferin could be a promising strategy to improve treatment for high-risk Neuroblastoma by activating multiple cell-death pathways and overcoming drug resistance.

Technical Abstract: Disease relapse and drug resistance significantly hinder the successful treatment of high-risk Neuroblastoma (NB). Natural compounds, such as osajin and pomiferin—iso'avones extracted from Osage orange (Maclura pomifera [Raf.] Schneid.) may offer novel approaches to target multiple cell death pathways and overcome drug resistance. We investigated the anti-proliferative effects and mechanisms of cell death activation in high-risk NB cell lines treated with osajin and pomiferin. Both compounds reduced proliferation and induced cytotoxicity in NB cell lines, with pomiferin showing a lower IC50 than osajin. Using multiple techniques, we show that pomiferin induced a dose dependent increase in apoptotic cells. Additionally, lipid peroxidation assay indicated that pomiferin induced ferroptosis, while increased gasdermin E cleavage suggested activation of pyroptosis. Pomiferin also significantly impaired autophagic machinery, though no changes were observed in phosphorylated MLKL, indicating 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.