Gnanamony Manu, Thomas Maria, Nguyen Thu Hien, Brownstein Korey, de Alarcon Pedro A
Department of Pediatrics, University of Illinois College of Medicine Peoria, One Illini Drive, Peoria, IL 61605, USA.
Functional Foods Research Unit, United States Department of Agriculture, Agricultural Research Service, National Center for Agricultural Utilization Research, Peoria, IL 61604, USA.
Int J Mol Sci. 2025 Apr 11;26(8):3600. doi: 10.3390/ijms26083600.
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 ( [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 -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.
对化疗诱导的细胞凋亡产生抗性显著阻碍了高危神经母细胞瘤（NB）的成功治疗。天然化合物，如从桑橙（[Raf.] Schneid.）中提取的奥沙金和波米佛林异黄酮，具有已知的抗炎和抗癌特性，可能有潜力作为一种治疗剂来靶向NB中的传统耐药性。在本研究中，我们研究了奥沙金和波米佛林在NB细胞系中的抗增殖和细胞毒性潜力。两种化合物均降低了细胞增殖并诱导了细胞毒性，波米佛林的半数抑制浓度（IC50）低于奥沙金。使用多种技术，我们表明波米佛林诱导了凋亡的剂量依赖性增加。除了凋亡，我们还鉴定了多种细胞死亡途径的激活。波米佛林通过抑制谷胱甘肽过氧化物酶4（GPX4）并增加脂质过氧化来诱导铁死亡。此外，波米佛林处理显著损害了自噬机制。LAN5，一种MYCN扩增的细胞系，对波米佛林有反应，显示出gasdermin E切割增加，提示细胞焦亡。磷酸化混合谱系激酶结构域样蛋白（p-MLKL）未观察到变化，表明不存在坏死性凋亡。总之，我们的综合评估表明，波米佛林在高危NB细胞中激活了多种细胞死亡途径，可能为克服对传统化疗的耐药性提供一种有价值的策略。
