Polyphyllin I induces rapid ferroptosis in acute myeloid leukemia through simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering of lipid peroxidation

• Published in: Journal of natural medicines 2024-06, Vol.78 (3), p.618-632
• Main Authors: Zhou, Xinyu, Zhang, Duanna, Lei, Jieting, Ren, Jixia, Yang, Bo, Cao, Zhixing, Guo, Chuanjie, Li, Yuzhi
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute myeloid leukemia; Animals; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Complementary & Alternative Medicine; Cytotoxicity; Diosgenin - analogs & derivatives; Diosgenin - pharmacology; Diosgenin - therapeutic use; Ferroptosis; Ferroptosis - drug effects; Humans; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; Medicinal Chemistry; Mice; Molecular Docking Simulation; myeloid leukemia; neoplasm progression; Original Paper; Paris polyphylla; Pharmacology/Toxicology; Pharmacy; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - metabolism; Plant Sciences; Saponins; Saponins - chemistry; Saponins - pharmacology; steroid saponins; Sterol regulatory element-binding protein; therapeutics
• ISSN: 1340-3443; 1861-0293; 1861-0293
• DOI: 10.1007/s11418-024-01811-4

Acute myeloid leukemia (AML) is a malignant disease that is difficult to completely cure. Polyphyllin I (PPI), a steroidal saponin isolated from Paris polyphylla , has exhibited multiple biological activities. Here, we discovered the superior cytotoxicity of PPI on AML cells MOLM-13 with an IC 50 values of 0.44 ± 0.09 μM. Mechanically, PPI could cause ferroptosis via the accumulation of intracellular iron concentration and triggering lipid peroxidation. Interestingly, PPI could induced stronger ferroptosis in a short time of about 6 h compared to erastin. Furthermore, we demonstrate that PPI-induced rapid ferroptosis is due to the simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering lipid peroxidation, and PI3K inhibitor Alpelisib can enhance the activity of erastin-induced ferroptosis. Molecular docking simulations and kinase inhibition assays demonstrated that PPI is a PI3K inhibitor. In addition, PPI significantly inhibited tumor progression and prolonged mouse survival at 4 mg/kg with well tolerance. In summary, our study highlights the therapeutic potential of PPI for AML and shows its unique dual mechanism. Graphical abstract