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

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

  • J Nat Med. 2024 Jun;78(3):618-632. doi: 10.1007/s11418-024-01811-4.
Xinyu Zhou 1,  Duanna Zhang 1,  Jieting Lei 1,  Jixia Ren 2,  Bo Yang 3 4,  Zhixing Cao 5,  Chuanjie Guo 6 7,  Yuzhi Li 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
  • 2 College of Life Science, Liaocheng University, Liaocheng, 252059, China.
  • 3 Department of Pharmacy, Panzhihua Central Hospital, Dali University, Panzhihua, China.
  • 4 Department of Pharmacy, The Seventh People's Hospital of Chengdu, Chengdu, China.
  • 5 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. caozhixing@cdutcm.edu.cn.
  • 6 School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. guochuanjie@cdutcm.edu.cn.
  • 7 Department of Pharmacy, The Seventh People's Hospital of Chengdu, Chengdu, China. guochuanjie@cdutcm.edu.cn.
  • 8 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China. liyuzhi@cdutcm.edu.cn.
PMID: 38668832 DOI: 10.1007/s11418-024-01811-4
Abstract

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 IC50 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.

Keywords

AML; Ferroptosis; PI3K/SREBP-1/SCD1; Polyphyllin I; ROS.

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