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26-04-2024 | Acute Myeloid Leukemia | Original Paper

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

Authors: Xinyu Zhou, Duanna Zhang, Jieting Lei, Jixia Ren, Bo Yang, Zhixing Cao, Chuanjie Guo, Yuzhi Li

Published in: Journal of Natural Medicines | Issue 3/2024

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.

Graphical abstract

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Title: Polyphyllin I induces rapid ferroptosis in acute myeloid leukemia through simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering of lipid peroxidation
Authors: Xinyu Zhou
Duanna Zhang
Jieting Lei
Jixia Ren
Bo Yang
Zhixing Cao
Chuanjie Guo
Yuzhi Li
Publication date: 26-04-2024
Publisher: Springer Nature Singapore
Keyword: Acute Myeloid Leukemia
Published in: Journal of Natural Medicines / Issue 3/2024
Print ISSN: 1340-3443
Electronic ISSN: 1861-0293
DOI: https://doi.org/10.1007/s11418-024-01811-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Graphical abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Graphical abstract

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