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

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Journal of Natural Medicines Pub Date : 2024-04-26 DOI:10.1007/s11418-024-01811-4

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

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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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多粘菌素 I 通过同时靶向 PI3K/SREBP-1/SCD1 轴和引发脂质过氧化，诱导急性髓性白血病的快速铁变态反应。

急性髓性白血病（AML）是一种难以完全治愈的恶性疾病。多粘菌素 I（PPI）是从巴黎多粘菌素中分离出来的一种甾体皂甙，具有多种生物活性。在这里，我们发现了 PPI 对 AML 细胞 MOLM-13 的卓越细胞毒性，其 IC50 值为 0.44 ± 0.09 μM。从机理上讲，PPI 可通过细胞内铁浓度的积累和引发脂质过氧化而导致铁变态反应。有趣的是，与厄拉斯汀相比，PPI能在短时间内（约6小时）诱导更强的铁变态反应。此外，我们还证明了PPI诱导的快速铁中毒是由于同时靶向PI3K/SREBP-1/SCD1轴和引发脂质过氧化所致，而PI3K抑制剂Alpelisib能增强厄拉斯汀诱导铁中毒的活性。分子对接模拟和激酶抑制实验证明，PPI 是一种 PI3K 抑制剂。此外，PPI能明显抑制肿瘤进展，并延长小鼠的生存期，4 mg/kg的剂量具有良好的耐受性。总之，我们的研究突出了PPI治疗急性髓细胞白血病的潜力，并显示了其独特的双重机制。

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来源期刊

Journal of Natural Medicines 医学-药学

CiteScore

6.90

自引率

3.00%

发文量

审稿时长

1.7 months

期刊介绍： The Journal of Natural Medicines is an international journal publishing original research in naturally occurring medicines and their related foods and cosmetics. It covers: -chemistry of natural products -biochemistry of medicinal plants -pharmacology of natural products and herbs, including Kampo formulas and traditional herbs -botanical anatomy -cultivation of medicinal plants. The journal accepts Original Papers, Notes, Rapid Communications and Natural Resource Letters. Reviews and Mini-Reviews are generally invited.