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Translational Therapeutics

Targeting NQO1/GPX4-mediated ferroptosis by plumbagin suppresses in vitro and in vivo glioma growth

British Journal of Cancer volume 127, pages 364–376 (2022)Cite this article

Subjects

Abstract

Background

Ferroptosis has attracted increasing interest in cancer therapy. Emerging evidences suggest that naturally occurring naphthoquinones exhibit potent anti-glioma effects via various mechanisms.

Methods

The anti-glioma effects of plumbagin were evaluated by in vitro and in vivo experiments. Anti-glioma mechanism of plumbagin was studied by proteomics, flow cytometry, MDA assay, western blot, and RT-PCR. Gene knockdown/overexpression, molecular docking, PharmMappper database, and coimmunoprecipitation were used to study the targets of plumbagin.

Results

Plumbagin showed higher blood–brain barrier penetration ability than that of lapachol and shikonin and elicited significant growth inhibitory effects in vitro and in vivo. Ferroptosis was the main mechanism of plumbagin-induced cell death. Mechanistically, plumbagin significantly downregulated the protein and mRNA levels of xCT and decreased GPX4 protein levels. NAD(P)H quinone dehydrogenase 1 (NQO1) was revealed as a plumbagin predictive target using PharmMappper database and molecular docking. Plumbagin enhanced NQO1 activity and decreased xCT expression, resulting in NQO1-dependent cell death. It also induced GPX4 degradation via the lysosome pathway and caused GPX4-dependent cell death.

Conclusions

Plumbagin inhibited in vitro and in vivo glioma growth via targeting NQO1/GPX4-mediated ferroptosis, which might be developed as a novel ferroptosis inducer or anti-glioma candidate.

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Fig. 1: PLB significantly inhibited glioma growth in vitro and in vivo.
Fig. 2: PLB induced ferroptosis in glioma cells.
Fig. 3: PLB induced ferroptosis-dependent cell death.
Fig. 4: xCT and GPX4 expression levels decreased in PLB-induced ferroptosis.
Fig. 5: PLB induced GPX4-dependent cell death by causing GPX4 degradation.
Fig. 6: PLB induced ferroptosis by targeting NQO1.

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Data availability

Data are also available as Supplementary Information.

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Acknowledgements

We thank Mrs. Yang Hui in core facility centre of Capital Medical University for their technique assistance in transmission electron microscopy analysis.

Funding

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81774191 and 82174265), the International Collaborative of Ministry of Science and Technology (No. 2017YEE0915000), and National Science Foundation of Shandong Province in China (Nos. ZR201911020118 and ZR201911110299).

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Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, China

    Sheng Zhan, Li Lu, Shu-shan Pan, Xiao-qian Wei, Rong-rong Miao, Xiao-hui Liu, Ming Xue, Xiu-kun Lin & Huan-li Xu

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Contributions

Conceptualisation, H-lX, X-kL, MX; methodology, SZ, LL, R-rM, X-qW, S-sP; formal analysis, SZ, H-lX; writing—original draft preparation, SZ, LL; writing—review and editing, H-lX, X-kL, MX; funding acquisition, H-lX, X-kL. All authors have approved the final article.

Corresponding author

Correspondence to Huan-li Xu.

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The authors declare no competing interests.

Ethics approval and consent to participate

All animal experiments were approved by the Committee of Animal Experiments and Experimental Animal Welfare of Capital Medical University in Beijing, China (Nos. AEEI-2019078 and 37363) and performed in accordance with the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978).

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Zhan, S., Lu, L., Pan, Ss. et al. Targeting NQO1/GPX4-mediated ferroptosis by plumbagin suppresses in vitro and in vivo glioma growth. Br J Cancer 127, 364–376 (2022). https://doi.org/10.1038/s41416-022-01800-y

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