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

• Published in: British journal of cancer Vol. 127; no. 2; pp. 364 - 376
• Main Authors: Zhan, Sheng, Lu, Li, Pan, Shu-shan, Wei, Xiao-qian, Miao, Rong-rong, Liu, Xiao-hui, Xue, Ming, Lin, Xiu-kun, Xu, Huan-li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20-07-2022; Nature Publishing Group
• Subjects: 631/154/1435; 631/67/1059; Apoptosis; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Cancer Research; Cell death; Cell Line, Tumor; Drug Resistance; Epidemiology; Ferroptosis; Flow cytometry; Glioma; Glioma - drug therapy; Glioma - genetics; Glioma - metabolism; Humans; Kinases; Molecular Docking Simulation; Molecular Medicine; mRNA; NAD(P)H Dehydrogenase (Quinone) - genetics; NADPH dehydrogenase; Naphthoquinones - pharmacology; Oncology; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Plumbagin; Proteomics; Shikonin
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-022-01800-y

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.