1. Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT.
- Author
-
Wang Z, Ding Y, Wang X, Lu S, Wang C, He C, Wang L, Piao M, Chi G, Luo Y, and Ge P
- Subjects
- Amino Acid Transport System y+ metabolism, Animals, Brain Neoplasms pathology, Cell Line, Tumor transplantation, Cyclohexylamines pharmacology, Disease Models, Animal, Diterpenes therapeutic use, Down-Regulation drug effects, Gene Expression Regulation, Neoplastic drug effects, Glioma pathology, Glutathione metabolism, Humans, Hydrogen Peroxide metabolism, Iron metabolism, Mice, Mice, Nude, Mitochondria drug effects, Mitochondria metabolism, NADPH Oxidase 4 metabolism, Phenylenediamines pharmacology, Rats, Reactive Oxygen Species metabolism, Up-Regulation drug effects, Apoptosis drug effects, Brain Neoplasms drug therapy, Diterpenes pharmacology, Glioma drug therapy, Lipid Peroxidation drug effects
- Abstract
Ferroptosis is a form of programmed cell death decided by iron-dependent lipid peroxidation, but its role in glioma cell death remains unclear. In this study, we found Pseudolaric acid B (PAB) inhibited the viabilities of glioma cells in vitro and in vivo, which was accompanied by abnormal increases of intracellular ferrous iron, H
2 O2 and lipid peroxidation, as well as depletion of GSH and cysteine. In vitro studies revealed that the lipid peroxidation and the cell death caused by PAB were both inhibited by iron chelator deferoxamine, but exacerbated by supplement of ferric ammonium citrate. Inhibition of lipid peroxidation with ferrostatin-1 or GSH rescued PAB-induced cell death. Morphologically, the cells treated with PAB presented intact membrane, shrunken mitochondria with increased membrane density, and normal-sized nucleus without chromatin condensation. Mechanistically, PAB improved intracellular iron by upregulation of transferrin receptor. The increased iron activated Nox4, which resulted in overproduction of H2 O2 and lipid peroxides. Moreover, PAB depleted intracellular GSH via p53-mediated xCT pathway, which further exacerbated accumulation of H2 O2 and lipid peroxides. Thus, PAB triggers ferroptosis in glioma cells and is a potential medicine for glioma treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF