Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system xc-. Among the existing system xc- inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system xc- and inducer of ferroptosis potentially suitable for in vivo applications[1]. The IC50 of GSH depletion by IKE was 34 nM in SUDHL6 cells. Analysis of lipid reactive oxygen species (ROS) by flow cytometry using the lipid peroxidation probe C11-BODIPY revealed a dose-dependent increase in lipid ROS upon IKE treatment in SUDHL6 cells. Immunofluorescence staining with an anti-dihydropyridine-MDA-lysine adduct antibody (mAb 1F83) revealed that dihydropyridine-MDA-lysine adduct abundance was increased upon IKE treatment[1]. The system xc- component SLC7A11, prostaglandin-endoperoxide synthase 2 (PTGS2, which encodes cyclooxygenase-2), and ChaC GSH-specific γ-glutamylcyclotransferase 1 (CHAC1) expression was significantly increased in SUDHL6 cells following IKE treatment[1]. IKE exhibits antitumor activity in DLBCL (diffuse large B cell lymphoma) xenograft model, which correlates with an increase of lipid peroxidation in tumors. These findings suggest that IKE can be effective as a potential therapeutic regimen for DLBCL[1].
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