Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model


Authors: Y. Zhang, H. Tan, J.D. Daniels, F. Zandkarimi, H. Liu, L.M. Brown, K. Uchida, O.A. O'Connor and B.R. Stockwell

Journal: Cell Chemical Biology

DOI: 10.1016/j.chembiol.2019.01.008

Publication - Abstract

February 27, 2019

Abstract

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. We investigated the pharmacokinetic and pharmacodynamic features of IKE in a diffuse large B cell lymphoma (DLBCL) xenograft model and demonstrated that IKE exerted an antitumor effect by inhibiting system xc, leading to glutathione depletion, lipid peroxidation, and the induction of ferroptosis biomarkers both in vitro and in vivo. Using untargeted lipidomics and qPCR, we identified distinct features of lipid metabolism in IKE-induced ferroptosis. In addition, biodegradable polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles were employed to aid in IKE delivery and exhibited reduced toxicity compared with free IKE in a DLBCL xenograft model.

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