2. Academic Validation
  3. Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model

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

  • Cell Chem Biol. 2019 May 16;26(5):623-633.e9. doi: 10.1016/j.chembiol.2019.01.008.
Yan Zhang 1,  Hui Tan 1,  Jacob D Daniels 2,  Fereshteh Zandkarimi 3,  Hengrui Liu 1,  Lewis M Brown 3,  Koji Uchida 4,  Owen A O'Connor 5,  Brent R Stockwell 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Columbia University, New York, NY 10027, USA.
  • 2 Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
  • 3 Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Quantitative Proteomics and Metabolomics Center, Columbia University, New York, NY 10027, USA.
  • 4 Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
  • 5 Center for Lymphoid Malignancies, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10019, USA.
  • 6 Department of Chemistry, Columbia University, New York, NY 10027, USA; Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: bstockwell@columbia.edu.
PMID: 30799221 DOI: 10.1016/j.chembiol.2019.01.008
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.

Keywords

DLBCL; ROS; cancer; cell death; cysteine; cystine; erastin; ferroptosis; glutathione; lipidomics; lymphoma; nanoparticle; peroxidation; system x(c)(–).

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