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

Yan Zhang; Hui Tan; Jacob D Daniels; Fereshteh Zandkarimi; Hengrui Liu; Lewis M Brown; Koji Uchida; Owen A O'Connor; Brent R Stockwell

doi:10.1016/j.chembiol.2019.01.008

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. Epub 2019 Feb 21.

Authors

Yan Zhang¹, Hui Tan¹, Jacob D Daniels², Fereshteh Zandkarimi³, Hengrui Liu¹, Lewis M Brown³, Koji Uchida⁴, Owen A O'Connor⁵, Brent R Stockwell⁶

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.

Abstract

Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system x_c^-. Among the existing system x_c^- inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system x_c^- 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 x_c^-, 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)(–).

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Cell Proliferation / drug effects
Disease Models, Animal
Drug Carriers / chemistry
Female
Ferroptosis / drug effects*
Half-Life
Humans
Imidazoles / chemistry
Imidazoles / pharmacology*
Imidazoles / therapeutic use
Ketones / chemistry
Ketones / pharmacology*
Ketones / therapeutic use
Lipid Metabolism / genetics
Lipid Peroxidation / drug effects
Lymphoma / drug therapy
Lymphoma / metabolism
Lymphoma / pathology
Male
Mice
Mice, Inbred NOD
Mice, SCID
Nanoparticles / chemistry
Piperazines / chemistry*
Piperazines / pharmacology
Piperazines / therapeutic use
Polyethylene Glycols / chemistry
Polyglactin 910 / chemistry

Substances

Antineoplastic Agents
Drug Carriers
Imidazoles
Ketones
Piperazines
erastin
imidazole ketone erastin
polyethylene glycol-poly(lactic-co-glycolic acid)-polyethylene glycol
Polyglactin 910
Polyethylene Glycols

Abstract

Publication types

MeSH terms

Substances

Grants and funding