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

被引：685

作者：

Zhang, Yan ^{[1
]}

Tan, Hui ^{[1
]}

Daniels, Jacob D. ^{[2
]}

Zandkarimi, Fereshteh ^{[3
,4
]}

Liu, Hengrui ^{[1
]}

Brown, Lewis M. ^{[3
,4
]}

Uchida, Koji ^{[5
]}

O'Connor, Owen A. ^{[6
]}

Stockwell, Brent R. ^{[1
,3
]}

机构：

[1] Columbia Univ, Dept Chem, New York, NY 10027 USA

[2] Columbia Univ, Dept Pharmacol, Med Ctr, New York, NY 10032 USA

[3] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

[4] Columbia Univ, Quantitat Prote & Metabol Ctr, New York, NY 10027 USA

[5] Univ Tokyo, Grad Sch Agr & Life Sci, Tokyo 1138657, Japan

[6] Columbia Univ, Coll Phys & Surg, Ctr Lymphoid Malignancies, Med Ctr, New York, NY 10019 USA

来源：

CELL CHEMICAL BIOLOGY | 2019年 / 26卷 / 05期

关键词：

CELL-DEATH; LIPID-PEROXIDATION; NANOPARTICLES; DRUG; OPTIMIZATION; FORM;

D O I：

10.1016/j.chembiol.2019.01.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 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 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.

引用

页码：623 / +

页数：20

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