Department of Chemistry, Columbia University, New York, NY 10027, USA.
Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
Cell Chem Biol. 2019 May 16;26(5):623-633.e9. doi: 10.1016/j.chembiol.2019.01.008. Epub 2019 Feb 21.
Ferroptosis is a form of regulated cell death that can be induced by inhibition of the cystine-glutamate antiporter, system x. Among the existing system x inhibitors, imidazole ketone erastin (IKE) is a potent, metabolically stable inhibitor of system x 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, 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.
铁死亡是一种受调控的细胞死亡形式，可以通过抑制胱氨酸-谷氨酸反向转运体系统 x 来诱导。在现有的系统 x 抑制剂中，咪唑酮类化合物 erastin（IKE）是一种有效的、代谢稳定的系统 x 抑制剂，能够诱导铁死亡，具有潜在的体内应用价值。我们在弥漫性大 B 细胞淋巴瘤（DLBCL）异种移植模型中研究了 IKE 的药代动力学和药效学特征，证明 IKE 通过抑制系统 x 发挥抗肿瘤作用，导致谷胱甘肽耗竭、脂质过氧化和铁死亡生物标志物的诱导，无论是在体外还是体内。通过非靶向脂质组学和 qPCR，我们鉴定了 IKE 诱导的铁死亡中脂质代谢的独特特征。此外，我们还使用可生物降解的聚乙二醇-聚（乳酸-共-羟基乙酸）纳米粒来辅助 IKE 的递送，与 DLBCL 异种移植模型中的游离 IKE 相比，其毒性降低。
