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Identification and initial characterization of a potent inhibitor of ferroptosis
Journal of Cellular Biochemistry ( IF 4 ) Pub Date : 2020-12-29 , DOI: 10.1002/jcb.29870
Nishanth Kuganesan 1 , Samkeliso Dlamini 2 , Jade McDaniel 2 , Viranga L M Tillekeratne 2 , William R Taylor 1
Affiliation  

Ferroptosis is a form of iron‐dependent cell death characterized by elevated lipid peroxides and reactive oxygen species (ROS). Glutathione (GSH) plays an essential role in scavenging ROS to maintain cell viability and acts as a cofactor of GSH peroxidase 4 (GPX4) that protects lipids from oxidation. We have previously described a novel class of small molecules that induce ferroptosis in certain types of cancer cells. These compounds induce ferroptosis by blocking the uptake of cystine required for GSH synthesis. Even though ferroptosis is a well‐established form of cell death, signaling pathways that modulate this process are not known. Therefore, we used a panel of growth factors/kinase inhibitors to test effects on ferroptosis induced by our lead compound. We discovered that BMS536924, a dual inhibitor of insulin‐like growth and insulin receptors, is a potent inhibitor of ferroptosis. Further investigation indicated that the anti‐ferroptotic activity of BMS536924 does not lie in its ability to inhibit insulin signal transduction. Instead, we provide evidence that BMS536924 binds iron, an essential cofactor in ferroptosis. Our results suggest caution in interpreting the effects of BMS536924 in investigations of insulin signaling and uncover a novel ferroptosis inhibitor.

中文翻译:

一种有效的铁死亡抑制剂的鉴定和初步表征

铁死亡是一种铁依赖性细胞死亡形式,其特征是脂质过氧化物和活性氧 (ROS) 升高。谷胱甘肽 (GSH) 在清除 ROS 以维持细胞活力方面发挥重要作用,并作为保护脂质免受氧化的 GSH 过氧化物酶 4 (GPX4) 的辅助因子。我们之前已经描述了一类新的小分子,可在某些类型的癌细胞中诱导铁死亡。这些化合物通过阻断 GSH 合成所需的胱氨酸摄取来诱导铁死亡。尽管铁死亡是一种公认​​的细胞死亡形式,但调节这一过程的信号通路尚不清楚。因此,我们使用一组生长因子/激酶抑制剂来测试我们的先导化合物对铁死亡的影响。我们发现 BMS536924,胰岛素样生长和胰岛素受体的双重抑制剂,是一种有效的铁死亡抑制剂。进一步研究表明,BMS536924 的抗铁死亡活性并不在于其抑制胰岛素信号转导的能力。相反,我们提供了 BMS536924 与铁结合的证据,铁是铁死亡的重要辅助因子。我们的研究结果表明,在解释 BMS536924 在胰岛素信号传导研究中的作用时要谨慎,并发现一种新型的铁死亡抑制剂。
更新日期:2021-02-16
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