Identification and initial characterization of a potent inhibitor of ferroptosis

Abstract

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.

Tumor suppressor p53 promotes ferroptosis in oxidative stress conditions independent of modulation of ferroptosis by p21, CDKs, RB, and E2F

“…Absorbance was normalized to DMSO and given as 1 or 100% for cell viability. We have recently shown that, in the context of ferroptosis, methylene blue staining results are very similar to MTT assay (47). Results are representative of at least two independent experiments.…”

“…To gain more insight into the role of p53 in ferroptosis we used CETZOLE 1 discovered in our lab (18). Cell death induced by CETZOLE 1 has many of the hallmarks of ferroptosis including elevated lipid ROS, loss of reduced glutathione and reversal by ferroptotic inhibitors liproxstatin and ferrostatin (19,47) Some of the studies reported herein were repeated using the GPX4 inhibitor RSL3 and the well-documented ferroptosis compound Erastin. Using a variety of inducible systems we observed that p53 enhanced ferroptosis induced by CETZOLE-1.…”

Efficient Magnetic Nanocatalyst-Induced Chemo- and Ferroptosis Synergistic Cancer Therapy in Combination with T1–T2 Dual-Mode Magnetic Resonance Imaging Through Doxorubicin Delivery

“…In addition, GPX4 protein could effectively eliminate cellular ROS through converting GSH into GSSG, and then avoid ferroptosis. 34,35 Therefore, the expression of GPX4 was considered to be an important ferroptotic marker. In Fig.…”

Tunable Cysteine-Targeting Electrophilic Hetero-Aromatic Warheads Induce Ferroptosis

“…Compounds 27-30 were subjected to halogenation at the 2-position using perfluorobutyl iodide or carbon tetrabromide to generate the corresponding iodo and bromo analogs (31)(32)(33)(34)(35)(36)(37)(38) 33 . They were then subjected to Sonogashira, Suzuki and decarboxylative cross coupling to provide the corresponding terminal alkyne (43)(44)(45), terminal alkene (39)(40)(41) and propyne analogs (45), respectively. The corresponding alkene and alkyne selenium analogs (( 42) and (47), respectively) were synthesized as shown in scheme 3 from intermediate (26) through peptide coupling with the corresponding carboxylate followed by deoxygenative cyclization with POCl3 34 .…”