FA16 is a ferroptosis inducer and an inhibitor of the system xc- cystine/glutamate transporter.[1] It reduces the viability of various cancer cell lines, including HT-1080 fibrosarcoma and A375 melanoma cells (IC50s = 1.26 and 2.31 µM, respectively), 786-O renal cell carcinoma cells (IC50 = 0.7 µM), and MDA-MB-231 breast cancer cells (IC50 = 4.34 µM) but not several non-cancer cell lines at 20 µM. FA16-induced death of HT-1080 cells can be blocked by the ferroptosis inhibitors ferrostatin-1 , Trolox , and deferoxamine (DFO; ) and potentiated by ferric ammonium citrate or ferric citrate. FA16-induced death of HT-1080 cells can also be blocked by β-mercaptoethanol, which prevents cell death induced by system xc- cystine/glutamate transporter inhibition by increasing intracellular cystine bioavailability. FA16 (5 µM) increases the production of reactive oxygen species (ROS) in HT-1080 cells, an effect that can be blocked by ferrostatin-1, and inhibits glutamate release from HT-1080 cells in an enzyme-coupled glutamate release assay. FA16 (15 and 30 mg/kg) reduces tumor growth and increases intratumoral levels of 4-hydroxy nonenal (4-HNE; ) and malondialdehyde (MDA), markers of lipid peroxidation, in a HepG2 mouse xenograft model. It also has an increased half-life and slower clearance than the ferroptosis inducer erastin in human and rat liver microsomes.
References:
[1].Fang, Y., Tan, Q., Zhou, H., et al.Discovery and optimization of 2-(trifluoromethyl)benzimidazole derivatives as novel ferroptosis inducers in vitro and in vivoEur. J. Med. Chem.245(Pt 1)114905(2023).