FA16 is a Specific Ferroptosis Inducer with Metabolic Stability

Ferroptosis is an iron-dependent form of regulatory cell death (RCD). Ferroptosis is an oxidative cell death distinct from apoptosis, driven by intense lipid peroxidation. System X_c^–-GSH-GPX4 is the main ferroptosis inhibition pathway. Among them, system System X_c^– is a cystine/glutamic acid antitransporter. It is responsible for the introduction of extracellular cysteine, supplies cells with cysteine needed for glutathione biosynthesis. GPX4 can use reduced glutathione (GSH) to reduce lipid peroxide to lipid alcohol, thereby inhibiting lipid peroxidation and iron death. Therefore, triggering iron death is an effective antitumor strategy. Here will introduce a powerful system System X_c^– inhibitor and ferroptosis inducer, FA16.

FA16 potently induces ferroptosis via system System X_c^–, which suppresses tumor progression.

FA16 is a specific ferroptosis inducer without leading to apoptosis or necroptosis. And it (1 μM; 5 min) exhibits metabolic stability in both human and rat liver microsomes. Specifically, FA16 shows lethality against human HT1080 fibrosarcoma cells with an IC₅₀ value of 1.26 μM. Moreover, it (5 μM; 10 h) induces lipid ROS accumulation and inhibits glutamic acid release in HT1080 cells. And it (5 μM; 24 h) also causes mitochondrial atrophy and increases membrane density. Furthermore, FA16 is a system System X_c^– inhibitor. It (0.5-5 μM; 12 h) inhibits the GSH levels dose-dependently and up-regulates system System X_c^– SLC7A11 and CHAC1 gene expression.

Therefore, FA16 has been demonstrated anti-tumor efficacy in vivo. It (15 mg/kg, 30 mg/kg; i.p.; every other day for 21 days) significantly inhibits tumor growth in a 786-O xenograft mouse model. FA16 has good safety (does not cause weight loss) and also induces ferroptosis in tumor tissue.

Above all, FA16 is a suitable ferroptosis-inducing tool. It acts function by inhibiting system System X_c^–, interfering with GSH biosynthesis. Meanwhile, it effectively suppresses tumor growth with in vivo safety.

Reference:

[1] Fang Y, et al. Eur J Med Chem. 2023 Jan 5;245(Pt 1):114905.