anti-NSCLC agent-2

Anti-NSCLC agent-2 (compound 6o) is an inhibitor of SLC7A11 and GPX4, resulting in decreased expression of these crucial regulators of ferroptosis. It disrupts redox homeostasis, depletes glutathione, accumulates lipid peroxides, and induces ferroptosis in non-small cell lung cancer cells. Anti-NSCLC agent-2 is applicable for research on non-small cell lung cancer.

Anti-NSCLC agent-2 (compound 6o) effectively inhibits the proliferation of non-small cell lung cancer cell lines including A549, H1299, H2030, H1975, A549/T, and A549/CDDP, with IC50 values ranging from 1.54 nM to 11.72 nM, showing no significant toxicity to normal HUVECs at effective concentration levels. At 100 μM for 2.5 hours, this compound releases 10.02 μM of nitric oxide in A549 cells. Its antiproliferative activity on A549 and A549/CDDP cells at 50 nM over 48 hours is nitric oxide-dependent, as demonstrated by a concentration-dependent reversal through hemoglobin scavenging. Similarly, at 100 nM for 48 hours, the ferroptosis-dependent antiproliferative effect is reversed by Ferrostatin-1 in a concentration-dependent manner. The compound also increases ferrous ion accumulation and lipid peroxidation in these cells in a dose-dependent manner, with green/red fluorescence ratios rising to 1.51 and 1.10, respectively. At 15-60 nM for 12 hours, it downregulates SLC7A11 and GPX4 protein expression in A549 and A549/CDDP cells through a ferroptotic mechanism. Dose- and time-dependent increase in reactive oxygen species levels is observed at 20-80 nM over 3-12 hours. It depletes intracellular glutathione and reduces the GSH/GSSG ratio at 40-80 nM over 12 hours, disrupting redox homeostasis. Furthermore, it elevates mitochondrial nitric oxide levels (20 nM for A549 cells and 80 nM for A549/CDDP cells over 4 hours) and induces dose-dependent mitochondrial membrane potential collapse and increased mitochondrial reactive oxygen species (superoxide) levels.

Compound 6o, known as anti-NSCLC agent-2, exhibits dose-dependent in vivo antiproliferative effects on cisplatin-resistant A549/CDDP xenografts when administered intravenously at 5-10 mg/kg every two days for 20 days. A 10 mg/kg dose demonstrates superior efficacy compared to 10 mg/kg of cisplatin, with good safety and no observed organ toxicity.