7-氟-4-(4-氯苯氧基)喹啉化合物对肺癌A549细胞焦亡研究OA

Objective To explore 7-Fluoro-4-(4-chlorophenoxy)(IB)molecular mechanisms of inducing pyroptosis in lung cancer A549 cells.Methods The potential targets of IB were screened by bioinformatics,and the"drug-target-pathway"network was constructed,and its binding ability to cysteine-aspartate-specific proteolytic enzymes(caspase)-1 and caspase-3 was analysed by molecular docking.The spheroid model of A549 was established by three-dimensional culture of coating solution,and the induction of pyroptosis of IB and its mechanism were verified by acid phosphatase assay,enzyme-linked immunosorbent assay,western blotting assay and cell thermal displacement assay.Results A total of 23 intersecting targets(caspase-1,caspase-3,epidermal growth factor receptor,etc.)were screened,and Kyoto Encyclopedia of Genes and Genomes(KEGG)Enrichment Analysis showed that nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome was significantly regulated.IB binds to caspase-1 and caspase-3 with high affinity;IB inhibited cell proliferation in a dose-dependent manner,upregulated interleukin-1β(IL-1β)secretion,activated NOD-like receptor pyrotin domain-associated protein 3(NLRP3)/caspase-1/caspase-3,and promoted gasdermin D(GSDMD)/gasdermin E(GSDME)cleavage.Cellular thermal displacement assays confirmed that 7-fluoro-4-(4-chlorophenoxy)quinoline directly binds to caspase-1/3,and disulfiram reverses the pyroptosis phenotype.Conclusion 7-Fluoro-4-(4-chlorophenoxy)quinoline co-induces pyroptosis in A549 cells through the NLRP3/caspase-1/GSDMD classical pathway and caspase-3/GSDME non-canonical pathway,providing a new strategy for the treatment of non-small cell lung cancer.