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8‐Epi‐xanthatin induces the apoptosis of DU145 prostate carcinoma cells through signal transducer and activator of transcription 3 inhibition and reactive oxygen species generation

Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in many human cancers. We tried to find STAT3 inhibitors from natural sources and found that Xanthium fruit extracts decreased phosphorylation of STAT3‐Y705. 8‐Epi‐xanthatin (EXT) was isolated from the extracts. When DU145 cancer cells were treated with EXT, p‐STAT3‐Y705 was decreased with an IC50 of 3.2 μM. EXT decreased the expression of STAT3 target genes, such as cyclin A, cyclin D1, and BCL‐2, and induced PARP cleavage, indicating apoptotic cell death. Downregulation of EXT‐induced p‐STAT3‐Y705 was rescued by pretreating DU145 cells with antioxidants, such as N‐acetyl‐L‐cysteine (NAC), indicating that reactive oxygen species (ROS) were involved in the EXT‐induced inhibition of STAT3 activation. Furthermore, we proved the association of EXT with STAT3 protein by using a drug affinity responsive target stability (DARTS) assay and a cellular thermal shift assay (CETSA). EXT inhibited proliferation of DU145 cells with a GI50 of 6 μM and reduced tumor growth in mice xenografted with DU145 cells. Immunoblotting showed that phosphorylation of STAT3‐Y705 was lower in EXT‐treated tumor tissue than in control tissues. Collectively, we found that EXT binds to, and inhibits, STAT3 activation and could be a lead compound for anticancer therapy.