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. 2021 Mar;35(3):1508-1520.
doi: 10.1002/ptr.6918. Epub 2020 Nov 8.

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

Yu-Jin Lee  1 , Jiyeon Choi  1 , Yae Jin Yoon  1 , Yugyeong Sim  1   2 , Hyung Won Ryu  3 , Sei-Ryang Oh  3 , Doo-Young Kim  3 , Jihyun Hwang  4 , Seung-Wook Chi  2   4 , Dong Cho Han  1   2 , Byoung-Mog Kwon  1   2
Affiliations

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

Yu-Jin Lee et al. Phytother Res. 2021 Mar.

Abstract

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.

Keywords: 8-Epi-xanthatin; ROS; STAT3; Xanthium fruit; anticancer.

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