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

  • Phytother Res. 2021 Mar;35(3):1508-1520. doi: 10.1002/ptr.6918.
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
  • 1. Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
  • 2. University of Science and Technology in Korea, Daejeon.
  • 3. Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, South Korea.
  • 4. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
PMID: 33164240 DOI: 10.1002/ptr.6918
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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