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.

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.

• Authors: Yu-Jin Lee, Jiyeon Choi, Yae Jin Yoon, Yugyeong Sim, Hyung Won Ryu, Sei-Ryang Oh, Doo-Young Kim, Jihyun Hwang, Seung-Wook Chi, Dong Cho Han, Byoung-Mog Kwon
• Journal: Phytotherapy research : PTR (Phytother Res) Vol. 35 Issue 3 Pg. 1508-1520 (Mar 2021) ISSN: 1099-1573 [Electronic] England
• PMID: 33164240 (Publication Type: Journal Article)
• Copyright: © 2020 John Wiley & Sons Ltd.

Chemical References

• Antineoplastic Agents, Phytogenic
• Furans
• Reactive Oxygen Species
• STAT3 Transcription Factor
• xanthatin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Female
• Fruit (chemistry)
• Furans (pharmacology, therapeutic use)
• Humans
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms (drug therapy, genetics)
• Reactive Oxygen Species (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction