Chaetocochin J exhibits anti-hepatocellular carcinoma effect independent of hypoxia.

Autor: Hu P; State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Centre of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430062, Hubei, China., Hu L; State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Centre of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430062, Hubei, China., Chen Y; Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China., Wang F; Department of Pharmacy, Wuhan No.1 Hospital, 215 Zhongshan Road, Wuhan 430022, Hubei, China; Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, Hubei, China., Xiao Y; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China., Tong Z; State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Centre of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430062, Hubei, China., Li H; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China., Xiang M; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China., Tong Q; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China. Electronic address: qytong@hust.edu.cn., Zhang Y; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China. Electronic address: zhangyh@mails.tjmu.edu.cn.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Oct; Vol. 139, pp. 106701. Date of Electronic Publication: 2023 Jun 25.
DOI: 10.1016/j.bioorg.2023.106701
Abstrakt: The most studied epipolythiodioxopiperazine (ETP) alkaloids, such as chetomin, gliotoxin and chaetocin, were reported to exert their antitumor effects through targeting HIF-1α. Chaetocochin J (CJ) is another ETP alkaloid, of which the effect and mechanism on cancer are not fully elucidated. Considering the high incidence and mortality of hepatocellular carcinoma (HCC) in China, in the present study, using HCC cell lines and tumor-bearing mice as models, we explored the anti-HCC effect and mechanism of CJ. Particularly, we investigated whether HIF-1α is related to the function of CJ. The results showed that, both under normoxic and CoCl 2 induced-hypoxic conditions, CJ in low concentrations (<1 µM) inhibits the proliferation, induces G2/M phase arrest, leading to the disorder of metabolism, migration, invasion, and caspase-dependent apoptosis in HepG2 and Hep3B cells. CJ also showed anti-tumor effect on a nude xenograft mice model without significant toxicity. Moreover, we demonstrated that the key to CJ's function is mainly associate with its inhibition of PI3K/Akt/mTOR/p70S6K/4EBP1 pathway independent of hypoxia, and it also could suppress the expression of HIF-1α as well as disrupt the binding of HIF-1α/p300 and subsequently inhibits the expression of its target genes under hypoxic condition. These results demonstrated that CJ possessed a hypoxia-independent anti-HCC effects in vitro and in vivo, which was mainly attributable to its inhibition on the upstream pathways of HIF-1α.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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