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Thiostrepton as a Potential Therapeutic Agent for Hepatocellular Carcinoma.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Carcinoma, Hepatocellular*/drug therapy ; Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/metabolism ; Liver Neoplasms*/drug therapy ; Liver Neoplasms*/pathology ; Liver Neoplasms*/metabolism ; Thiostrepton*/pharmacology ; Thiostrepton*/therapeutic use ; Cell Proliferation*/drug effects ; Reactive Oxygen Species*/metabolism ; Apoptosis*/drug effects ; Membrane Potential, Mitochondrial*/drug effects; Humans ; Cell Line, Tumor ; Mitochondria/drug effects ; Mitochondria/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Movement/drug effects ; Mitophagy/drug effects ; Autophagy/drug effects
    • Abstract:
      Due to limited drug efficacy and drug resistance, it is urgent to explore effective anti-liver cancer drugs. Repurposing drugs is an efficient strategy, with advantages including reduced costs, shortened development cycles, and assured safety. In this study, we adopted a synergistic approach combining computational and experimental methods and identified the antibacterial drug thiostrepton (TST) as a candidate for an anti-liver cancer drug. Although the anti-tumor capabilities of TST have been reported, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unclear. TST was found here to inhibit the proliferation of HCC cells effectively, arresting the cell cycle and inducing cell apoptosis, as well as suppressing the cell migration. Further, our findings revealed that TST induced mitochondrial impairment, which was demonstrated by destroyed mitochondrial structures, reduced mitochondria, and decreased mitochondrial membrane potential (MMP). TST caused the production of reactive oxygen species (ROS), and the mitochondrial impairment and proliferation inhibition of HCC cells were completely restored by the ROS scavenger N-acetyl-L-cysteine (NAC). Moreover, we discovered that TST induced mitophagy, and autophagy inhibition effectively promoted the anti-cancer effects of TST on HCC cells. In conclusion, our study suggests TST as a promising candidate for the treatment of liver cancers, and these findings provide theoretical support for the further development and potential application of TST in clinical liver cancer therapy.
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    • Contributed Indexing:
      Keywords: ROS; hepatocellular carcinoma; mitochondrial impairment; mitophagy; thiostrepton
    • Accession Number:
      HR4S203Y18 (Thiostrepton)
      0 (Reactive Oxygen Species)
      0 (Antineoplastic Agents)
    • Publication Date:
      Date Created: 20240914 Date Completed: 20240914 Latest Revision: 20240916
    • Publication Date:
      20250114
    • Accession Number:
      PMC11395809
    • Accession Number:
      10.3390/ijms25179717
    • Accession Number:
      39273665