High-throughput screening of the natural STK11 agonist dauricine: A biphenylisoquinoline alkaloid exerting anti-NSCLC effects and reversing gefitinib resistance.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2005- : Amsterdam : Elsevier Science
      Original Publication: Amsterdam, North Holland Pub. Co.
    • Subject Terms:
      Drug Resistance, Neoplasm*/drug effects ; Protein Serine-Threonine Kinases*/metabolism ; Protein Serine-Threonine Kinases*/genetics ; AMP-Activated Protein Kinase Kinases* ; Lung Neoplasms*/drug therapy ; Lung Neoplasms*/pathology ; Lung Neoplasms*/genetics ; Lung Neoplasms*/metabolism ; Gefitinib*/pharmacology ; Carcinoma, Non-Small-Cell Lung*/drug therapy ; Carcinoma, Non-Small-Cell Lung*/pathology ; Carcinoma, Non-Small-Cell Lung*/genetics ; Carcinoma, Non-Small-Cell Lung*/metabolism ; High-Throughput Screening Assays* ; Antineoplastic Agents*/pharmacology; Animals ; Humans ; Cell Line, Tumor ; Mice ; Quinazolines/pharmacology ; Mice, Nude ; Xenograft Model Antitumor Assays ; Cell Proliferation/drug effects ; Tetrahydroisoquinolines ; Benzylisoquinolines
    • Abstract:
      Background: Serine/threonine kinase 11 (STK11) deletion and downregulation caused cancer progression, and were widely associated with drug resistance. Accurate screening of natural small molecules about anti-cancer and anti-drug resistance is the key to the development and utilization of natural product application, which could promote traditional Chinese medicine in the treatment of cancer. Dauricine, which is derived from the rhizome of Menispermum dauricum DC., has certain potential but unexplored mechanism for the treatment of cancer.
      Purpose: The aim of this study was to screen and validate the role and mechanism of natural STK11 agonists with anti-drug resistance from plants in the treatment of NSCLC.
      Methods: A lentiviral STK11 overexpression cell model was employed for the screening of natural STK11 agonists. The efficacy of dauricine in the treatment of NSCLC was validated on PC-9 and HCC827 cells. In vivo validation of dauricine activity was performed using nude mouse models equipped with PC9 xenografts. To investigate the anti-resistant effects of dauricine, gefitinib-resistant PC9 cell models were constructed.
      Results: As a natural agonist of STK11, it causes the activation of the STK11/AMPK pathway and inhibits the growth of PC-9 cells. Dauricine synergises the inhibitory effect with gefitinib on PC9. The up-regulation of STK11 protein expression by dauricine was demonstrated in vitro and in vivo, while restoring the sensitivity of PC9/GR to gefitinib by down-regulating the protein expression of Nrf2 and Pgp.
      Conclusion: Dauricine, a natural agonist of STK11, effectively inhibited NSCLC, and its combination treatment with gefitinib reversed drug-resistant NSCLC.
      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 © 2024. Published by Elsevier B.V.)
    • Contributed Indexing:
      Keywords: Anti-drug resistance; Dauricine; NSCLC; Nrf2; Pgp; STK11
    • Accession Number:
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
      EC 2.7.11.1 (STK11 protein, human)
      EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
      S65743JHBS (Gefitinib)
      0 (Antineoplastic Agents)
      8QTO90G5W5 (dauricine)
      0 (Quinazolines)
      0 (Tetrahydroisoquinolines)
      0 (Benzylisoquinolines)
    • Publication Date:
      Date Created: 20241003 Date Completed: 20241113 Latest Revision: 20241113
    • Publication Date:
      20241114
    • Accession Number:
      10.1016/j.ejphar.2024.177024
    • Accession Number:
      39362388