High-throughput screening of the natural STK11 agonist dauricine: a biphenylisoquinoline alkaloid exerting anti-NSCLC effects and reversing gefitinib resistance.
Zhigao Zhao, Qian Zhao, Zhiyuan Mao, Yang Tian, Li Yang, Yu Ma, Jian Gu, Rui Tan
{"title":"High-throughput screening of the natural STK11 agonist dauricine: a biphenylisoquinoline alkaloid exerting anti-NSCLC effects and reversing gefitinib resistance.","authors":"Zhigao Zhao, Qian Zhao, Zhiyuan Mao, Yang Tian, Li Yang, Yu Ma, Jian Gu, Rui Tan","doi":"10.1016/j.ejphar.2024.177024","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Dauricine, a natural agonist of STK11, effectively inhibited NSCLC, and its combination treatment with gefitinib reversed drug-resistant NSCLC.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ejphar.2024.177024","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍：
The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems.
The scope includes:
Behavioural pharmacology
Neuropharmacology and analgesia
Cardiovascular pharmacology
Pulmonary, gastrointestinal and urogenital pharmacology
Endocrine pharmacology
Immunopharmacology and inflammation
Molecular and cellular pharmacology
Regenerative pharmacology
Biologicals and biotherapeutics
Translational pharmacology
Nutriceutical pharmacology.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
