Network pharmacology analysis, molecular docking integrated experimental verification reveal β-sitosterol as the active anti-NSCLC ingredient of Polygonatum cyrtonema Hua by suppression of PI3K/Akt/ HIF-1α signaling pathway

被引:2
作者
Cao, Wen [1 ,2 ,3 ,4 ]
Yuan, Fangwei [2 ,3 ,5 ,6 ]
Liu, Tongyan [2 ,3 ,6 ,7 ]
Yin, Rong [2 ,3 ,6 ,7 ,8 ,9 ]
机构
[1] Jiangsu Canc Hosp, Dept Integrated Tradit Chinese & Western Med, Nanjing 210009, Jiangsu, Peoples R China
[2] Nanjing Med Univ, Affiliated Canc Hosp, Nanjing 21009, Peoples R China
[3] Jiangsu Inst Canc Res, Nanjing 21009, Peoples R China
[4] Nanjing Univ Chinese Med, Clin Coll 3, Nanjing 210023, Peoples R China
[5] Nanjing Med Univ, Clin Coll 4, Nanjing 210009, Peoples R China
[6] Jiangsu Canc Hosp, Dept Thorac Surg, Jiangsu Key Lab Mol & Translat Canc Res, Nanjing 21009, Peoples R China
[7] Jiangsu Canc Hosp, Dept Sci & technol, Nanjing 21009, Peoples R China
[8] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Nanjing 211116, Peoples R China
[9] Jiangsu Biobank Clin Resources, Biobank Lung Canc, Nanjing 21009, Peoples R China
关键词
NSCLC; Molecular docking; Network pharmacology; Polygonatum cyrtonema Hua; PI3K/Akt/HIF-1; alpha; LUNG ADENOCARCINOMA; CANCER; HYPOXIA; APOPTOSIS; ACTIVATION; RISK;
D O I
10.1016/j.jep.2024.117900
中图分类号
Q94 [植物学];
学科分类号
071001 ;
摘要
Ethnopharmacological relevance: Polygonatum cyrtonema Hua (Huangjing) is a Chinese herb that is considered by ancient Chinese healers to have the effect of nourishing yin and moisturizing the lungs. It is clinically used to treat diseases of the pulmonary system, including non-small cell lung cancer. However, the precise active components and underlying mechanisms of Huangjing in the context of treating NSCLC remain uncertain. Aim of the study: This study aimed to explore the active components and mechanisms of Huangjing for the treatment of NSCLC by means of data mining, network pharmacology, and in vitro and vivo experiments. Materials and methods: First, the main active compounds and key targets of Huangjing were predicted by network pharmacology. The potential key targets of Huangjing were molecularly docked with the main active compounds using Pymol. In vivo, we verified whether Huangjing and its main active compound have anti-lung cancer effects. Key targets were verified by PCR and immunohistochemistry. In vitro, we verified the effects of Huangjing's main active compound on the proliferation, apoptosis, and migration of A549 cells by CCK-8, colony formation, wound healing assay, and flow cytometry. Key targets and signaling pathway were validated by PCR and Western blot. Results: The network pharmacology results suggested that beta-sitosterol was the main active substance. TP53, JUN, AKT1, MAPK14, ESR1, RELA, HIF1A, and RXRA were potential targets of Huangjing. Molecular docking results suggested that MAPK14, HIF-1 alpha, and RXRA docked well with beta-sitosterol. In vivo tests also confirmed that Huangjing could significantly inhibit the growth of lung cancer tumors, while PCR and immunohistochemistry results suggested that the expression of HIF-1 alpha was significantly decreased. Critically, KEGG analysis indicated that the PI3K/Akt/HIF-1 alpha signaling pathway was recommended as one of the main pathways related to the antiNSCLC effect of Huangjing. We conducted in vitro experiments to confirm the significant impact of beta-sitosterol on the proliferation, apoptosis, migration, and colony formation of A549 cells. Furthermore, our findings indicate that a high dosage of beta-sitosterol may effectively decrease the expression of HIF-1 alpha, AKT1, JUN and RELA in A549 cells. Similarly, in vitro experiments also revealed that high doses of beta-sitosterol could inhibit the PI3K/Akt/ HIF-1 alpha signaling pathway. Conclusions: We discovered Huangjing and its main active ingredient, (3-sitosterol, can reduce HIF-1 alpha, AKT1, JUN and RELA expression and decrease non-small cell lung cancer growth through the PI3K/Akt/HIF-1 alpha signaling pathway.
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页数:12
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共 35 条
  • [1] The phosphoinositide 3-kinase pathway in human cancer: Genetic alterations and therapeutic implications
    Arcaro, Alexandre
    Guerreiro, Ana S.
    [J]. CURRENT GENOMICS, 2007, 8 (05) : 271 - 306
  • [2] AP-1 Transcription Factors as Regulators of Immune Responses in Cancer
    Atsaves, Vasileios
    Leventaki, Vasiliki
    Rassidakis, George Z.
    Claret, Francois X.
    [J]. CANCERS, 2019, 11 (07)
  • [3] Effect of resveratrol and β-sitosterol in combination on reactive oxygen species and prostaglandin release by PC-3 cells
    Awad, AB
    Burr, AT
    Fink, CS
    [J]. PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, 2005, 72 (03): : 219 - 226
  • [4] Awad AB, 2003, ONCOL REP, V10, P497
  • [5] ER-Mitochondria Calcium Flux by β-Sitosterol Promotes Cell Death in Ovarian Cancer
    Bae, Hyocheol
    Park, Sunwoo
    Ham, Jiyeon
    Song, Jisoo
    Hong, Taeyeon
    Choi, Jin-Hee
    Song, Gwonhwa
    Lim, Whasun
    [J]. ANTIOXIDANTS, 2021, 10 (10)
  • [6] [Anonymous], 2020, CA Cancer J Clin, V70, P313, DOI [10.3322/caac.21492, 10.3322/caac.21609]
  • [7] Requirement of Phosphatidylinositol(3,4,5)Trisphosphate in Phosphatidylinositol 3-Kinase-Induced Oncogenic Transformation
    Denley, Adam
    Gymnopoulos, Marco
    Kang, Sohye
    Mitchell, Christina
    Vogt, Peter K.
    [J]. MOLECULAR CANCER RESEARCH, 2009, 7 (07) : 1132 - 1138
  • [8] β-Sitosterol blocks the LEF-1-mediated Wnt/β-catenin pathway to inhibit proliferation of human colon cancer cells
    Gu, Shengliang
    Liu, Fahui
    Xie, Xueheng
    Ding, Meng
    Wang, Zhen
    Xing, Xiaoyan
    Xiao, Tianbao
    Sun, Xiaobo
    [J]. CELLULAR SIGNALLING, 2023, 104
  • [9] Cancer Stem Cells, Hypoxia and Metastasis
    Hill, Richard P.
    Marie-Egyptienne, Delphine T.
    Hedley, David W.
    [J]. SEMINARS IN RADIATION ONCOLOGY, 2009, 19 (02) : 106 - 111
  • [10] Treatment with HIF-1α Antagonist PX-478 Inhibits Progression and Spread of Orthotopic Human Small Cell Lung Cancer and Lung Adenocarcinoma in Mice
    Jacoby, Joerg J.
    Erez, Baruch
    Korshunova, Maria V.
    Williams, Ryan R.
    Furutani, Kazuhisa
    Takahashi, Osamu
    Kirkpatrick, Lynn
    Lippman, Scott M.
    Powis, Garth
    O'Reilly, Michael S.
    Herbst, Roy S.
    [J]. JOURNAL OF THORACIC ONCOLOGY, 2010, 5 (07) : 940 - 949