Zuojin Pill Alleviates Precancerous Lesions of Gastric Cancer by Modulating the MEK/ERK/c-Myc Pathway: An Integrated Approach of Network Pharmacology, Molecular Dynamics Simulation, and Experimental Validation

• Published in: Drug design, development and therapy development and therapy, 2024-01, Vol.18, p.5905-5929
• Main Authors: Liang, Lan, He, Chenming, Han, Xue, Liu, Jia, Yang, Liuhong, Chang, Fengjiao, Zhang, Yami, Lin, Jie
• Format: Article
• Language: English
• Subjects: Acids; Adenosine; Animals; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; c-Myc protein; Caffeic acid; Cancer; Cell cycle; Cell Proliferation - drug effects; Chinese medicine; Chromatography; Core protein; Disease; Dose-Response Relationship, Drug; Drug dosages; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - pharmacology; Electrons; Extracellular signal-regulated kinase; Gastric cancer; Herbal medicine; High performance liquid chromatography; Humans; Janus kinase 2; Lesions; Liquid chromatography; Male; Malignancy; MAP Kinase Signaling System - drug effects; Mass spectrometry; Mass spectroscopy; Mice; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular interactions; Molecular modelling; Molecular Structure; Myc protein; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Network Pharmacology; Original Research; Pharmacology; Precancerous Conditions - drug therapy; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Proteins; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - metabolism; Quadrupoles; Rats; Scientific imaging; Stat3 protein; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Traditional Chinese medicine; Tumor necrosis factor-α
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S487371

Precancerous lesions of gastric cancer (PLGC) represent critical stages in gastric cancer progression, with a high risk of malignancy. Current treatments, such as Helicobacter pylori eradication, show limited efficacy in reversing precancerous molecular changes. Zuojin Pill (ZJP), a traditional Chinese medicine, has demonstrated potential for treating digestive disorders and may offer a promising approach for PLGC intervention. This study aims to investigate the therapeutic effects and mechanisms of ZJP in treating PLGC, focusing on its active components, target pathways, and molecular interactions. By using advanced analytical techniques, we provide a scientific foundation for ZJP's potential application in early gastric cancer intervention. Using ultra-high performance liquid chromatography-quadrupole orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap HRMS), we identified active components in ZJP. A network pharmacology approach was then applied to construct a "ZJP-compound-target-disease" network. Molecular docking and molecular dynamics simulations were conducted to analyze the stability and interactions of the main active components of ZJP with core protein targets in PLGC. Animal experiments were used to validate significant targets and pathways in vivo. Tangeritin, Isorhamnetin, Caffeic Acid, Azelaic Acid, and Adenosine were identified as the main active components of ZJP in the treatment of PLGC, with key targets including PIK3R1, MAPK3, SRC, JAK2, STAT3, and PIK3CA. Molecular docking and molecular dynamics simulations further confirmed the relationship between compounds and target proteins. The potential molecular mechanism of ZJP predicted by network pharmacology analysis was confirmed in PLGC rats. ZJP downregulated IL-6, TNF-α, c-myc, p-MEK1 and p-ERK1/2, effectively reversing the progression of PLGC. ZJP can reverse MNNG-induced PLGC, potentially through inhibition of the MEK/ERK/c-myc pathway and regulation of cellular proliferation and apoptosis.