Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Licochalcone C suppresses gastric cancer progression and enhances 5-FU chemosensitivity by targeting RAC3-mediated PI3K-AKT-mTOR signaling.
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Wang Qingshui, Lu Yiping, Chen Yuluo, Zhou Jinxiu, Guo Kejia, Liu Yifei, Huang Yimin, Zheng Yi, Li Hao, Ye Yan, Lin Jia, Huang Minghan, Xue Fangqin, Lin Yao
Аннотация
BACKGROUND: Gastric cancer remains a leading cause of cancer-related mortality worldwide, with limited sensitivity to 5-fluorouracil (5-FU) representing a major obstacle to effective chemotherapy. Licochalcones, bioactive chalcones derived from licorice, have demonstrated broad-spectrum anticancer activities, yet the role of Licochalcone C in enhancing 5-FU sensitivity in gastric cancer remains unexplored.
PURPOSE: This study aimed to investigate the antitumor effects of Licochalcone C on gastric cancer and evaluate its potential to enhance 5-FU chemosensitivity, along with elucidating the underlying molecular mechanisms.
STUDY DESIGN: The antitumor and chemosensitizing effects of Licochalcone C were systematically evaluated using human gastric cancer cell lines, patient-derived organoids, clinical specimens, and a mouse xenograft model.
METHODS: Cell proliferation, colony formation, migration, invasion, and cell cycle distribution were assessed by standard assays. Biotin-labeled Licochalcone C pull-down with mass spectrometry, molecular docking, cellular thermal shift assay, and co-immunoprecipitation were employed for target identification. Western blot and transcriptomic analyses defined the signaling mechanisms.
RESULTS: Licochalcone C inhibited gastric cancer cell proliferation, migration, and invasion while inducing G1 arrest, and markedly enhanced 5-FU sensitivity in cell lines, organoids, and xenograft models. Mechanistically, Licochalcone C directly bound RAC3, suppressing the RAC3-mediated PI3K-AKT-mTOR pathway and downregulating P-glycoprotein. Clinically, RAC3 overexpression correlated with advanced stage, poor survival, and unfavorable chemotherapy response.
CONCLUSION: Licochalcone C functions as a RAC3-targeting chemosensitizer that enhances 5-FU efficacy by inhibiting PI3K-AKT-mTOR signaling and P-glycoprotein expression, supporting its development as a therapeutic adjuvant for gastric cancer.
PURPOSE: This study aimed to investigate the antitumor effects of Licochalcone C on gastric cancer and evaluate its potential to enhance 5-FU chemosensitivity, along with elucidating the underlying molecular mechanisms.
STUDY DESIGN: The antitumor and chemosensitizing effects of Licochalcone C were systematically evaluated using human gastric cancer cell lines, patient-derived organoids, clinical specimens, and a mouse xenograft model.
METHODS: Cell proliferation, colony formation, migration, invasion, and cell cycle distribution were assessed by standard assays. Biotin-labeled Licochalcone C pull-down with mass spectrometry, molecular docking, cellular thermal shift assay, and co-immunoprecipitation were employed for target identification. Western blot and transcriptomic analyses defined the signaling mechanisms.
RESULTS: Licochalcone C inhibited gastric cancer cell proliferation, migration, and invasion while inducing G1 arrest, and markedly enhanced 5-FU sensitivity in cell lines, organoids, and xenograft models. Mechanistically, Licochalcone C directly bound RAC3, suppressing the RAC3-mediated PI3K-AKT-mTOR pathway and downregulating P-glycoprotein. Clinically, RAC3 overexpression correlated with advanced stage, poor survival, and unfavorable chemotherapy response.
CONCLUSION: Licochalcone C functions as a RAC3-targeting chemosensitizer that enhances 5-FU efficacy by inhibiting PI3K-AKT-mTOR signaling and P-glycoprotein expression, supporting its development as a therapeutic adjuvant for gastric cancer.
Предметные рубрики MeSH
ChalconesStomach NeoplasmsDrug Resistance, NeoplasmFluorouracilAntimetabolites, AntineoplasticHumansFemaleAnimalsMiceCell Line, TumorMice, Inbred BALB CXenograft Model Antitumor AssaysG1 Phase Cell Cycle CheckpointsSignal TransductionTOR Serine-Threonine KinasesProto-Oncogene Proteins c-aktPhosphatidylinositol 3-Kinasesrac GTP-Binding ProteinsAntineoplastic Agents, PhytogenicGlycyrrhiza