Compound Muji Granules enhances cisplatin efficacy against alpha-fetoprotein-producing gastric cancer by suppressing epidermal growth factor receptor signaling

Abstract

BACKGROUND

Alpha-fetoprotein-producing gastric cancer (AFPGC) is an aggressive subtype with frequent liver and nodal metastases and poor outcomes. Resistance to standard chemotherapy is common. Compound Muji Granules (CMG), a traditional multi-component herbal formulation reported to reduce serum alpha-fetoprotein, has shown antitumor activity in solid tumors.

AIM

To evaluate the effects of CMG combined with cisplatin in AFPGC cells and investigated the role of the epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway.

METHODS

The human AFPGC cell line FU97 was treated with CMG, cisplatin, or both. Proliferation (cell counting kit-8), alpha-fetoprotein secretion, cell-cycle distribution and apoptosis (flow cytometry), and migration and invasion (Transwell assays) were assessed. Expression of EGFR, PI3K, AKT, and mTOR was measured by quantitative real-time-polymerase chain reaction and Western blotting. Network pharmacology and molecular docking were used to identify putative CMG targets. An EGFR-overexpressing FU97 model was generated to test pathway dependence.

RESULTS

CMG reduced FU97 cell proliferation, migration, and invasion; lowered alpha-fetoprotein secretion; and induced G0-G1 arrest and apoptosis as compared with control. The combination of CMG and cisplatin produced greater growth inhibition and apoptosis than either agent alone (P < 0.05). Combination therapy down-regulated EGFR, PI3K, AKT, and mTOR at the transcript and protein levels, consistent with suppression of the EGFR-PI3K-AKT-mTOR pathway. In EGFR-overexpressing FU97 cells, CMG plus cisplatin retained antiproliferative and proapoptotic activity, indicating efficacy in an EGFR-driven context.

CONCLUSION

CMG suppresses AFPGC cell growth, induces cell-cycle arrest and apoptosis, enhances cisplatin activity, and inhibits the EGFR-PI3K-AKT-mTOR pathway, supporting further evaluation of CMG combined with chemotherapy in AFPGC.

Keywords: Compound Muji Granules; Alpha-fetoprotein-producing gastric cancer; Cisplatin; Epidermal growth factor receptor-phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin pathway; FU97 cells

Core Tip: Compound Muji Granules (CMG) markedly inhibited proliferation, migration, and invasion of alpha-fetoprotein (AFP)-producing gastric cancer FU97 cells, reduced AFP secretion, and induced G0/G1 arrest and apoptosis. Notably, CMG combined with cisplatin produced stronger growth inhibition and pro-apoptotic effects than either agent alone. Network pharmacology and molecular docking identified epidermal growth factor receptor (EGFR) as a key CMG target, and quantitative real-time polymerase chain reaction/western blotting confirmed that the combination suppresses the EGFR-phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin pathway at both messenger RNA and protein levels. Importantly, the antitumor activity of CMG plus cisplatin persisted in an EGFR-driven FU97 model, supporting CMG as a potential chemosensitizer for AFP-producing gastric cancer.