Ginsenoside CK inhibits EMT and overcomes oxaliplatin resistance in gastric cancer by targeting the PI3K/Akt pathway.

[BACKGROUND] Gastric cancer remains a leading cause of cancer mortality, with oxaliplatin (L-OHP) resistance posing a major therapeutic challenge. Ginsenosides have shown potential in addressing chemoresistance.

[PURPOSE] This study aimed to investigate whether ginsenoside Compound K (CK), a derivative of protopanaxadiol ginsenosides, could overcome L-OHP resistance in gastric cancer cells.

[METHODS] The anti-cancer effects of CK were investigated using L-OHP-resistant HGC27/L cells through comprehensive in vitro experiments. Cell viability, migration, invasion, apoptosis, and colony formation were evaluated under CK treatment alone or combined with L-OHP. Drug efflux was specifically assessed using Rhodamine 123 staining. To understand the molecular mechanism, network pharmacology and molecular docking analyses were employed, which identified the PI3K/Akt pathway as a crucial target of CK. This finding was further validated through Western blotting and RT-qPCR analyses, focusing on PI3K/Akt signaling components and EMT markers. Finally, drug-resistant gastric cancer xenograft models were established to evaluate the therapeutic efficacy of CK alone and in combination with L-OHP in vivo.

[RESULTS] CK effectively suppressed cell viability, migration, invasion, drug efflux, and colony formation while enhancing apoptosis in resistant cells. Mechanistically, CK inhibited the PI3K/Akt pathway, leading to reduced P-glycoprotein (P-gp) expression and EMT reversal. These effects were confirmed using PI3K pathway modulators. In xenograft models, CK significantly inhibited tumor growth and reduced PI3K/Akt activity, P-gp expression, and EMT markers.

[CONCLUSION] This study demonstrates that CK overcomes L-OHP resistance through PI3K/Akt pathway inhibition and EMT prevention, suggesting that combining CK with L-OHP may improve outcomes in chemoresistant gastric cancer patients.