Ginsenoside Rg2 inhibits the cell viability of cisplatin-resistant epithelial ovarian cancer by suppressing CACNA1G-mediated calcium signaling.

Most patients with epithelial ovarian cancer (EOC) treated with cisplatin (cDDP) ultimately develop resistance. Owing to its anti-tumor effects and low toxicity, ginsenoside Rg2 (G-Rg2) is regarded as a potential active compound for the chemotherapy of EOC. By leveraging expression profiles of cDDP-sensitive and -resistant EOC patients from GEO datasets, we employed weighted gene co-expression network analysis (WGCNA) to screen for candidate differentially expressed genes relevant to the treatment of cDDP-resistant EOC. Based on this analysis, we identified the key target of G-Rg2 for addressing cDDP resistance in EOC through network pharmacology, clinical data analysis, and molecular docking techniques. Following screening, CACNA1G was selected as the potential target of G-Rg2 for treating cDDP-resistant EOC. Subsequently, G-Rg2 was extracted from American ginseng berry using a chromatographic separation and purification method involving a saturated n-butanol layer. Experimental validation was performed via RNA sequencing, immunostaining, western blot, and flow cytometry in cDDP-resistant EOC cells to ascertain the alterations induced by G-Rg2 treatment. The stereoisomers of G-Rg2 [20(S)-G-Rg2 and 20(R)-G-Rg2] were utilized to treat cDDP-resistant EOC cells, demonstrating that G-Rg2 inhibits CACNA1G-mediated calcium signaling and downstream ERK phosphorylation, processes associated with cell proliferation. Compared to 20(S)-G-Rg2, 20(R)-G-Rg2 exhibited a more significant inhibitory effect on the CACNA1G-mediated calcium influx and downstream signaling, avoiding activation of anti-apoptotic pathways. Collectively, this study elucidates that G-Rg2 inhibits the cell viability of cDDP-resistant EOC by suppressing CACNA1G-mediated calcium signaling pathway, suggesting its potential application as an adjuvant chemotherapy agent for cDDP-resistant EOC.