PD15, a steroidal saponin, induces apoptosis of HCT116 colorectal cancer cells via suppressing the Akt/GSK3β pathway

PD15, a novel natural steroidal saponin extracted from the rhizomes of Paris delavayi Franchet, has demonstrated a strong cytotoxic effect against HepG2 and U87MG cells. However, its therapeutic effects on colorectal cancer (CRC) and the underlying molecular mechanisms remain unclear. MTT assay, clonogenic assay, Hoechst 33258 staining, flow cytometry, molecular docking, and western blot were used to investigate the mechanism of PD15 in HCT116 cell lines. Additionally, the anti-CRC effects of PD15 were evaluated in vivo using HCT116 xenograft models. PD15 significantly inhibited cell proliferation and induced G0/G1 phase arrest in HCT116 cells. Furthermore, PD15 upregulated cleaved Caspase 3 and 9, cleaved PARP, and Bax expression levels while downregulating Bcl-2, leading to apoptosis. Further experiments revealed that PD15 downregulated the protein expression of p-Akt and p-GSK3β, with LY294002 (a PI3K/Akt inhibitor) enhancing PD15-induced apoptosis and its effects on Akt/GSK3β-associated proteins. In addition, molecular docking demonstrated that PD15 exhibited strong binding affinity with Akt and GSK3β. Critically, PD15 inhibited CRC growth in vivo without causing apparent toxicity in mice. These findings indicate that PD15 could trigger apoptosis by suppressing the Akt/GSK3β signaling pathway in HCT116 cells.