Work

Dammarenediol II enhances etoposide‐induced apoptosis by targeting O ‐ GlcNAc transferase and Akt/ GSK3β / mTOR signaling in liver cancer

Year: 2025

Type: article

Abstract: Combining chemotherapy with chemosensitizing agents is a common strategy to enhance anticancer efficacy while mitigating treatment‐related side effects. This study investigated the potential of dammarenediol II (DM2), a ginsenoside precursor, to enhance the anticancer effects of etoposide by downregulating O ‐linked β‐N‐acetylglucosamine modification ( O ‐GlcNAcylation) and modulating the Akt signaling pathway in HepG2 human liver cancer cells. The effect of DM2 on O ‐GlcNAcylation regulation was analyzed using Pharmaco‐Net, an artificial intelligence–driven drug screening platform and further validated using O ‐GlcNAc transferase (OGT) activity assay. DM2 cotreatment enhanced etoposide's anticancer efficacy, which was quantitatively evaluated by viability, Annexin V binding, membrane integrity, and caspase‐3/7 activity assays in HepG2 cells. Results showed that DM2 reduced O ‐GlcNAc levels by directly interacting with OGT, as confirmed through Pharmaco‐Net. Cotreatment with 40 μ m DM2 and 20 μ m etoposide produced synergistic anticancer effects, lowering etoposide's IC 50 for cell viability by 2.29‐fold and its EC 50 for caspase‐3/7 activity by 3.64‐fold. Mechanistically, DM2 dose‐dependently suppressed Akt/GSK3β/mTOR signaling. Using the Akt activator SC79, additional experiments confirmed that Akt signaling acts downstream of O ‐GlcNAcylation regulated by etoposide and DM2. These effects were also observed in multiple human liver cancer cell lines, as well as in A549 lung and Caco‐2 colorectal cancer cells. This supports the broader anticancer and Akt‐inhibitory potential of DM2. This study is the first to demonstrate that DM2 enhances anticancer synergy by suppressing O ‐GlcNAcylation and Akt signaling, highlighting its potential as a novel chemotherapy adjuvant.

Source: Molecular Oncology

DOI: 10.1002/1878-0261.70199