Deltonin enhances gastric carcinoma cell apoptosis and chemosensitivity to cisplatin via inhibiting PI3K/AKT/mTOR and MAPK signaling

BACKGROUND: As an active ingredient derived from Dioscorea zingiberensis C.H. Wright, deltonin has been reported to show anti-cancer effects in a variety of malignancies. AIM: To investigate the role and mechanism of action of deltonin in promoting gastric carcinoma (GC) cell apoptosis and chemosensitivity to cisplatin. METHODS: The GC cell lines AGS, HGC-27, and MKN-45 were treated with deltonin and then subjected to flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltetrazolium bromide assays for cell apoptosis and viability determination. Western blot analysis was conducted to examine alterations in the expression of apoptosis-related proteins (Bax, Bid, Bad, and Fas), DNA repair-associated proteins (Rad51 and MDM2), and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/AKT/mTOR) and p38-mitogen-activated protein kinase (MAPK) axis proteins. Additionally, the influence of deltonin on GC cell chemosensitivity to cisplatin was evaluated both in vitro and in vivo. RESULTS: Deltonin treatment weakened viability, enhanced apoptosis, and dampened DNA repair in GC cell lines in a dose-dependent pattern. Furthermore, deltonin mitigated PI3K, AKT, mTOR, and p38-MAPK phosphorylation. HS-173, an inhibitor of PI3K, attenuated GC cell viability and abolished deltonin inhibition of GC cell viability and PI3K/AKT/mTOR and p38-MAPK pathway activation. Deltonin also promoted the chemosensitivity of GC cells to cisplatin via repressing GC cell proliferation and growth and accelerating apoptosis. CONCLUSION: Deltonin can boost the chemosensitivity of GC cells to cisplatin via inactivating p38-MAPK and PI3K/AKT/mTOR signaling.