Resveratrol synergizes with cisplatin in antineoplastic effects against AGS gastric cancer cells by inducing endoplasmic reticulum stress‑mediated apoptosis and G2/M phase arrest.

Abstract

Gastric cancer (GC) is a common gastrointestinal malignancy, and cisplatin (DDP) is an important component of chemotherapeutic regimens for GC. However, the application of DDP is limited by its dose-dependent systemic toxicity. Resveratrol (RES) is a natural polyphenol compound that has chemopreventive and therapeutic effects against various cancers, including GC. However, whether RES can sensitize GC cells to DDP remains unknown. Following RES/DDP combination treatment, cell viability was determined by Cell Counting Kit-8 and colony-forming assays, and cell apoptosis and the cell cycle were detected by FITC-Annexin V/PI staining assay and PI staining assay, respectively, followed by flow cytometry. Moreover, western blotting was performed to evaluate the protein expression levels, and the intracellular free Ca2+ concentration was determined by a Fluo-4 AM probe after cell cotreatment with RES and DDP. The present results demonstrated that RES/DDP combination treatment significantly inhibited cell viability, promoted cell apoptosis and induced G2/M phase arrest in AGS cells. In addition, it was determined that RES combined with DDP significantly increased the levels of Bax, cleaved poly-ADP-ribose polymerase (PARP), glucose-regulated protein 78 (GRP78), PRKR-like ER kinase (PERK), p-eukaryotic translation initiation factor 2α (p-eIF2α), CCAAT/enhancer binding protein homologous protein (CHOP) and cleaved caspase-12, whereas Bcl-2 expression was downregulated following RES/DDP cotreatment. Moreover, RES/DDP cotreatment significantly upregulated phosphorylated cyclin-dependent kinase 1 (p-CDK1, Tyr15), p21Waf1/Cip1 and p27Kip1 protein levels and downregulated Cdc25C protein levels. In conclusion, RES and DDP synergistically inhibited the growth of the gastric adenocarcinoma cell line AGS by inducing endoplasmic reticulum stress-mediated apoptosis and G2/M phase arrest via activation of the PERK/eIF2α/activating transcription factor 4 (ATF4)/CHOP signaling pathway and caspase-12 and by inactivating the CDK1-cyclin B1 complex. These results indicated that RES is a promising adjuvant for DDP during GC chemotherapy.