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 Ca 2+ 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), p21 Waf1/Cip1 and p27 Kip1 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.

Multiple Effects of Resveratrol on Osteosarcoma Cell Lines

“…These data represent a strong motivation to explore the combined effects of RSV with chemotherapeutic agents. As reported in the literature, strong evidence on breast, gastric, and prostate cancer cells, subjected to combined treatment with RSV–DOX or RSV–CIS, has shown a synergistic behavior of RSV towards chemotherapeutic agents [ 61 , 62 , 63 ]. The combined treatments showed variable effects: viability inhibition, apoptosis promotion, epithelial–mesenchymal transition inhibition, intracellular drugs accumulation, and reduction of bone loss due to chemotherapy [ 17 , 64 , 65 ].…”

Molecular and Cellular Mechanisms of Propolis and Its Polyphenolic Compounds against Cancer

“…G1-S or G2-M transitions are regulated by checkpoints that may arrest cell cycle progression in environmental stress conditions. As balanced interactions between cyclins, cyclin-dependent kinases (CDK), and CDK inhibitors (CDI) regulate progression through the cell cycle [ 132 ], altered expression of the cell-cycle-specific proteins by dietary components potentially may sustain the proliferation of neoplastic cells and serve as “effect” biomarkers of their cytotoxic activity. The phenolic compounds of propolis, such as genistein, quercetin, kaempferol, myricetin, luteolin, chrysin, and apigenin, have been confirmed to modulate cell proliferation through an effect on the cell cycle by inducing CDI (p21 and p27) and inhibiting CDK4, CDK2, cyclin D1, and cyclin E [ 133 , 134 , 135 , 136 , 137 , 138 , 139 ].…”

Nano-Based Drug Delivery of Polyphenolic Compounds for Cancer Treatment: Progress, Opportunities, and Challenges

“…Many studies have shown that the abnormal fluctuation of the phosphorylation level of eIF2α is associated with the proliferation and invasiveness of tumor cells [ 70 , 71 ]. A combinational treatment of resveratrol and cisplatin can increase the level of phosphorylated eIF2α, which leads to increased intracellular Ca 2+ levels, thereby triggering endoplasmic reticulum stress and apoptosis of gastric cancer cells [ 72 ]. Alongside these treatments, the accumulation of intracellular reactive oxygen species (ROS) has also been shown to be associated with the induction of apoptosis [ 73 ].…”