期刊
ONCOLOGY REPORTS
卷 44, 期 4, 页码 1605-1615出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/or.2020.7708
关键词
resveratrol; gastric cancer; cisplatin; apoptosis; endoplasmic reticulum stress; G2; M cell cycle arrest
类别
资金
- Zhejiang Traditional Chinese Medicine Science and Technology Project [2017ZZ010]
- Key Research and Development Program of Zhejiang Province [2019C03031]
- Zhejiang Medical Science and Technology Program [2018266817]
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 2 alpha (p-eIF2 alpha), 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/eIF2 alpha/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.
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