ABSTRACT
AIM:To investigate the enhancing effect of quercetin on the 5-fluorouracil-induced apoptosis in gastric cancer.METHODS: MTT assay was conducted to evaluate the effect of quercetin on the 5-fluorouracil-induced death of gastric cancer cell line BGC-823.Co-immunoprecipitation and Western blot analysis were performed to detect the expression of c-Jun and Bcl-xL,phosphorylation of c-Jun,activation of caspase-9 and caspase-3,and release of cytochrome C in BGC-823 cells treated with quercetin and 5-fluorouracil.The apoptosis of BGC-823 cells treated with quercetin and 5-fluorouracil was analyzed by flow cytometry.RESULTS: Adjuvant therapy of quercetin significantly enhanced the 5-fluorouracil-induced death of BGC-823 cells.Meanwhile, quercetin decreased the half maximal inhibitory concentration (IC50)of 5-fluorouracil to BGC-823 cells.Quercetin treatment significantly inhibited the expression of c-Jun,and inhibited the 5-fluorouracil-induced phosphorylation of c-Jun and the interaction between c-Jun and activating transcription factor 2 (ATF2).Subsequently,quercetin inhibited the up-regulation of Bcl-xL induced by 5-fluorouracil in the BGC-823 cells. However,transfection with c-Jun plasmid abolished the promoting effect of quercetin on 5-fluorouracil-induced cell death. In addition, quercetin promoted 5-fluorouracil-induced release of cytochrome C from mitochondria and caspase-dependent apoptosis in BGC-823 cells.CONCLUSION:Quercetin treatment enhances 5-fluorouracil-induced mitochondrial apoptosis in BGC-823 cells through c-Jun/ATF2/Bcl-xL pathway.
ABSTRACT
<p><b>OBJECTIVE</b>5-Fluorouracil (5-FU)-based combination therapies are standard treatments for gastrointestinal cancer, where the modulation of autophagy is becoming increasingly important in offering effective treatment for patients in clinical practice. This review focuses on the role of autophagy in 5-FU-induced tumor suppression and cancer therapy in the digestive system.</p><p><b>DATA SOURCES</b>All articles published in English from 1996 to date those assess the synergistic effect of autophagy and 5-FU in gastrointestinal cancer therapy were identified through a systematic online search by use of PubMed. The search terms were "autophagy" and "5-FU" and ("colorectal cancer" or "hepatocellular carcinoma" or "pancreatic adenocarcinoma" or "esophageal cancer" or "gallbladder carcinoma" or "gastric cancer").</p><p><b>STUDY SELECTION</b>Critical reviews on relevant aspects and original articles reporting in vitro and/or in vivo results regarding the efficiency of autophagy and 5-FU in gastrointestinal cancer therapy were reviewed, analyzed, and summarized. The exclusion criteria for the articles were as follows: (1) new materials (e.g., nanomaterial)-induced autophagy; (2) clinical and experimental studies on diagnostic and/or prognostic biomarkers in digestive system cancers; and (3) immunogenic cell death for anticancer chemotherapy.</p><p><b>RESULTS</b>Most cell and animal experiments showed inhibition of autophagy by either pharmacological approaches or via genetic silencing of autophagy regulatory gene, resulting in a promotion of 5-FU-induced cancer cells death. Meanwhile, autophagy also plays a pro-death role and may mediate cell death in certain cancer cells where apoptosis is defective or difficult to induce. The dual role of autophagy complicates the use of autophagy inhibitor or inducer in cancer chemotherapy and generates inconsistency to an extent in clinic trials.</p><p><b>CONCLUSION</b>Autophagy might be a therapeutic target that sensitizes the 5-FU treatment in gastrointestinal cancer.</p>