| Background:Gastric cancer(GC)ranks as the fourth in mortality among all the malignancies worldwide.Helicobacter pylori(H.pylori)is a primary carcinogen for gastric cancer.H.pylori infection can lead to gastric mucosal epithelial inflammation,metaplasia and even cancerization.More than 70%of patients in China are diagnosed at advanced stages with peripheral invasion or metastasis,surgical resection usually cannot prevent progress of GC successfully.Therefore,chemotherapy has become one of the most important components of gastric cancer treatment.Although fluorouracil combined with platinum-based chemotherapy is frequently used as systematic chemotherapy for gastric cancer,but its side effects and chemoresistance are still problems to be solved.Therefore,it is urgent to develop new efficient drugs to treat GC patients.Polygoni orientalis Fructus(POF),is a well-known medicinal plant which used to treat abdominal mass,tumor,stomachache,ascites,also possessed heaptoprotective and anti-cancer activities.In POF,the main bioactive compounds are flavonoids,which include quercetin,taxifolin,kaempferol,and eriodictyol.Among these natural flavonoids,the anti-cancer capabilities of quercetin,taxifolin,and kaempferol have been extensively investigated.Similarly,it has been indicated that eriodictyol have tumor prevention.In a chemical carcinogen 1,2-dimethylhydrazine-induced animal model of colon cancer,through the antioxidant defense mechanism,eriodictyol decreases lipid peroxidation levels and inhibits preneoplastic lesions.This indicates that eriodictyol can be applied in cancer treatment.Objective:To compare the anti-gastric cancer effects of four flavonoid compounds(quercetin,taxifolin,kaempferol and eriodictyol)in the POF,and to investigate the anti-cancer effects and molecular mechanism of eriodictyol towards GC both in vitro and in vivo.Methods:CCK-8 assays were performed to examine the inhibitory effects of common flavonoids from POF on GC cell viability.Colony formation assays were used to determine cell colony formation after eriodictyol treatment.Cell cycle distribution was analyzed using flow cytometry.Induction of apoptosis was assessed with Annexin V/PI staining and measurement of related proteins.Anti-cancer effects in vivo were investigated using a xenograft mouse model.Potential targets of eriodictyol were clarified by network pharmacological analysis,evaluated the binding site and binding energy by molecular docking,and validated the inhibitory effect of eriodictyol on the target with Western blot.Results:We found quercetin,taxifolin,kaempferol and eriodictyol both have inhibitory effects on the viability of gastric cancer cells,among which eriodictyol had the most effective inhibitory effect.Eriodictyol suppressed colony formation of GC cells and induced cell apoptosis.The inhibitory effects of eriodictyol on tumor growth were also validated using a xenograft mouse model.Moreover,no obvious toxicity was identified with eriodictyol treatment.Network pharmacology analysis revealed that PI3K/AKT signaling ranked first among the anti-GC targets.The molecular docking model of eriodictyol and PI3K was constructed,and was found that the binding ability of eriodictyol and PI3K was better than ATP and PI3K.Furthermore,efficient inhibition of phosphorylation and activation of PI3K/AKT by eriodictyol was validated in GC cells.Conclusions:Eriodictyol exhibited the most effective inhibitory effect on cell viability of GC cells among the common flavonoids from POF,and has no obvious toxicity to normal gastric epithelial cells.In vitro and in vivo experiments have shown that eriodictyol has anti-gastric cancer effect,and PI3K/AKT signaling pathway is the main target.These findings suggest that eriodictyol has the potential to be a natural source of anti-GC agents. |
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