Lestaurtinib Sensitizes Gastric Cancer Cells To TRAIL-induced Apoptosis And Its Molecular Mechanisms

Objective: Gastric cancer is a common type of malignant tumor with relatively poor prognosis and presents a serious threat to global health.Gastric cancer(GC)is the third most frequent cause of cancer-related deaths around the world.Human Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand(TRAIL)have been developed to induce apoptosis selectively in tumor cells,while preserving normal cells.Molecular targeted therapy provides new ideas and hope for the treatment of gastic cancer.However,the research on TRAIL-relatedagents has lagged behind and has been limited by the extensive drug resistance in many malignant cancer cells.Therefore,current research is focus on sensitizing the TRAIL-induced tumor cell apoptosis.Lestaurtinib,also known as CEP-701,is a specific tyrosine kinase inhibitor.Lestaurtinib can regulate multiple signaling pathways,cause growth arrest and induce programmed cell death in various cancer cells.However,the effect and specific mechanism of Lestaurtinib on gastric cancer is still unknown.The regulatory effect on TRAIL-induced tumor cell apoptosis is also unclear.Methods: MTT,cell colony formation and flow cytometry was used to observe the effect of TRAIL on the proliferation and apoptosis of gastric cancer cells.After TRAIL treatment,Lestaurtinib was applied to treat the gastric cancer cell line AGS.The effects of Lestaurtinib and TRAIL on cell proliferation and apoptosis were observed.In addition,we further verified the effects through the nude mice tumorigenic experiments in vivo.We further explored the mechanism of Lestaurtinib on TRAIL-induced apoptosis of gastric cancer cells by Westernblot.Results:(1)TRAIL could induce the apoptosis of gastric cancer cells,however,the apoptosis rate of cells was significantly low.(2)Combined with TRAIL,Lestaurtinib promoted the apoptosis of gastric cancer cells,and its apoptosis rate was better than that of monotherapy.(3)Lestaurtinib and TRAIL verified the synergistic effect in tumor-bearing experiments in nude mice in vivo.(4)Lestaurtinib promoted TRAIL-induced apoptosis of gastric cancer cells through inducing DR5 upregulation,which in turn caused the down-regulation of c FLIP.Conclusion: This study shows that the combination of Lestaurtinib and TRAIL can significantly induce the apoptosis of gastric cancer cells.These results provide a theoretical and experimental basis for the clinical treatment of gastric cancer.