Vortioxetine hydrobromide inhibits the growth of gastric cancer cells in vivo and in vitro by targeting JAK2 and SRC

Abstract Gastric cancer is the fourth leading cause of cancer deaths worldwide. Most patients are diagnosed in the advanced stage, and inadequate therapeutic strategies and the high recurrence rate leads to the poor 5-year survival rate. Therefore, effective chemoprevention drugs for gastric cancer are urgently needed. Repurposing clinical drugs is an effective strategy for cancer chemoprevention. In this study, we found vortioxetine hydrobromide, an FDA-approved drug, is a dual JAK2/SRC inhibitor, and has inhibitory effects on cell proliferation of gastric cancer. Computational docking analysis, pull-down assay, cellular thermal shift assay (CETSA) and in vitro kinase assays were used to illustrate whether vortioxetine hydrobromide directly bound to JAK2 and SRC kinases and inhibited their kinase activities. The results of non-reducing SDS-PAGE and Western blotting indicated that vortioxetine hydrobromide suppressed STAT3 dimerization, nuclear translocation and transcriptional activity. Furthermore, vortioxetine hydrobromide inhibited the cell proliferation dependent on JAK2 and SRC gene expression and suppressed the growth of gastric cancer PDX model in vivo. These data demonstrated that vortioxetine hydrobromide, as a novel dual JAK2/SRC inhibitor, curbed the growth of gastric cancer in vitro and in vivo by JAK2/SRC-STAT3 signaling pathways. It highlights that vortioxetine hydrobromide has the potential application in the chemoprevention of gastric cancer.