Gastric cancer is the fourth leading cause of cancer deaths worldwide. Most patients are diagnosed in the advanced stage. Inadequate therapeutic strategies and the high recurrence rate lead to the poor 5-year survival rate. Therefore, effective chemopreventive drugs for gastric cancer are urgently needed. Repurposing clinical drugs is an effective strategy for discovering cancer chemopreventive drugs. In this study, we find that 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 are used to illustrate vortioxetine hydrobromide directly binds to JAK2 and SRC kinases and inhibits their kinase activities. The results of non-reducing SDS-PAGE and Western blotting indicate that vortioxetine hydrobromide suppresses STAT3 dimerization and nuclear translocation activity. Furthermore, vortioxetine hydrobromide inhibits the cell proliferation dependent on JAK2 and SRC and suppresses the growth of gastric cancer PDX model in vivo. These data demonstrate that vortioxetine hydrobromide, as a novel dual JAK2/SRC inhibitor, curbs the growth of gastric cancer in vitro and in vivo by JAK2/SRC-STAT3 signaling pathways. Our results highlight that vortioxetine hydrobromide has the potential application in the chemoprevention of gastric cancer.

胃癌是全球第四大癌症死亡原因。大多数患者确诊时已是晚期。不充分的治疗策略和高复发率导致较差的 5 年生存率。因此，迫切需要有效的胃癌化学预防药物。临床药物再利用是发现癌症化学预防药物的有效策略。在这项研究中，我们发现 FDA 批准的药物沃替西汀氢溴酸盐是一种双重 JAK2/SRC 抑制剂，对胃癌细胞增殖具有抑制作用。计算对接分析、下拉分析、细胞热转移分析 (CETSA) 和体外激酶分析用于说明氢溴酸沃替西汀直接结合 JAK2 和 SRC 激酶并抑制它们的激酶活性。非还原性 SDS-PAGE 和 Western blotting 的结果表明 vortioxetine hydrobromide 抑制 STAT3 二聚化和核转位活性。此外，vortioxetine hydrobromide 抑制依赖于 JAK2 和 SRC 的细胞增殖，并抑制体内胃癌 PDX 模型的生长。这些数据表明，氢溴酸沃替西汀作为一种新型 JAK2/SRC 双重抑制剂，通过 JAK2/SRC-STAT3 信号通路在体外和体内抑制胃癌的生长。我们的研究结果表明，氢溴酸沃替西汀在胃癌的化学预防中具有潜在的应用价值。vortioxetine hydrobromide 抑制依赖于 JAK2 和 SRC 的细胞增殖并抑制体内胃癌 PDX 模型的生长。这些数据表明，氢溴酸沃替西汀作为一种新型 JAK2/SRC 双重抑制剂，通过 JAK2/SRC-STAT3 信号通路在体外和体内抑制胃癌的生长。我们的研究结果表明，氢溴酸沃替西汀在胃癌的化学预防中具有潜在的应用价值。vortioxetine hydrobromide 抑制依赖于 JAK2 和 SRC 的细胞增殖并抑制体内胃癌 PDX 模型的生长。这些数据表明，氢溴酸沃替西汀作为一种新型 JAK2/SRC 双重抑制剂，通过 JAK2/SRC-STAT3 信号通路在体外和体内抑制胃癌的生长。我们的研究结果表明，氢溴酸沃替西汀在胃癌的化学预防中具有潜在的应用价值。