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

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.

Azelnidipine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by targeting MEK1/2.

Epidemiological and mechanistic studies suggest that some US Food and Drug Administration (FDA)-approved drugs can reduce the incidence of cancer and inhibit tumor growth. Therefore, investigating FDA-approved drugs for cancer chemoprevention is a promising strategy. In this study, we screened FDA-approved drugs and found that azelnidipine, a Ca channel blocker widely used in the treatment of hypertension, inhibits the growth of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. We identified that MEK1/2 were direct targets of azelnidipine through pull-down assay and cellular thermal shift assay. Azelnidipine could suppress kinase activity of MEK1/2 through in vitro kinase assay. Hypophosphorylation of ERK1/2 decreased the levels of Cyclin D1/CDK6 in ESCC cells after azelnidipine treatment. More importantly, azelnidipine, like trametinib, inhibited the growth of ESCC in vivo. In conclusion, azelnidipine, a novel dual MEK1/2 inhibitor, exerted antitumor effects against ESCC cell lines and patient-derived xenograft in ESCC.

Arbidol inhibits human esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase.

Human esophageal cancer has a global impact on human health due to its high incidence and mortality. Therefore, there is an urgent need to develop new drugs to treat or prevent the prominent pathological subtype of esophageal cancer, esophageal squamous cell carcinoma (ESCC). Based upon the screening of drugs approved by the Food and Drug Administration, we discovered that Arbidol could effectively inhibit the proliferation of human ESCC in vitro. Next, we conducted a series of cell-based assays and found that Arbidol treatment inhibited the proliferation and colony formation ability of ESCC cells and promoted G1-phase cell cycle arrest. Phosphoproteomics experiments, in vitro kinase assays and pull-down assays were subsequently performed in order to identify the underlying growth inhibitory mechanism. We verified that Arbidol is a potential ataxia telangiectasia and Rad3-related (ATR) inhibitor via binding to ATR kinase to reduce the phosphorylation and activation of minichromosome maintenance protein 2 at Ser108. Finally, we demonstrated Arbidol had the inhibitory effect of ESCC in vivo by a patient-derived xenograft model. All together, Arbidol inhibits the proliferation of ESCC in vitro and in vivo through the DNA replication pathway and is associated with the cell cycle.

Tegaserod Maleate Suppresses the Growth of Gastric Cancer In Vivo and In Vitro by Targeting MEK1/2.

Gastric cancer (GC) ranks fifth in global incidence and fourth in mortality. The current treatments for GC include surgery, chemotherapy and radiotherapy. Although treatment strategies for GC have been improved over the last decade, the overall five-year survival rate remains less than 30%. Therefore, there is an urgent need to find novel therapeutic or preventive strategies to increase GC patient survival rates. In the current study, we found that tegaserod maleate, an FDA-approved drug, inhibited the proliferation of gastric cancer cells, bound to MEK1/2 and suppressed MEK1/2 kinase activity. Moreover, tegaserod maleate inhibited the progress of gastric cancer by depending on MEK1/2. Notably, we found that tegaserod maleate suppressed tumor growth in the patient-derived gastric xenograft (PDX) model. We further compared the effect between tegaserod maleate and trametinib, which is a clinical MEK1/2 inhibitor, and confirmed that tegaserod maleate has the same effect as trametinib in inhibiting the growth of GC. Our findings suggest that tegaserod maleate inhibited GC proliferation by targeting MEK1/2.

Oxethazaine inhibits esophageal squamous cell carcinoma proliferation and metastasis by targeting aurora kinase A.

Esophageal squamous cell carcinoma (ESCC), a malignant neoplasm with high incidence, is a severe global public health threat. The current modalities used for treating ESCC include surgery, chemotherapy, and radiotherapy. Although ESCC management and treatment strategies have improved over the last decade, the overall 5-year survival rate remains <20%. Therefore, the identification of novel therapeutic strategies that can increase ESCC patient survival rates is urgently needed. Oxethazaine, an amino-amide anesthetic agent, is mainly prescribed in combination with antacids to relieve esophagitis, dyspepsia, and other gastric disorders. In the present study, we found that oxethazaine inhibited the proliferation and migration of esophageal cancer cells. According to the results of in vitro screening and binding assays, oxethazaine binds directly to AURKA, suppresses AURKA activity, and inhibits the downstream effectors of AURKA. Notably, we found that oxethazaine suppressed tumor growth in three patient-derived esophageal xenograft mouse models and tumor metastasis in vivo. Our findings suggest that oxethazaine can inhibit ESCC proliferation and metastasis in vitro and in vivo by targeting AURKA.

Nuplazid suppresses esophageal squamous cell carcinoma growth in vitro and in vivo by targeting PAK4.

BACKGROUND: Due to the high recurrence and low 5-year survival rates of esophageal squamous cell carcinoma (ESCC) after treatment, the discovery of novel drugs for recurrence chemoprevention is of particular importance. METHODS: We screened the FDA-approved drug library and found that Nuplazid, an atypical antipsychotic that acts as an effective 5-HT 2 A receptor inverse agonist, could potentially exert anticancer effects in vitro and in vivo on ESCC. RESULTS: Pull-down results indicated that Nuplazid binds with p21-activated kinase 4 (PAK4), and a kinase assay showed that Nuplazid strongly suppressed PAK4 kinase activity. Moreover, Nuplazid exhibited inhibitory effects on ESCC in vivo. CONCLUSIONS: Our findings indicate that Nuplazid can suppress ESCC progression through targeting PAK4.