背景:食管鳞状细胞癌(ESCC)是世界上消化系统肿瘤相关死亡的主要原因之一。不幸的是,在临床实践中,ESCC患者缺乏有效的化学预防剂,导致极高的死亡率。
方法:筛选处方药物库,以发现ESCC细胞中的关键抗肿瘤特性。磷酸蛋白质组学,激酶阵列,应用下拉测定和药物亲和反应靶标稳定测定(DARTS)来探索机制并搜索协同靶标。建立的PDX小鼠模型用于确定多潘立酮的治疗效果。
结果:在筛选处方药库之后,我们发现多潘立酮具有抗肿瘤特性。多潘立酮,作为胃动力剂,已广泛用于临床胃肠动力障碍。尽管研究有限,有迹象表明多潘立酮可能具有抗肿瘤特性。在这项研究中,我们确定多潘立酮在体外和体内均显着抑制ESCC的增殖。我们使用磷酸化蛋白质组学来揭示p-ERK,多潘立酮治疗后p-SMAD3下调。然后,激酶测定和下拉测定的结果进一步验证了多潘立酮与MEK1/2和CDK4直接结合,导致其激酶活性受到抑制。此外,我们的结果表明,MEK/ERK和CDK4/SMAD3信号通路是多潘立酮抗ESCC的主要通路。
结论:总的来说,这些研究结果表明,多潘立酮是MEK1/2和CDK4的有效"多靶点"抑制剂,为ESCC的化学预防提供了潜在的益处.
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of digestive system tumor related death in the world. Unfortunately, effective chemopreventive agent is lack for patients with ESCC in clinical practice, which leads to the extremely high mortality rate.
METHODS: A library of prescribed drugs was screened for finding critical anti-tumor properties in ESCC cells. The phosphoproteomics, kinase array, pulldown assay and drug affinity responsive target stabilization assay (DARTS) were applied to explore mechanisms and searched for synergistic targets. Established models of PDX in mice were used to determine the therapeutic effect of domperidone.
RESULTS: After screening a library of prescribed drugs, we discovered that domperidone has anti-tumor properties. Domperidone, acting as a gastroprokinetic agent, has been widely used in clinic for gastrointestinal motility disorders. Despite limited research, there are indications that domperidone may have anti-tumor properties. In this study, we determined that domperidone significantly inhibited ESCC proliferation in vitro and in vivo. We employed phosphoproteomics to reveal p-ERK, and p-SMAD3 down-regulation upon domperidone treatment. Then, the results of kinase assay and pulldown assay further validated that domperidone directly combined with MEK1/2 and CDK4, leading to the inhibition of their kinase activity. Furthermore, our results revealed that MEK/ERK and CDK4/SMAD3 signal pathway were major pathways in domperidone against ESCC.
CONCLUSIONS: Collectively, these findings suggest that domperidone serves as an effective \"multi-target\" inhibitor of MEK1/2 and CDK4, offering potential benefits for the chemoprevention of ESCC.