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Domperidone inhibits cell proliferation via targeting MEK and CDK4 in esophageal squamous cell carcinoma
Qiang Yuan1,2, Yunshu Shi1,2, Yuhan Zhang1,2
1The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.
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.
Conclusion:
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.
Insights
Domperidone demonstrates significant anti-tumor effects against esophageal squamous cell carcinoma (ESCC) by inhibiting key pathways. This research highlights domperidone as a potential chemopreventive agent for ESCC patients.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer mortality globally.
- A lack of effective chemopreventive agents contributes to high ESCC mortality rates.
Purpose of the Study:
- To screen existing drugs for anti-tumor properties against ESCC.
- To investigate the anti-cancer mechanisms of domperidone in ESCC.
Main Methods:
- Screening of a drug library against ESCC cells.
- Utilized phosphoproteomics, kinase arrays, pulldown assays, and DARTS.
- Validated therapeutic effects using patient-derived xenograft (PDX) mouse models.
Main Results:
- Domperidone significantly inhibited ESCC proliferation in vitro and in vivo.
- Identified down-regulation of p-ERK and p-SMAD3 signaling pathways.
- Confirmed direct binding of domperidone to MEK1/2 and CDK4, inhibiting their kinase activity.
Conclusions:
- Domperidone acts as a multi-target inhibitor of MEK1/2 and CDK4.
- These findings suggest domperidone's potential as a chemopreventive strategy for ESCC.
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