2. Academic Validation
  3. Domperidone inhibits cell proliferation via targeting MEK and CDK4 in esophageal squamous cell carcinoma

Domperidone inhibits cell proliferation via targeting MEK and CDK4 in esophageal squamous cell carcinoma

  • Cancer Cell Int. 2024 Mar 25;24(1):114. doi: 10.1186/s12935-024-03291-8.
Qiang Yuan 1 2,  Yunshu Shi 1 2,  Yuhan Zhang 1 2,  Yaqian Shi 1 3,  Zubair Hussain 1 3,  Jimin Zhao 1 3,  Yanan Jiang 1 3,  Yan Qiao 1 3,  Yaping Guo 1 3,  Jing Lu 1 3,  Ziming Dong 1 3,  Zigang Dong 4 5,  Junyong Wang 6,  Kangdong Liu 7 8 9 10 11
Affiliations

Affiliations

  • 1 The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China.
  • 2 China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China.
  • 3 Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China.
  • 4 The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China. zgdong@hci-cn.org.
  • 5 China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China. zgdong@hci-cn.org.
  • 6 The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China. wangjunyong@zzu.edu.cn.
  • 7 The Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
  • 8 China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
  • 9 State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
  • 10 Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
  • 11 Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
PMID: 38528618 DOI: 10.1186/s12935-024-03291-8
Abstract

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.

Keywords

CDK4; Domperidone; ESCC; MEK1/2.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z