Arbidol inhibits human esophageal squamous cell carcinoma growth in vitro and in vivo through suppressing ataxia telangiectasia and Rad3-related protein kinase
Ning Yang,
Xuebo Lu,
Yanan Jiang,
Lili Zhao,
Donghao Wang,
Yaxing Wei,
Yin Yu,
Myoung Ok Kim,
Kyle Vaughn Laster,
Xin Li,
Baoyin Yuan,
Zigang Dong,
Kangdong Liu
Affiliations
Ning Yang
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; China-US Hormel Cancer Institute, Zhengzhou, China
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; China-US Hormel Cancer Institute, Zhengzhou, China
Yanan Jiang
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; China-US Hormel Cancer Institute, Zhengzhou, China; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China
Lili Zhao
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
Donghao Wang
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; China-US Hormel Cancer Institute, Zhengzhou, China
Yaxing Wei
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; China-US Hormel Cancer Institute, Zhengzhou, China
Yin Yu
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; China-US Hormel Cancer Institute, Zhengzhou, China
Myoung Ok Kim
Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, Republic of Korea
Kyle Vaughn Laster
China-US Hormel Cancer Institute, Zhengzhou, China
Xin Li
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China
Baoyin Yuan
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China
Zigang Dong
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; China-US Hormel Cancer Institute, Zhengzhou, China; Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, China
Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; China-US Hormel Cancer Institute, Zhengzhou, China; Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China; Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, China
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.
