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

Abstract

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. Based upon a screening of drugs approved by the Food and Drug Administration, we discovered that Arbidol could effectively inhibit the proliferation of human esophageal squamous cell carcinoma 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. Phospho-proteomics experiments, in vitro kinase assays and pull-down assays were subsequently performed in order to identify the underlying growth inhibitory mechanism. We verified Arbidol is a potential ATR inhibitor via binding to ATR kinase to reduce the phosphorylation and activation of MCM2 at Ser108. Finally, we demonstrated Arbidol had the inhibitory effect of ESCC in vivo by a PDX 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.

Patient-derived tumor models: a suitable tool for preclinical studies on esophageal cancer

“…Arbidol is a potential ataxia-telangiectasia-and-Rad3-related (ATR) inhibitor that interacts with ATR at ASN 2346 and HIS2361, down-regulates MCM2, and affects the activity of ATR kinase, which in turn affects the cell cycle. It inhibits the proliferation of ESCC in vitro through the DNA replication pathway and cell cycle as has been verified in ESCC PDX models [52]. This finding suggests that arbidol may be used as a novel drug against ESCC.…”