Screening Of FDA-approved Drug Library Identifies Propafenone As A Novel Anticancer Drug In ESCC

Background: Esophageal squamous cell carcinoma(ESCC)is one of the most common malignant tumors with poor survival and limited therapeutic options.The aim of this study is to identify novel anticancer strategy from the existing Food and Drug Administration(FDA)-approved drugs that have been used in clinic to treat other diseases.Methods: A FDA-approved drug library was used to identify potential anticancer drugs.WST-1 assay,colony formation assay and tumor xenograft experiments were performed to determine the effect of propafenone on proliferation of ESCC cells in vitro and in vivo.The Ki-67 proliferation index and CD31 microvessel density of tumor xenografts were detected by immunohistochemistry.Proteomics experiment was used to identify the differentially expressed proteins in the propafenone-treated cells and the data was analyzed by IPA.Flow cytometry analysis was carried out to examine the cell apoptosis and mitochondrial membrane potential.Western blot assay was used to investigate the molecular mechanisms involved in propafenone-induced cell apoptosis and mitochondrial dysfunction.Results: Propafenone,a FDA-approved drug for treatment of arrhythmias,was found to induce apoptosis and exert a significantly inhibitory effect on the proliferation and colony formation of ESCC cells in a dose-dependent manner without observed cytotoxicity on normal esophageal epithelial cells.Moreover,propafenone markedly suppressed growth of tumor xenografts in nude mice by reducing Ki-67 proliferation index and angiogenesis,but did not damage the vital organs of nude mice.Mechanistically,our data from proteomics analysis,Western blot and flow cytometry demonstrated that propafenone caused mitochondrial dysfunction,as indicated by decreased mitochondrial membrane potential and reduced expressions of Bcl-xL and Bcl-2.Conclusions: This study firstly validates that propafenone,a FDA-approved drug to treat arrhythmias,could be a novel therapeutic agent for the treatment of esophageal cancer without obvious side effect.