. The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou 450001 China . China-US (Henan) Hormel Cancer Institute, Zhengzhou 450003, China . Basic Medicine Sciences Research Center, Zhengzhou University, Zhengzhou 450052, China . State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou 450001, China . Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou 450001, China . Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou 450001, China
Treatment options for patients with esophageal squamous cell carcinoma (ESCC) often result in poor prognosis and declining health-related quality of life. Screening FDA-approved drugs for cancer chemoprevention is a promising and cost-efficient strategy. Here, we found that dronedarone, an antiarrhythmic drug, could inhibit the proliferation of ESCC cells. Moreover, we conducted phosphorylomics analysis to investigate the mechanism of dronedarone-treated ESCC cells. Through computational docking models and pull-down assays, we demonstrated that dronedarone could directly bind to CDK4 and CDK6 kinases. We also proved that dronedarone effectively inhibited ESCC proliferation by targeting CDK4/CDK6 and blocking the G0/G1 phase through RB1 phosphorylation inhibition by in vitro kinase assays and cell cycle assays. Subsequently, we found that knocking out CDK4 and CDK6 decreased the susceptibility of ESCC cells to dronedarone. Furthermore, dronedarone suppressed the growth of ESCC in patient-derived tumor xenograft models in vivo. Thus, our study demonstrated that dronedarone could be repurposed as a CDK4/6 inhibitor for ESCC chemoprevention.
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