Dronedarone inhibits the proliferation of esophageal squamous cell carcinoma through the CDK4/CDK6-RB1 axis in vitro and in vivo

Abstract

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.

Keywords

dronedarone / CDK4/6 / RB1 / esophageal squamous cell carcinoma / chemoprevention / PDX model

Bo Li et al

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Acknowledgements

Technical support was provided by Zhuo Bao, Xiangyu Wu, and Yongwei Ding from the Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University. This research was funded by the National Natural Science Foundation of China (No. 81872335), Central Plains Science and Technology Innovation Leading Talents (No. 224200510015), National Natural Science Youth Foundation (No. 81902486), Fundamental Research Project of key scientific research in Henan Province (No. 23ZX007), and Science and Technology Project of Henan Province (No. 212102310187). We thank all members of our team for their critical input and suggestions.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1062-x and is accessible to authorized users. The sequencing data have been deposited in the Integrated Proteome Resources under project IPX0005359000.

Compliance with ethics guidelines

Conflicts of interest Bo Li, Jing Zhang, Yin Yu, Yinhua Li, Yingying Chen, Xiaokun Zhao, Ang Li, Lili Zhao, Mingzhu Li, Zitong Wang, Xuebo Lu, Wenjie Wu, Yueteng Zhang, Zigang Dong, Kangdong Liu, and Yanan Jiang declare that they have no conflict of interest.

The study was approved by the Research Ethics Committee of Zhengzhou University, and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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