食管鳞状细胞癌 (ESCC) 患者的治疗选择通常会导致预后不良和健康相关生活质量下降。筛选 FDA 批准的癌症化学预防药物是一种有前途且具有成本效益的策略。在这里，我们发现决奈达隆是一种抗心律失常药物，可以抑制食管鳞癌细胞的增殖。此外，我们进行了磷酸组学分析，以研究决奈达隆处理 ESCC 细胞的机制。通过计算对接模型和下拉分析，我们证明决奈达隆可以直接与 CDK4 和 CDK6 激酶结合。我们还通过体外激酶测定和细胞周期测定证明决奈达隆通过靶向CDK4/CDK6并通过RB1磷酸化抑制阻断G0/G1期来有效抑制ESCC增殖。随后，我们发现敲除CDK4和CDK6降低了ESCC细胞对决奈达隆的敏感性。此外，决奈达隆在体内抑制患者来源的肿瘤异种移植模型中食管鳞癌的生长。因此，我们的研究表明决奈达隆可以重新用作 ESCC 化学预防的 CDK4/6 抑制剂。© 2024。高等教育出版社。

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.© 2024. Higher Education Press.