Dronedarone inhibits the proliferation of esophageal squamous cell carcinoma through the CDK4/CDK6-RB1 axis in vitro and in vivo
2025-01-07
(Press-News.org)
Esophageal squamous cell carcinoma (ESCC) is a severe health threat, being a predominant subtype of esophageal cancer and contributing significantly to cancer-related mortality globally. Despite advancements in combination therapies, patient prognosis remains poor, highlighting an urgent need for novel treatment strategies. In this context, a study explores the potential of dronedarone, an FDA-approved drug, in inhibiting ESCC proliferation through the CDK4/CDK6-RB1 axis, both in vitro and in vivo. The research reveals that dronedarone, previously used for atrial fibrillation, could significantly suppress ESCC cell growth by targeting the CDK4/6-RB1 pathway, a key regulator of the cell cycle, thereby providing a promising therapeutic candidate for ESCC.
The study commenced with a screen of FDA-approved drugs to identify potential chemopreventive agents against ESCC. Dronedarone emerged as a potent inhibitor of ESCC cell proliferation. Through a series of in vitro experiments, including cytotoxicity assays, cell proliferation tests, and anchorage-independent cell growth assays, it was demonstrated that dronedarone had a substantial inhibitory effect on ESCC cells, with minimal impact on non-malignant esophageal epithelial cells. Phosphoproteomics analysis following dronedarone treatment revealed downregulation of phosphorylation sites on the retinoblastoma protein 1 (RB1), suggesting the involvement of CDK4/6 in dronedarone's mechanism of action. Computational docking models and pull-down assays confirmed dronedarone's direct binding to CDK4 and CDK6, inhibiting their kinase activity and subsequently reducing RB1 phosphorylation at specific sites, leading to cell cycle arrest in the G1 phase.
Further investigation into the role of CDK4/CDK6 in ESCC was conducted through CRISPR-mediated gene knockout experiments. The depletion of CDK4/CDK6 in ESCC cells not only reduced their proliferation but also decreased their sensitivity to dronedarone, underscoring the significance of these kinases as therapeutic targets. In vivo experiments using patient-derived xenograft (PDX) models in immunodeficient mice demonstrated that dronedarone treatment significantly reduced tumor size and weight, with no observable adverse effects on body weight or organ health. The treatment also led to a decrease in Ki67 levels, a marker of tumor proliferation, and reduced phosphorylation of RB1, reinforcing the drug's efficacy in inhibiting the CDK4/CDK6-RB1 axis in ESCC.
The findings of this study are particularly noteworthy given the limited options for ESCC chemoprevention and the potential for dronedarone to serve as a rapid and practical clinical application. The drug's ability to target CDK4/6 directly, leading to cell cycle arrest and reduced tumor growth, positions it as a candidate for further investigation in the chemoprevention and treatment of ESCC. The study's results support the repurposing of an existing drug for a new indication, offering a promising direction for improving patient outcomes in ESCC.
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[Press-News.org] Dronedarone inhibits the proliferation of esophageal squamous cell carcinoma through the CDK4/CDK6-RB1 axis in vitro and in vivo
