Credit score: 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, Yanan Jiang
Esophageal squamous cell carcinoma (ESCC) is a extreme well being risk, being a predominant subtype of esophageal most cancers and contributing considerably to cancer-related mortality globally. Regardless of developments together therapies, affected person prognosis stays poor, highlighting an pressing want for novel therapy methods.
On this context, a research showing in Frontiers of Drugs explores the potential of dronedarone, an FDA-approved drug, in inhibiting ESCC proliferation by means of the CDK4/CDK6-RB1 axis, each in vitro and in vivo.
The analysis reveals that dronedarone, beforehand used for atrial fibrillation, might considerably suppress ESCC cell progress by focusing on the CDK4/6-RB1 pathway, a key regulator of the cell cycle, thereby offering a promising therapeutic candidate for ESCC.
The research commenced with a display of FDA-approved medication to establish potential chemopreventive brokers towards ESCC. Dronedarone emerged as a potent inhibitor of ESCC cell proliferation. By a collection of in vitro experiments, together with cytotoxicity assays, cell proliferation checks, and anchorage-independent cell progress assays, it was demonstrated that dronedarone had a considerable inhibitory impact on ESCC cells, with minimal impression on non-malignant esophageal epithelial cells.
Phosphoproteomics evaluation following dronedarone therapy revealed downregulation of phosphorylation websites on the retinoblastoma protein 1 (RB1), suggesting the involvement of CDK4/6 in dronedarone’s mechanism of motion.
Computational docking fashions and pull-down assays confirmed dronedarone’s direct binding to CDK4 and CDK6, inhibiting their kinase exercise and subsequently lowering RB1 phosphorylation at particular websites, resulting in cell cycle arrest within the G1 section.
Additional investigation into the function of CDK4/CDK6 in ESCC was carried out by means of CRISPR-mediated gene knockout experiments. The depletion of CDK4/CDK6 in ESCC cells not solely diminished their proliferation but additionally decreased their sensitivity to dronedarone, underscoring the importance of those kinases as therapeutic targets.
In vivo experiments utilizing patient-derived xenograft (PDX) fashions in immunodeficient mice demonstrated that dronedarone therapy considerably diminished tumor dimension and weight, with no observable opposed results on physique weight or organ well being.
The therapy additionally led to a lower in Ki67 ranges, a marker of tumor proliferation, and diminished phosphorylation of RB1, reinforcing the drug’s efficacy in inhibiting the CDK4/CDK6-RB1 axis in ESCC.
The findings of this research are notably noteworthy given the restricted choices for ESCC chemoprevention and the potential for dronedarone to function a fast and sensible medical utility.
The drug’s potential to focus on CDK4/6 immediately, resulting in cell cycle arrest and diminished tumor progress, positions it as a candidate for additional investigation within the chemoprevention and therapy of ESCC. The research’s outcomes help the repurposing of an present drug for a brand new indication, providing a promising route for enhancing affected person outcomes in ESCC.
Extra data:
Bo Li et al, Dronedarone inhibits the proliferation of esophageal squamous cell carcinoma by means of the CDK4/CDK6-RB1 axis in vitro and in vivo, Frontiers of Drugs (2024). DOI: 10.1007/s11684-024-1062-x
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Accepted drug dronedarone discovered to inhibit the proliferation of esophageal squamous cell carcinoma (2025, January 7)
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