Zhai Lin-Hui, Jia Xing-Long, Chen Yu-Lu, Liu Mu-Yin, Zhang Jing-Dan, Ma Shao-Jie, Wang Xiu-Jun, Cheng Wen-Hao, He Jing-Liang, Zhou Jiao-Jiao, Zuo Ling-Yi, Zhang Mei-Qi, Yuan Qing, Xu Meng-Han, Ji Jing, Tan Min-Jia, Liu Bin
Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
Translational Research Institute of Brain and Brain-like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
Acta Pharmacol Sin. 2025 Mar;46(3):702-714. doi: 10.1038/s41401-024-01422-5. Epub 2024 Nov 20.
Colchicine is a widely prescribed anti-inflammatory drug for the treatment of gout, familial Mediterranean fever and pericarditis, but its narrow therapeutic window presents a significant risk of severe toxicity. Despite its clinical relevance, the molecular mechanisms underlying colchicine's pharmacological effects and associated toxicity and explored potential therapeutic interventions to mitigate its adverse effects. We showed the colchicine's impact on cellular morphology in human umbilical vein endothelial cells (HUVEC) and HeLa cells including cell rounding and detachment following 24 h of exposure that revealed pronounced cytotoxic effects. We then established a large-scale screening model to identify small molecules capable of reversing colchicine-induced cellular toxicity, and identified MLN4924, an inhibitor of the Cullin-RING E3 ligase (CRL) system, as a promising candidate for mitigating colchicine-induced cellular injury. Through a comprehensive multi-omics approach including transcriptomics, proteomics, phosphoproteomics and ubiquitinomics, we systematically characterized the molecular perturbations caused by colchicine and delineated the protective mechanisms of MLN4924. We found that MLN4924 exerted its protective effects by modulating critical cellular pathways, specifically preventing the dysregulation of cell cycle progression, mitotic disruption and microtubule destabilization triggered by colchicine. Furthermore, proteomic and phosphoproteomic analyses revealed significant alterations in kinase signaling networks, with combined inhibition of CDK1 and PAK1 emerging as an effective strategy to counteract colchicine-induced cellular dysfunction. These results not only provide a detailed molecular characterization of colchicine toxicity but also identify key therapeutic targets, laying the groundwork for the development of targeted interventions to mitigate colchicine-induced adverse effects in clinical practice.
秋水仙碱是一种广泛应用于治疗痛风、家族性地中海热和心包炎的抗炎药物，但其治疗窗狭窄，存在严重毒性的重大风险。尽管其具有临床相关性，但秋水仙碱药理作用及相关毒性的分子机制尚未完全明确，因此探索了潜在的治疗干预措施以减轻其不良反应。我们展示了秋水仙碱对人脐静脉内皮细胞（HUVEC）和HeLa细胞形态的影响，包括暴露24小时后细胞变圆和脱离，这揭示了明显的细胞毒性作用。然后，我们建立了一个大规模筛选模型，以鉴定能够逆转秋水仙碱诱导的细胞毒性的小分子，并确定了MLN4924，一种Cullin-RING E3连接酶（CRL）系统的抑制剂，作为减轻秋水仙碱诱导的细胞损伤的有前景的候选药物。通过包括转录组学、蛋白质组学、磷酸蛋白质组学和泛素组学在内的综合多组学方法，我们系统地表征了秋水仙碱引起的分子扰动，并描绘了MLN4924的保护机制。我们发现MLN4924通过调节关键细胞途径发挥其保护作用，特别是防止秋水仙碱引发的细胞周期进程失调、有丝分裂破坏和微管不稳定。此外，蛋白质组学和磷酸蛋白质组学分析揭示了激酶信号网络的显著变化，联合抑制CDK1和PAK1成为对抗秋水仙碱诱导的细胞功能障碍的有效策略。这些结果不仅提供了秋水仙碱毒性的详细分子特征，还确定了关键治疗靶点，为开发针对性干预措施以减轻秋水仙碱在临床实践中引起的不良反应奠定了基础。
