江苏海洋大学刘彬等研究人员合作发现，综合多组学分析阐明秋水仙碱诱导的毒性机制并揭示MLN4924和激酶抑制剂的治疗潜力。该项研究成果于2024年11月20日在线发表在《中国药理学报》杂志上。

研究人员展示了秋水仙碱对人脐静脉内皮细胞（HUVEC）和HeLa细胞的细胞形态学影响，包括在暴露24小时后细胞变圆和脱落，并揭示了明显的细胞毒性效应。接着，研究人员建立了一个大规模筛选模型，旨在识别能够逆转秋水仙碱引起的细胞毒性的分子，并发现MLN4924——一种Cullin-RING E3连接酶（CRL）系统抑制剂——作为减轻秋水仙碱引起的细胞损伤的有前途的候选药物。

通过包括转录组学、蛋白组学、磷酸蛋白组学和泛素组学在内的综合多组学方法，研究人员系统地表征了秋水仙碱引起的分子扰动，并勾画了MLN4924的保护机制。研究人员发现，MLN4924通过调节关键的细胞途径发挥保护作用，特别是防止秋水仙碱引起的细胞周期进程失调、有丝分裂干扰和微管不稳定性。此外，蛋白组学和磷酸蛋白组学分析揭示了激酶信号网络的显著变化，其中联合抑制CDK1和PAK1作为对抗秋水仙碱引起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表征，还确定了关键的治疗靶点，为开发针对秋水仙碱诱导不良反应的靶向干预措施奠定了基础。

研究人员表示，秋水仙碱是一种广泛处方的抗炎药，用于治疗痛风、家族性地中海热和心包炎，但其狭窄的治疗窗口带来了严重毒性的显著风险。尽管其在临床上的应用相关性较高，但秋水仙碱的药理作用及相关毒性机制仍未完全明确，同时也有探索潜在的治疗干预措施来减轻其不良反应。

附：英文原文

Title: Comprehensive multi-omics analysis elucidates colchicine-induced toxicity mechanisms and unveils the therapeutic potential of MLN4924 and kinase inhibitors

Author: 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

Issue&Volume: 2024-11-20

Abstract: 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 24h 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.

DOI: 10.1038/s41401-024-01422-5

Source: https://www.nature.com/articles/s41401-024-01422-5