Article

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

Lin-hui Zhai1,2, Xing-long Jia3,4, Yu-lu Chen1, Mu-yin Liu3,5, Jing-dan Zhang6,7, Shao-jie Ma1, Xiu-jun Wang1, Wen-hao Cheng1, Jing-liang He1, Jiao-jiao Zhou1, Ling-yi Zuo1, Mei-qi Zhang1, Qing Yuan1, Meng-han Xu1, Jing Ji1, Min-jia Tan3,6,7, Bin Liu1
1 Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China
2 Translational Research Institute of Brain and Brain-like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200434, China
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4 School of Pharmacy, Fudan University, Shanghai 201203, China
5 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
6 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
7 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
Correspondence to: Min-jia Tan: mjtan@simm.ac.cn, Bin Liu: liubin@jou.edu.cn,
DOI: 10.1038/s41401-024-01422-5
Received: 28 August 2024
Accepted: 5 November 2024
Advance online: 20 November 2024

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 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.
Keywords: colchicine; MLN4924; multi-omics analysis; phosphoproteomics; ubiquitinomics; kinase inhibitor

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