Nocodazole is an anti-mitotic drug and a rapid and reversible microtubule polymerization inhibitor. It inhibits Abl, Abl (E255K), and Abl (T315I) in cell-free assays with IC50 values of 0.21μM, 0.53μM, and 0.64μM, respectively[1]. Nocodazole binds to β-tubulin and disrupts microtubule assembly/disassembly dynamics, thereby arresting mitosis and inducing apoptosis in tumor cells[2]. Nocodazole can increase CRISPR-mediated homologous recombination efficiency, enhancing the precision of gene editing efficacy[3].
In vitro, Nocodazole (50 ng/ml) treatment of HuH7 cells for 16 hours synchronizes approximately 50% of the cells at the G2/M phase, with intracellular microtubule fibers mainly distributed in the peripheral region of the cells and without forming a bipolar spindle[4]. Nocodazole (20µM) treatment of emsCOS-1 cells for 30 minutes results in the dispersion of Golgi stacks throughout the cytoplasm[5]. Nocodazole (1 nM) treatment of CHO cells inhibits microtubule dynamics, slowing migration and increasing the frequency and duration of the resting state while maintaining cell directionality. Nocodazole (70nM) has the opposite effect of low drug concentrations, causing cells to move more randomly[6].
In vivo, Nocodazole (5 mg/kg) administered intraperitoneally for six weeks significantly reduces the tumor volume and weight in mice transplanted with COLO 205 tumors, with enhanced antitumor effects observed when combined with ketoconazole[7].
References:
[1] Park H, Hong S. Nocodazole is a high-affinity ligand for the cancer-related kinases ABL, c-KIT, BRAF, and MEK[J]. ChemMedChem, 2011, 7(1): 53-56.
[2] Jordan M A, Wilson L. Microtubules and actin filaments: dynamic targets for cancer chemotherapy[J]. Current opinion in cell biology, 1998, 10(1): 123-130.
[3] Chen S, Chen D, Liu B, et al. Modulating CRISPR/Cas9 genome-editing activity by small molecules[J]. Drug Discovery Today, 2022, 27(4): 951-966.
[4] Makiyama T, Obama T, Watanabe Y, et al. Behavior of intracellular lipid droplets during cell division in HuH7 hepatoma cells[J]. Experimental Cell Research, 2023, 433(2): 113855.
[5] Mukai, K., Konno, H., Akiba, T. et al. Activation of STING requires palmitoylation at the Golgi[J]. Nat Commun 7, 11932 (2016).
[6] Ganguly A, Yang H, Sharma R, Patel KD, Cabral F. The role of microtubules and their dynamics in cell migration[J]. J Biol Chem. 2012, 287(52):43359-69.
[7] Wang Y J, Jeng J H, Chen R J, et al. Ketoconazole potentiates the antitumor effects of nocodazole: In vivo therapy for human tumor xenografts in nude mice[J]. Molecular Carcinogenesis: Published in cooperation with the University of Texas MD Anderson Cancer Center, 2002, 34(4): 199-210.
Nocodazole是一种抗有丝分裂药物，是一种快速可逆的微管聚合抑制剂，在无细胞试验中抑制Abl，Abl（E255K）和Abl（T315I），IC50值分别为0.21μM，0.53μM和0.64μM[1]。Nocodazole与β-微管蛋白结合并破坏微管组装/拆卸动力学，从而阻止有丝分裂并诱导肿瘤细胞凋亡[2]。Nocodazole可提高CRISPR介导的同源重组效率，对增强精确的基因编辑效力具有加成作用[3]。
在体外，Nocodazole（50 ng/ml）处理HuH7细胞16h，使大约50%的细胞同步于G2/M期，细胞内微管蛋白纤维主要分布在细胞的外围区域，并且没有形成双极纺锤体[4]。Nocodazole（20µM）处理emsCOS-1细胞30min，会导致细胞质中分散的高尔基体堆栈[5]。Nocodazole（1nM）处理CHO细胞，可抑制微管动力学，减缓迁移并增加静息状态的频率和持续时间，但细胞的方向性得以保持。Nocodazole（70nM）与低药物浓度的影响相反，会导致细胞更加随机地移动[6]。
在体内，Nocodazole（5mg/kg）通过腹腔注射治疗移植了COLO 205肿瘤的小鼠6周，显著减小了肿瘤体积和重量，且在酮康唑的联合治疗下抗肿瘤效应增强[7]。