Nocodazole

Nocodazole, an anti-mitotic drug, is a rapidly-reversible inhibitor of microtubule polymerization which inhibits Abl, Abl(E255K) and Abl(T315I)with theIC50 value of 0.21 μM, 0.53 μM and 0.64 μM in cell-free assays, respectively[1].

In vitro: Nocodazolewas a high-affinity ligand for the cancer-related kinases including Abl phosphorylated, c-Kit, BRAF, and MEK with the Kd values of 0.091 μM, 1.6 μM, 1.8 μM and 1.6 μM, respectively. In addition, the Kd for Abl(E255K) phosphorylated, Abl(T315I) phosphorylated, BRAF(V600E) and PI3Kγ was 0.12 μM, 0.17 μM, 1.1 μM and 1.5 μM, respectively. In chronic lymphocytic leukemia cells, Nocodazole induced apoptosis. In some human colon carcinoma cells, Nocodazole decrease D apoptosis. Also, Nocodazole inhibited insulin-stimulated glucose transport. Nocodazole impaired the morphology and directionality of migrating medial gan-glionic eminence cells [1]. At high concentrations, Nocodazole rapidly depolymerized microtubules in cells, while low concentrations of Nocodazole inhibited microtubule dynamic instability [2].In SH-SY5Y cells, Nocodazole disrupted microtubules by binding to β-tubulin, prevented the formation of one of the two interchain disulfide linkages and impaired the transport of vesicles. Nocodazole significantly attenuated METH-induced cell death and lysosomal dysfunction [3]. Nocodazole (≥ 50 nM) resulted in a rapid reduction in fibroblast locomotion to a new rate that was maintained for > 2 hours. Nocodazole(100 nM) decreased the rate of locomotion by more than 60%; and 300 nM nocodazole completely stopped cell locomotion[4].

In vivo: In athymic mice bearing COLO 205 tumor xenografts,after 6 wk of treatment with Ketoconazole (50 mg/kg/three times per week)plus Nocodazole (5 mg/kg/three times per week), the antitumor effects of ND were significantly potentiated by KT. The tumor volume and tumor weight of the mice are significantly reduced as compared with those treated with Ketoconazole or Nocodazole alone. Nocodazole treatment in combination with Ketoconazole strongly enhanced apoptosis of COLO 205 tumor xenografts treated with Ketoconazole or Nocodazole alone [5].

诺可唑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，可抑制Abl、Abl（E255K）和Abl（T315I），在无细胞测定中，IC50值分别为0.21μM、0.53μM和0.64μM[1]。

体外：诺可唑类是癌症相关激酶的高亲和力配体，包括Abl磷酸化、c-Kit、BRAF和MEK，Kd值分别为0.091μM、1.6μM、1.8μM和1.6μM。此外，Abl（E255K）磷酸化、Abl（T315I）磷酸化，BRAF（V600E）和PI3Kγ的Kd分别为0.12μM、0.17μM、1.1μM和1.5μM。在慢性淋巴细胞白血病细胞中，诺可唑诱导细胞凋亡。在一些人结肠癌细胞中，诺可唑可减少D细胞凋亡。此外，诺可唑抑制胰岛素刺激的葡萄糖转运。诺可唑损害了迁移的内侧干胶质隆起细胞的形态和方向性[1]。在高浓度下，诺可唑快速解聚细胞中的微管，而低浓度的诺可唑抑制微管动态不稳定性[2]。在SH-SY5Y细胞中，诺可唑通过与β-微管蛋白结合破坏微管，阻止两个链间二硫键之一的形成，并损害囊泡的运输。诺可唑显著减轻METH诱导的细胞死亡和溶酶体功能障碍[3]。诺可唑（≥50 nM）导致成纤维细胞运动迅速减少，达到维持2小时以上的新速率。诺可唑（100nM）使运动速率降低60%以上；并且300nM诺可唑完全停止细胞运动[4]。

体内：在携带COLO 205肿瘤异种移植物的无胸腺小鼠中，用酮康唑（50 mg/kg/每周三次）和诺可唑（5 mg/kg/周三次）治疗6周后，KT显著增强了ND的抗肿瘤作用。与单独用酮康唑或诺可唑治疗的小鼠相比，小鼠的肿瘤体积和肿瘤重量显著降低。诺唑与酮康唑联合治疗强烈增强了用酮康唑或单独诺唑治疗的COLO 205肿瘤异种移植物的凋亡[5]。

References:
[1].  Park H, Hong S, Hong S. Nocodazole is a High‐Affinity Ligand for the Cancer‐Related Kinases ABL, c‐KIT, BRAF, and MEK[J]. ChemMedChem, 2012, 7(1): 53-56.
[2]. Xu K, Schwarz P M, Ludue a R F. Interaction of nocodazole with tubulin isotypes[J]. Drug development research, 2002, 55(2): 91-96.
[3]. Nara A, Aki T, Funakoshi T, et al. Hyperstimulation of macropinocytosis leads to lysosomal dysfunction during exposure to methamphetamine in SH-SY5Y cells[J]. Brain research, 2012, 1466: 1-14.
[4]. Liao G, Nagasaki T, Gundersen G G. Low concentrations of nocodazole interfere with fibroblast locomotion without significantly affecting microtubule level: implications for the role of dynamic microtubules in cell locomotion[J]. Journal of Cell Science, 1995, 108(11): 3473-3483.
[5]. 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, 2002, 34(4): 199-210.