Biological activity of 4-substituted methoxybenzoyl-aryl-thiazole: an active microtubule inhibitor.
Biological activity of 4-substituted methoxybenzoyl-aryl-thiazole: an active microtubule inhibitor.
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DOI：
10.1158/0008-5472.can-10-1725
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发表时间：
2011-01-01
期刊：
影响因子：
11.2
通讯作者：
Dalton JT
中科院分区：
文献类型：
--
作者：
Li CM;Wang Z;Lu Y;Ahn S;Narayanan R;Kearbey JD;Parke DN;Li W;Miller DD;Dalton JT
微管的形成是一个动态的过程，涉及αβ-微管蛋白杂二聚体的聚合和解聚。促进或抑制微管蛋白聚合的药物可以破坏这一动态过程，阻止细胞处于细胞周期的G2/M期。尽管以微管蛋白为靶点的药物一般在亚纳摩尔范围内显示出细胞毒作用，但由于药物外排而产生的耐药性是抗微管蛋白药物中的一种常见现象。我们最近报道了一类4-取代甲氧基苯甲酰基芳基噻唑(SMART)，它具有很强的体外活性和广谱的细胞毒性。三种不同芳环取代基的SMART化合物SMART-H(H)、SMART-F(F)和SMART-OH(OH)的体内外抗癌活性研究表明，它们能有效地与微管蛋白中秋水仙碱结合部位结合，抑制微管蛋白聚合，使癌细胞停滞在细胞周期的G2/M期，并诱导其凋亡。这些智能化合物在体外也同样有效地抑制亲本细胞和过度表达MDR的细胞的生长，表明它们可以克服多药耐药性。在人前列腺癌(PC-3)和黑色素瘤(A375)异种移植瘤模型上的体内抗肿瘤效果研究表明，SMART-H和SMART-F治疗后的%T/C值在4-30%之间。此外，在体内，较高剂量(15 mg/kg)的SMART-H治疗21天没有产生任何明显的神经毒性。这些研究首次提供了体内证据和概念证明，即智能化合物与目前FDA批准的用于癌症治疗的抗微管蛋白药物具有类似的疗效，但它们可以绕过P-糖蛋白介导的耐药性。
Formation of microtubules is a dynamic process that involves polymerization and depolymerization of αβ-tubulin heterodimers. Drugs that enhance or inhibit tubulin polymerization can destroy this dynamic process, arresting cells in the G2/M phase of the cell cycle. Although drugs that target tubulin generally demonstrate cytotoxic potency in the sub-nanomolar range, resistance due to drug efflux is a common phenomenon among the antitubulin agents. We recently reported a class of 4-Substituted Methoxybenzoyl-Aryl-Thiazoles (SMART) that exhibited great in vitro potency and broad spectrum cellular cytotoxicity. Evaluation of the in vitro and in vivo anti-cancer activities of three SMART compounds, SMART-H (H), SMART-F (F) and SMART-OH (OH) with varying substituents at the 4-position of aryl ring, demonstrated that they bind potently to the colchicine binding site in tubulin, inhibit tubulin polymerization, arrest cancer cells in G2/M phase of the cell cycle, and induce their apoptosis. The SMART compounds also equi-potently inhibit the growth of parental and MDR-over-expressing cells in vitro, indicating that they can overcome multidrug resistance. In vivo anti-tumor efficacy studies in human prostate (PC-3) and melanoma (A375) cancer xenograft models demonstrated that SMART-H and SMART-F treatments resulted in %T/C values ranging from 4–30%. In addition, in vivo SMART-H treatment for 21 days at the higher dose (15 mg/kg) failed to produce any apparent neurotoxicity. These studies provide the first in vivo evidence and proof-of-concept that SMART compounds are similarly efficacious to currently FDA approved antitubulin drugs for cancer treatment, but they can circumvent P-glycoprotein-mediated drug resistance.