Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
Pharmacology. 2013;92(1-2):90-8. doi: 10.1159/000351852. Epub 2013 Aug 16.
The polymerization of tubulin molecules forms microtubules which are considered an attractive target for cancer treatment. Herein, we synthesized a new tubulin inhibitor, MPT0B169 (2-dimethylamino-N-[1-(4-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indol-7-yl]-acetamide) and demonstrated its action in leukemia cell lines HL60 and NB4 and lymphoma cell line U937. We found that MPT0B169 prevented tubulin assembly by binding the colchicine-binding site of tubulin in vitro. MPT0B169 also induced tubulin depolymerization in vivo. MPT0B169 inhibited the growth of HL60, NB4, and U937 cells in dose- and time-dependent manners. It also inhibited the growth of paclitaxel-resistant cancer cells. In addition, MPT0B169 caused G2/M cell cycle arrest in nonresistant and paclitaxel-resistant cancer cells, with a concomitant increase in cyclin B1 levels and cyclin-dependent kinase 1 (CDK1) phosphorylation. These results suggest that MPT0B169, a tubulin inhibitor, inhibits cell growth and induces G2/M cell cycle arrest of cancer cells through the disruption of tubulin polymerization.
微管蛋白分子的聚合形成微管，被认为是癌症治疗的一个有吸引力的靶点。在此，我们合成了一种新的微管蛋白抑制剂 MPT0B169（2-二甲基氨基-N-[1-（4-甲氧基苯磺酰基）-2,3-二氢-1H-吲哚-7-基]-乙酰胺），并证明了其在白血病细胞系 HL60 和 NB4 以及淋巴瘤细胞系 U937 中的作用。我们发现 MPT0B169 通过在体外结合微管蛋白的秋水仙碱结合位点来阻止微管蛋白的组装。MPT0B169 还在体内诱导微管蛋白解聚。MPT0B169 以剂量和时间依赖的方式抑制 HL60、NB4 和 U937 细胞的生长，还抑制紫杉醇耐药癌细胞的生长。此外，MPT0B169 导致非耐药和紫杉醇耐药癌细胞中的 G2/M 细胞周期停滞，同时 cyclin B1 水平和细胞周期蛋白依赖性激酶 1（CDK1）磷酸化增加。这些结果表明，微管蛋白抑制剂 MPT0B169 通过破坏微管蛋白聚合来抑制癌细胞的生长并诱导其 G2/M 细胞周期停滞。
