Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Acta Pharmacol Sin. 2012 Feb;33(2):261-70. doi: 10.1038/aps.2011.156.
To evaluate the anti-cancer effects of a new sulfonamide derivative, 2-(N-(3-chlorophenyl)-4-methoxyphenylsulfonamido)-N-hydroxypropanamide (MPSP-001).
Human cancer cell lines (HepG2, THP-1, K562, HGC-27, SKOV3, PANC-1, SW480, Kba, HeLa, A549, MDA-MB-453, and MCF-7) were examined. The cytotoxicity of MPSP-001 was evaluated using the WST-8 assay. Cell cycle distribution was examined with flow cytometry. Mitotic spindle formation was detected using immunofluorescence microscopy. Apoptosis-related proteins were examined with Western blot using specific phosphorylated protein antibodies. Competitive tubulin-binding assay was performed to test whether the compound competitively bound to the colchicine site. Molecular docking was performed to explore the possible binding conformation.
MPSP-001 potently inhibited the growth of the 12 different types of human cancer cells with the IC(50) values ranging from 1.9 to 15.7 μmol/L. The compound exerted potent inhibition on the drug-resistant Kb/VCR and MCF-7/ADR cells, as on Kba and MCF-7 cells. In HeLa, HGC-27, A549, and other cells, the compound (5 μmol/L) caused cell cycle arrest at the G(2)/M phase, and subsequently induced cell apoptosis. In Hela cells, it prevented the mitotic spindle formation. Furthermore, the compound dose-dependently inhibited polymerization of tubulin in vitro, and directly bound to the colchicine-site of β-tubulin. Molecular docking predicted that the compound may form two hydrogen bonds to the binding pocket. The compound showed synergistic effects with colchicine and taxol in blocking mitosis of HeLa cells.
MPSP-001 shows a broad-spectrum of anti-tumor efficacy in vitro and represents a novel structure with anti-microtubule activity.
评估新型磺胺衍生物 2-（N-（3-氯苯基）-4-甲氧基苯磺酰胺基）-N-羟基丙酰胺（MPSP-001）的抗癌作用。
检测人癌细胞系（HepG2、THP-1、K562、HGC-27、SKOV3、PANC-1、SW480、Kba、HeLa、A549、MDA-MB-453 和 MCF-7）。用 WST-8 法评估 MPSP-001 的细胞毒性。用流式细胞术检测细胞周期分布。用免疫荧光显微镜检测有丝分裂纺锤体形成。用特异性磷酸化蛋白抗体通过 Western blot 检测凋亡相关蛋白。用竞争性微管结合试验检测化合物是否竞争性结合秋水仙碱结合位点。进行分子对接以探索可能的结合构象。
MPSP-001 强力抑制 12 种不同类型的人癌细胞生长，IC（50）值范围为 1.9 至 15.7 μmol/L。该化合物对耐药性 Kb/VCR 和 MCF-7/ADR 细胞，以及 Kba 和 MCF-7 细胞均表现出强烈的抑制作用。在 HeLa、HGC-27、A549 和其他细胞中，该化合物（5 μmol/L）使细胞周期停滞在 G（2）/M 期，随后诱导细胞凋亡。在 HeLa 细胞中，它阻止有丝分裂纺锤体形成。此外，该化合物在体外剂量依赖性地抑制微管蛋白聚合，并直接结合到微管蛋白的秋水仙碱结合位点。分子对接预测，该化合物可能与结合口袋形成两个氢键。该化合物与秋水仙碱和紫杉醇联合使用时，在阻断 HeLa 细胞有丝分裂方面具有协同作用。
MPSP-001 在体外显示出广谱的抗肿瘤功效，代表了一种具有抗微管活性的新型结构。
