Mitotic arrest induced by XK469, a novel antitumor agent, is correlated with the inhibition of cyclin B1 ubiquitination
Mitotic arrest induced by XK469, a novel antitumor agent, is correlated with the inhibition of cyclin B1 ubiquitination
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DOI：
10.1002/ijc.1570
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发表时间：
2002-01-01
影响因子：
6.4
通讯作者：
Chen, BD
中科院分区：
文献类型：
--
作者：
Lin, H;Liu, XY;Chen, BD
XK 469（NSC 697887）是一种新型抗肿瘤药物，对多种肿瘤具有广泛的活性。以前的研究表明XK 469是一种拓扑异构酶唇毒，其功能活性与4 '-（9-吖啶氨基）甲磺酰间茴香胺（m-AMSA）相似。我们研究的目的是使用人HCT-116（H116）结肠肿瘤细胞模型进一步研究其作用机制。连续暴露的浓度-存活曲线表明XK 469对H116细胞具有低细胞毒活性。细胞周期分析表明，XK 469是一种阶段特异性细胞周期阻滞剂，与细胞周期蛋白BI、细胞周期蛋白A和p53水平升高相关，但与CDKI（cdc 2）或细胞周期蛋白E水平升高无关。相反，用m-AMSA处理H116细胞引起细胞周期蛋白A和BI的总降解，但增强细胞周期蛋白E和p53的表达。XK 469处理的细胞中细胞周期蛋白BI的积累与细胞周期蛋白BI泛素化的抑制相关，这是蛋白酶体介导的蛋白质周转的必需代谢过程。然而，在用rn-AMSA或秋水仙碱（一种已知的有丝分裂抑制剂）处理的细胞中未检测到对细胞周期蛋白BI泛素化的抑制。此外，与rn-AMSA不同，XK 469在H116细胞中不诱导半胱天冬酶活化或凋亡性细胞死亡。我们的研究结果表明，XK 469是一种具有独特作用机制的时相特异性细胞周期抑制剂，其作用机制与抑制细胞周期蛋白BI的泛素化及其在早期M期的积累有关。(C)2002 Wiley-Liss，Inc.
XK469 (NSC 697887) is a novel antitumor agent with broad activity against a variety of tumors. Previous studies suggest that XK469 is a topoisomerase lip poison with functional activity similar to that of 4'- (9-acridinylamino) methanesulfon-m-anisidide (m-AMSA). The goal of our study was to investigate its mechanism of action further using a human HCT-116 (H116) colon tumor cell model. Concentration-survival curves with continuous exposure indicated that XK469 had low cytotoxic activity against H116 cells. Cell cycle analysis revealed that XK469 is a phase-specific cell cycle blocker that is associated with increased levels of cyclin BI, cyclin A and p53 but not CDKI (cdc2) or cyclin E. In contrast, treatment of H116 cells with m-AMSA caused a total degradation of both cyclin A and BI but enhanced expression of cyclin E and p53. Accumulation of cyclin BI in XK469-treated cells was correlated with the inhibition of cyclin BI ubiquitination, a metabolic process mandatory for proteasome-mediated protein turnover. However, no inhibition of cyclin BI ubiquitination was detected in cells treated with rn-AMSA or colchicine, a known mitotic inhibitor. Furthermore, unlike rn-AMSA, XK469 did not induce caspase activation or apoptotic cell death in H116 cells. Our results suggest that XK469 is a phase-specific cell cycle inhibitor with a unique mechanism of action that is correlated with the inhibition of cyclin BI ubiquitination and its accumulation at early M phase. (C) 2002 Wiley-Liss, Inc.