Lu Yu-Jhang, Yang Sheng-Huei, Chien Ching-Ming, Lin Yi-Hsiung, Hu Xiu-Wei, Wu Zchong-Zcho, Wu Ming-Jung, Lin Shinne-Ren
Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100 Shi-Chuan 1st Road, Kaohsiung 807, Taiwan, ROC.
Toxicol In Vitro. 2007 Feb;21(1):90-8. doi: 10.1016/j.tiv.2006.09.008. Epub 2006 Sep 19.
(Z)-2-(6-(Thieanisyl-2-yl)hexa-3-en-1,5-diynyl)benzenamine (THDB), an enediyne compound, was identified in our laboratory as a novel antineoplastic agent with broad spectrum of antitumor activities against many human cancer cells. THDB was found to inhibit the growth of HL-60 cells in a time-and dose-dependent manner. Cell cycle analysis showed G2/M phase arrest in HL-60 cells following 48 h exposure to THDB. Analysis of the cell cycle regulatory proteins demonstrated that THDB did not change the steady-state levels of cyclin B1, cyclin E, Cdk1 and Cdc25C, but decreased the protein levels of Cdk2 and cyclin A. THDB also caused a marked increase in apoptosis, as characterized by DNA fragmentation (DNA ladder and sub G1 formation), and poly (ADP-ribose) polymerase (PARP) cleavage, which was associated with activation of caspase-3, caspase-8 and caspase-9. Moreover, the THDB-induced apoptosis was significantly attenuated in the presence of specific inhibitors of caspase-3, -8 and -9. These molecular alterations provide an insight into THDB-caused growth inhibition, G2/M arrest and apoptotic death of HL-60 cells.
（Z）-2-（6-（噻吩甲酰-2-基）-3-己烯-1,5-二炔基）苯胺（THDB）是一种烯二炔化合物，在我们实验室被鉴定为一种新型抗肿瘤药物，对多种人类癌细胞具有广泛的抗肿瘤活性。发现THDB以时间和剂量依赖性方式抑制HL-60细胞的生长。细胞周期分析显示，HL-60细胞在暴露于THDB 48小时后出现G2/M期阻滞。对细胞周期调节蛋白的分析表明，THDB没有改变细胞周期蛋白B1、细胞周期蛋白E、细胞周期蛋白依赖性激酶1（Cdk1）和细胞周期蛋白磷酸酶25C（Cdc25C）的稳态水平，但降低了细胞周期蛋白依赖性激酶2（Cdk2）和细胞周期蛋白A的蛋白水平。THDB还导致凋亡显著增加，其特征为DNA片段化（DNA梯形条带和亚G1峰形成）以及聚（ADP-核糖）聚合酶（PARP）裂解，这与半胱天冬酶-3、半胱天冬酶-8和半胱天冬酶-9的激活有关。此外，在存在半胱天冬酶-3、-8和-9的特异性抑制剂时，THDB诱导的凋亡显著减弱。这些分子改变为深入了解THDB导致的HL-60细胞生长抑制、G2/M期阻滞和凋亡死亡提供了线索。
