Park Sang Eun, Choi Hye Joung, Yee Su Bog, Chung Hae Young, Suh Hongsuk, Choi Yung Hyun, Yoo Young Hyun, Kim Nam Deuk
Department of Pharmacy, Pusan National University, Busan 609-735, South Korea.
Int J Oncol. 2004 Jul;25(1):231-6.
As previously demonstrated, the synthetic bile acid derivatives mediate anti-proliferative properties in a variety of human cancer cells. In the present study, the effects of the synthetic derivatives of ursodeoxycholic acid (UDCA), HS-1030 and HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on the proliferation of HT-29 human colon cancer cells were investigated. Whereas UDCA and CDCA had no effect on the growth of cells in the concentration ranges we have tested, HS-1199 and HS-1200 completely inhibited cell proliferation, while HS-1030 and HS-1183 showed weak inhibitory activities. Simultaneous estimation of cell cycle parameters and apoptosis by flow cytometry showed that the synthetic bile acid derivatives produced the arrest of cell cycle progression at the G1 phase and ensuing increase of sub-G1 fraction, which resulted in the induction of apoptosis. The induction of apoptosis was confirmed by observation of cleavages of poly(ADP-ribose) polymerase and DNA fragmentation. Furthermore, Western blot analysis showed decreased expression levels of cyclin D1, cyclin E, cyclin A, Cdk2, Cdk4, and Cdk6 proteins. In addition, the synthetic bile acid derivatives markedly induced the level of Cdk inhibitor, p21WAF1/CIP1, in a p53-independent manner. Furthermore, the exposure of cells to the synthetic bile acid derivatives resulted in a decrease in the level of pRb and enhanced binding between pRb and E2F-1. Based on these data, these synthetic bile acid derivatives may serve as potential lead compounds in the treatment of colon cancer.
如先前所示，合成胆汁酸衍生物在多种人类癌细胞中介导抗增殖特性。在本研究中，研究了熊去氧胆酸（UDCA）的合成衍生物HS - 1030和HS - 1183以及鹅去氧胆酸（CDCA）的合成衍生物HS - 1199和HS - 1200对HT - 29人结肠癌细胞增殖的影响。虽然在我们测试的浓度范围内UDCA和CDCA对细胞生长没有影响，但HS - 1199和HS - 1200完全抑制细胞增殖，而HS - 1030和HS - 1183显示出较弱的抑制活性。通过流式细胞术同时估计细胞周期参数和凋亡表明，合成胆汁酸衍生物使细胞周期进程停滞在G1期，并随之导致亚G1期部分增加，从而诱导凋亡。通过观察聚（ADP - 核糖）聚合酶的裂解和DNA片段化证实了凋亡的诱导。此外，蛋白质印迹分析显示细胞周期蛋白D1、细胞周期蛋白E、细胞周期蛋白A、细胞周期蛋白依赖性激酶2（Cdk2）、细胞周期蛋白依赖性激酶4（Cdk4）和细胞周期蛋白依赖性激酶6（Cdk6）蛋白的表达水平降低。此外，合成胆汁酸衍生物以不依赖p53的方式显著诱导细胞周期蛋白依赖性激酶抑制剂p21WAF1/CIP1的水平。此外，细胞暴露于合成胆汁酸衍生物导致视网膜母细胞瘤蛋白（pRb）水平降低，并增强了pRb与E2F - 1之间的结合。基于这些数据，这些合成胆汁酸衍生物可能作为治疗结肠癌的潜在先导化合物。
