A novel organoselenium compound induces cell cycle arrest and apoptosis in prostate cancer cell lines
A novel organoselenium compound induces cell cycle arrest and apoptosis in prostate cancer cell lines
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DOI：
10.1016/j.bbrc.2003.08.032
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发表时间：
2003-09-26
影响因子：
3.1
通讯作者：
Zeng, HH
中科院分区：
文献类型：
--
作者：
Shi, CJ;Yu, LZ;Zeng, HH
硫氧还蛋白还原酶（TrxR）与硫氧还蛋白（Trx）共同作用是一种普遍存在的细胞内氧化还原酶系统，具有抗氧化和氧化还原调节作用。TrxR的特性与Trx的功能相结合，将该系统定位于细胞巯基氧化还原控制和抗氧化防御的核心。在一些人类肿瘤中，发现硫氧还蛋白系统过表达。由于其在刺激癌细胞生长和作为细胞凋亡抑制剂中的作用，Trx系统为开发治疗和预防癌症的药物提供了靶点。在先前的研究中，我们成功地合成了一种靶向TrxR的新型有机硒化合物BBSKE（1，2-[bis（1，2-Benzisoselenazolone-3（2 H）-ketone）]ethane，BBSKE，PCT：CN 02/00412），并且已经证明了其对来自各种器官的多种人类癌细胞的生长的抑制作用。在这项研究中，我们研究了BBSKE对PC-3和DU 145人前列腺癌细胞系中TrxR活性的抑制作用，以及其对这两种细胞系的抗肿瘤作用。BBSKE处理以剂量依赖性方式抑制两种细胞系中的TrxR活性，并且还以剂量依赖性方式抑制这两种细胞系的增殖。细胞周期分析显示，在两个细胞系的S期阻滞后48小时暴露于BBSKE。在S期阻滞期间，细胞周期调节蛋白的分析表明，BBSKE增加了cyclinA，cyclinE和P21的蛋白水平，但降低了cyclinB 1，cyclinD 1和Cdk 4的水平。BBSKE还能降低PC-3和DU 145前列腺癌细胞株Bcl-2蛋白表达水平，增加Bax蛋白表达水平，诱导细胞凋亡。这些结果表明，这种新的TrxR抑制剂通过S期阻滞和细胞凋亡抑制前列腺癌细胞的增殖，与细胞周期中的多个分子的调节有关。(C)2003年爱思唯尔公司All rights reserved.
Thioredoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquitous intracellular oxidoreductase system with antioxidant and redox regulatory roles. The properties of TrxR in combination with the functions of Trx position this system at the core of cellular thiol redox control and antioxidant defense. In some human tumors, the thioredoxin system is found overexpressed. Because of its role in stimulating cancer cell growth and as an inhibitor of apoptosis, the Trx system offers a target for the development of drugs to treat and prevent cancer. In a previous research, we successfully synthesized a novel organoselenium compound BBSKE(1,2-[bis(1,2-Benzisoselenazolone-3(2H)-ketone)]ethane, BBSKE, PCT: CN02/00412) targeting the TrxR, and it has demonstrated the inhibitory effect on the growth of a variety of human cancer cells from various organs. In this study, we investigated the inhibitory effect of BBSKE on TrxR activity in PC-3 and DU145 human prostate cancer cell lines, and its antitumoral effect on these two cell lines. Treatment of BBSKE inhibited the TrxR activity in both of the cell lines in a dose-dependent manner and it also inhibited the proliferation of these two cell lines in a dose-dependent manner. Cell cycle analysis showed S phase arrest in both of the cell lines following 48 h exposure to BBSKE. During the S arrest, analysis of cell cycle regulatory proteins demonstrated that BBSKE increased the protein levels of cyclinA, cyclinE, and P21, but decreased the levels of cyclinB1, cyclinD1, and Cdk4. Furthermore, BBSKE decreased the protein level of Bcl-2 but increased the level of Bax, and induced apoptosis in PC-3 and DU145 human prostate cancer cell lines. These results suggest that this novel TrxR inhibitor inhibits the proliferation of prostate cancer cells via S phase arrest and apoptosis in association with the regulation of multiple molecules in the cell cycle. (C) 2003 Elsevier Inc. All rights reserved.