Wang Shao-Xiang, Ju Huai-Qiang, Liu Kai-Sheng, Zhang Jia-Xuan, Wang Xiao, Xiang Yang-Fei, Wang Rui, Liu Jin-Yun, Liu Qiu-Ying, Xia Min, Xing Guo-Wen, Liu Zhong, Wang Yi-Fei
Guangzhoujinan Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center for Genetic Medicine, Jinan University, West Huangpu Road, Guangzhou, China.
Biosci Biotechnol Biochem. 2011;75(8):1540-5. doi: 10.1271/bbb.110225. Epub 2011 Aug 7.
SNX-2112 is a heat shock protein 90 (Hsp90) inhibitor with anticancer properties currently in clinical trials. This study investigated the effects of SNX-2112 on inhibition of cell growth, the cell cycle, and apoptosis in MCF-7 human breast cancer cells, in addition to the various molecular mechanisms. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis suggest that SNX-2112 inhibits cell growth in a time- and dose-dependent manner more potently than 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), a traditional Hsp90 inhibitor, probably as a result of cell-cycle arrest at the G2/M phase and the induction of apoptosis. Downregulation of Bcl-2 and Bcl-xL, upregulation of Bax, cleavage of caspase-9 and poly (ADP-ribose) polymerase (PARP), and degradation of the breast cancer-related Hsp90 client proteins human epidermal growth factor receptor-2 (HER2), Akt, Raf-1, and nuclear factor kappa-B kinase (IKK) were observed in SNX-2112 treated cells by Western blot assay. These findings suggest that the molecular mechanisms of cell-growth inhibition by SNX-2112 involve activation of the mitochondrial apoptotic pathway and the degradation of breast cancer-related proteins.
SNX-2112是一种具有抗癌特性的热休克蛋白90（Hsp90）抑制剂，目前正处于临床试验阶段。本研究调查了SNX-2112对MCF-7人乳腺癌细胞的细胞生长抑制、细胞周期和凋亡的影响，以及各种分子机制。3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）试验和流式细胞术分析结果表明，SNX-2112比传统的Hsp90抑制剂17-（烯丙基氨基）-17-去甲氧基格尔德霉素（17-AAG）更有效地以时间和剂量依赖性方式抑制细胞生长，这可能是由于细胞周期停滞在G2/M期并诱导凋亡所致。通过蛋白质免疫印迹法在经SNX-2112处理的细胞中观察到Bcl-2和Bcl-xL的下调、Bax的上调、半胱天冬酶-9和聚（ADP-核糖）聚合酶（PARP）的裂解，以及乳腺癌相关Hsp90客户蛋白人表皮生长因子受体-2（HER2）、Akt、Raf-1和核因子κB激酶（IKK）的降解。这些发现表明，SNX-2112抑制细胞生长的分子机制涉及线粒体凋亡途径的激活和乳腺癌相关蛋白的降解。
