Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Cancer Biol Ther. 2010 Apr 15;9(8):640-50. doi: 10.4161/cbt.9.8.11269. Epub 2010 Apr 20.
Accumulating evidence indicates that survivin plays a pivotal role in not only cell survival but also cell cycle progression. Op18/stathmin is an oncoprotein that regulates microtubule stabilization. Both survivin and Op18 have been proposed as therapeutic targets for cancer. However, few small molecule inhibitors of survivin and Op18 have been reported. In this study, we have identified a novel small molecule compound (GDP366) which potently and selectively inhibited the expression of both survivin and Op18. It decreased both the mRNA and protein levels of survivin and Op18. This inhibitory effect was not dependent on the status of p53 and p21 although GDP366 potently increased p53 and p21 levels. GDP366 significantly inhibited the growth of tumor cells in vitro and in vivo (nude mouse model) without rapid induction of apoptosis. GDP366 induced polyploidy in multiple types of cancer cell lines. GDP366 increased chromosomal instability, and induced cellular senescence by inhibiting telomerase activity. We conclude that GDP366 is a novel dual inhibitor of survivin and Op18. Our results warrant further translational evaluation of this compound.
越来越多的证据表明，survivin 不仅在细胞存活中发挥关键作用，而且在细胞周期进程中也发挥关键作用。Op18/stathmin 是一种癌蛋白，可调节微管的稳定。survivin 和 Op18 都被提议作为癌症的治疗靶点。然而，报道的 survivin 和 Op18 的小分子抑制剂很少。在这项研究中，我们鉴定了一种新型小分子化合物（GDP366），它能强有力且选择性地抑制 survivin 和 Op18 的表达。它降低了 survivin 和 Op18 的 mRNA 和蛋白水平。这种抑制作用不依赖于 p53 和 p21 的状态，尽管 GDP366 能强有力地增加 p53 和 p21 的水平。GDP366 显著抑制了体外和体内（裸鼠模型）肿瘤细胞的生长，而没有迅速诱导细胞凋亡。GDP366 在多种类型的癌细胞系中诱导了多倍体。GDP366 通过抑制端粒酶活性增加染色体不稳定性，并诱导细胞衰老。我们得出结论，GDP366 是 survivin 和 Op18 的新型双重抑制剂。我们的结果证明了进一步对该化合物进行转化评估的必要性。
