GDP366, a novel small molecule dual inhibitor of survivin and Op18, induces cell growth inhibition, cellular senescence and mitotic catastrophe in human cancer cells.
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.
Shi
Xianping
X
Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Wang
Deping
D
Ding
Ke
K
Lu
Zhongzheng
Z
Jin
Yanli
Y
Zhang
Jin
J
Pan
Jingxuan
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D016922:Cellular Senescence / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D050777:Stathmin / Q000037:antagonists & inhibitors*; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; C554753:GDP 366; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D010671:Phenylurea Compounds; D050777:Stathmin; D000077022:Survivin