Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells
Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells
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DOI：
10.1016/s1535-6108(03)00050-3
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发表时间：
2003-03-01
期刊：
影响因子：
50.3
通讯作者：
Stockwell, BR
中科院分区：
文献类型：
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作者：
Dolma, S;Lessnick, SL;Stockwell, BR
我们使用合成致死高通量筛选来询问23，550种化合物杀死工程致瘤细胞的能力，但不能杀死其同基因正常细胞对应物。我们鉴定了具有基因型选择活性的已知和新型化合物，包括多柔比星、柔红霉素、米托蒽醌、喜树碱、桑伐霉素、棘霉素、bouvardin、NSC146109和我们命名为erastin的新型化合物。这些化合物在hTERT、SV 40大和小T癌蛋白、人乳头瘤病毒16型（HPV）E6和E7癌蛋白和致癌HRAS存在下具有增加的活性。我们发现过表达hTERT和E7或LT增加了拓扑异构酶2 α的表达，过表达RAS（V12）和ST都增加了拓扑异构酶I的表达，并使细胞对erastin启动的非凋亡性细胞死亡过程敏感。
We used synthetic lethal high-throughput screening to interrogate 23,550 compounds for their ability to kill engineered tumorigenic cells but not their isogenic normal cell counterparts. We identified known and novel compounds with genotype-selective activity, including doxorubicin, daunorubicin, mitoxantrone, camptothecin, sangivamycin, echinomycin, bouvardin, NSC146109, and a novel compound that we named erastin. These compounds have increased activity in the presence of hTERT, the SV40 large and small T oncoproteins, the human papillomavirus type 16 (HPV) E6 and E7 oncoproteins, and oncogenic HRAS. We found that overexpressing hTERT and either E7 or LT increased expression of topoisomerase 2alpha and that overexpressing RAS(V12) and ST both increased expression of topoisomerase I and sensitized cells to a nonapoptotic cell death process initiated by erastin.