Identification of selective inhibitors of cancer stem cells by high-throughput screening.
Identification of selective inhibitors of cancer stem cells by high-throughput screening.
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DOI：
10.1016/j.cell.2009.06.034
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发表时间：
2009-08-21
期刊：
影响因子：
64.5
通讯作者：
Lander ES
中科院分区：
文献类型：
--
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
筛选特异性杀死上皮癌干细胞（CSC）的药物是不可能的，因为这些细胞在肿瘤细胞群中很罕见，而且它们在培养中相对不稳定。我们在这里描述了一种新的方法来筛选具有上皮CSC特异性毒性的药物。我们已经在化学筛选的背景下实施了这种方法，并发现了对乳腺CSC显示选择性毒性的化合物。在功能测定中，一种化合物（盐霉素）相对于紫杉醇（一种常用的乳腺癌化疗药物）将CSC的比例降低>100倍。用盐霉素治疗小鼠抑制体内乳腺肿瘤生长并诱导肿瘤细胞上皮分化增加。此外，总体基因表达分析表明，盐霉素而不是紫杉醇治疗导致先前通过分析直接从患者分离的乳腺组织鉴定的乳腺CSC基因表达丧失。这项研究表明，它是可能的，以确定具有特定毒性的代理上皮CSC，以及这样做提供了一个实用的方法。
Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here a novel approach to screening for agents with epithelial CSC-specific toxicity. We have implemented this method in the context of a chemical screen and have discovered compounds showing selective toxicity for breast CSCs. In functional assays, one compound (salinomycin) reduced the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin but not paclitaxel treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates that it is possible to identify agents with specific toxicity for epithelial CSCs as well as providing a practical approach for doing so.