Zhang Fang, Rothermund Kristi, Gangadharan Sajithlal B, Pommier Yves, Prochownik Edward V, Lazo John S
Section of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, The University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Oncotarget. 2012 Sep;3(9):998-1010. doi: 10.18632/oncotarget.632.
Cancer stem cells (CSCs) are a subpopulation generally thought to be responsible for cancer initiation and progression. Because CSCs are often rare in the total tumor cell population and differentiate rapidly when grown in culture, it has been challenging to uncover compounds that selectively target CSCs. We previously described CSC-emulating cells derived from breast cancer cell lines that maintained a stable undifferentiated state. We optimized a phenotypic assay with these cells and screened 1,280-bioactive compounds, identifying five that preferentially inhibited CSC-like cell proliferation. Using a compound-guided target identification approach, we found high topoisomerase I (Topo I) expression levels in breast CSC-like cells and primary breast CSCs. Structurally unrelated small molecules targeting Topo I preferentially inhibited CSC-like cells. These results illustrate the substantial power of this CSC phenotypic screening platform and promote Topo I as a potential molecular therapeutic target for therapies aimed at expunging CSCs.
癌症干细胞（CSCs）是通常被认为对癌症起始和进展负责的一个亚群。由于癌症干细胞在肿瘤细胞总数中往往很少见，并且在培养中生长时会迅速分化，因此发现选择性靶向癌症干细胞的化合物一直具有挑战性。我们之前描述了源自乳腺癌细胞系的模拟癌症干细胞的细胞，这些细胞维持稳定的未分化状态。我们用这些细胞优化了一种表型分析方法，并筛选了1280种生物活性化合物，鉴定出五种优先抑制类癌症干细胞样细胞增殖的化合物。使用化合物引导的靶点鉴定方法，我们发现乳腺类癌症干细胞样细胞和原发性乳腺癌症干细胞中拓扑异构酶I（Topo I）表达水平很高。靶向Topo I的结构不相关的小分子优先抑制类癌症干细胞样细胞。这些结果说明了这个癌症干细胞表型筛选平台的强大作用，并将Topo I作为旨在清除癌症干细胞的治疗方法的潜在分子治疗靶点加以推广。
