A 1536-well quantitative high-throughput screen to identify compounds targeting cancer stem cells.
A 1536-well quantitative high-throughput screen to identify compounds targeting cancer stem cells.
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DOI：
10.1177/1087057112458152
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发表时间：
2012-10
影响因子：
--
通讯作者：
Ferrer M
中科院分区：
文献类型：
--
作者：
Mathews LA;Keller JM;Goodwin BL;Guha R;Shinn P;Mull R;Thomas CJ;de Kluyver RL;Sayers TJ;Ferrer M
称为癌症干细胞 (CSC) 或肿瘤起始细胞 (TIC) 的肿瘤细胞亚群具有自我更新潜力，被认为可驱动转移和肿瘤形成。数据表明，这些细胞对当前的化疗和放射治疗有抵抗力，导致癌症复发。因此，寻找导致分化的肿瘤细胞以及CSC群体死亡的新药物和/或药物组合是一个关键的未满足的医疗需求。在这里，我们描述了如何使用干细胞生长培养基和非贴壁条件从癌细胞系中产生癌症源性 CSC，其数量能够实现高通量筛选 (HTS)。利用这些 CSC 开发了 1536 孔微孔板格式的细胞生长测定法，用于筛选集中的肿瘤药物和临床候选药物，以找到对这些高度侵袭性细胞具有细胞毒性的化合物。命中选择过程包括初级筛选期间的效力和功效测量，使我们能够有效地识别对球状来源的 CSC 具有有效细胞毒性作用的化合物。总体而言，这项研究展示了第一个使用 CSC 的小型化 HTS 测定法。这里描述的程序应该能够进一步测试化合物对 CSC 的影响，并帮助确定需要针对哪些途径来杀死它们。
Tumor cell subpopulations called cancer stem cells (CSCs) or tumor-initiating cells (TICs) have self-renewal potential and are thought to drive metastasis and tumor formation. Data suggest that these cells are resistant to current chemotherapy and radiation therapy treatments, leading to cancer recurrence. Therefore, finding new drugs and/or drug combinations that cause death of both the differentiated tumor cells as well as CSC populations is a critical unmet medical need. Here, we describe how cancer-derived CSCs are generated from cancer cell lines using stem cell growth media and nonadherent conditions in quantities that enable high-throughput screening (HTS). A cell growth assay in a 1536-well microplate format was developed with these CSCs and used to screen a focused collection of oncology drugs and clinical candidates to find compounds that are cytotoxic against these highly aggressive cells. A hit selection process that included potency and efficacy measurements during the primary screen allowed us to efficiently identify compounds with potent cytotoxic effects against spheroid-derived CSCs. Overall, this research demonstrates one of the first miniaturized HTS assays using CSCs. The procedures described here should enable further testing of the effect of compounds on CSCs and help determine which pathways need to be targeted to kill them.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
CD44+ CD24（ - ）前列腺细胞是早期的癌症祖/干细胞，为预后不良的患者提供了模型。
影响因子：
8.8
作者：
Hurt, E. M.;Kawasaki, B. T.;Klarmann, G. J.;Thomas, S. B.;Farrar, W. L.
通讯作者：
Farrar, W. L.
影响因子：
2.9
作者：
Mathews LA;Cabarcas SM;Hurt EM;Zhang X;Jaffee EM;Farrar WL
通讯作者：
Farrar WL
影响因子：
11.5
作者：
O'Brien, Catherine Adell;Kreso, Antonija;Jamieson, Catriona H. M.
通讯作者：
Jamieson, Catriona H. M.
影响因子：
8
作者：
Jeter, C. R.;Liu, B.;Liu, X.;Chen, X.;Liu, C.;Calhoun-Davis, T.;Repass, J.;Zaehres, H.;Shen, J. J.;Tang, D. G.
通讯作者：
Tang, D. G.