Computational analysis of image-based drug profiling predicts synergistic drug combinations: applications in triple-negative breast cancer.
Computational analysis of image-based drug profiling predicts synergistic drug combinations: applications in triple-negative breast cancer.
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DOI：
10.1016/j.molonc.2014.06.007
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发表时间：
2014-12
影响因子：
6.6
通讯作者：
Wong ST
中科院分区：
文献类型：
--
作者：
Brandl MB;Pasquier E;Li F;Beck D;Zhang S;Zhao H;Kavallaris M;Wong ST
开发了一种基于图像的分析和分析系统，以预测临床有效的协同药物组合，这可以加速识别用于治疗三阴性乳腺癌（TNBC）和其他具有挑战性的恶性肿瘤的有效多药物疗法。通过整合高内容筛选、计算分析和实验生物学，实现了治疗三阴性乳腺癌的有效药物组合的鉴定。该方法基于由55种FDA批准的药物和生物活性化合物诱导的细胞表型改变，这些药物和化合物使用荧光显微镜获得并保留在多变量化合物谱中。化合物谱之间的差异指导了5种组合的鉴定，评估了它们对TNBC细胞生长的定性相互作用。微管靶向药物长春碱与KSP/Eg 5马达蛋白抑制剂monastrol或ispinesib的组合在3种独立的TNBC细胞系中显示出有效的协同作用，这在正常成纤维细胞中未得到证实。协同相互作用是由有丝分裂阻滞增加介导的，细胞表现出典型的伊匹西诱导的单极有丝分裂纺锤体，这转化为增强的凋亡诱导。在TNBC的原位小鼠模型中证实了长春碱/ ispinesib组合的抗肿瘤活性。与单一药物治疗相比，联合治疗显著降低了肿瘤生长，而不会导致毒性增加。基于图像的分析和分析导致快速发现体外和体内有效对抗TNBC的药物组合，并有可能导致在其他难以治疗的癌症中开发新的治疗选择。
An imaged-based profiling and analysis system was developed to predict clinically effective synergistic drug combinations that could accelerate the identification of effective multi-drug therapies for the treatment of triple-negative breast cancer (TNBC) and other challenging malignancies. The identification of effective drug combinations for the treatment of triple-negative breast cancer was achieved by integrating high-content screening, computational analysis, and experimental biology. The approach was based on altered cellular phenotypes induced by 55 FDA-approved drugs and biologically active compounds, acquired using fluorescence microscopy and retained in multivariate compound profiles. Dissimilarities between compound profiles guided the identification of 5 combinations, which were assessed for qualitative interaction on TNBC cell growth. The combination of the microtubule-targeting drug vinblastine with KSP/Eg5 motor protein inhibitors monastrol or ispinesib showed potent synergism in 3 independent TNBC cell lines, which was not substantiated in normal fibroblasts. The synergistic interaction was mediated by an increase in mitotic arrest with cells demonstrating typical ispinesib-induced monopolar mitotic spindles, which translated into enhanced apoptosis induction. The antitumor activity of the combination vinblastine / ispinesib was confirmed in an orthotopic mouse model of TNBC. Compared to single drug treatment, combination treatment significantly reduced tumor growth without causing increased toxicity. Image-based profiling and analysis led to the rapid discovery of a drug combination effective against TNBC in vitro and in vivo, and has the potential to lead to the development of new therapeutic options in other hard-to-treat cancers.
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影响因子：
9.9
作者：
Nelander, Sven;Wang, Weiqing;Nilsson, Bjoern;She, Qing-Bai;Pratilas, Christine;Rosen, Neal;Gennemark, Peter;Sander, Chris
通讯作者：
Sander, Chris
影响因子：
48
作者：
Loo, Lit-Hsin;Wu, Lani F.;Altschuler, Steven J.
通讯作者：
Altschuler, Steven J.
影响因子：
46.9
作者：
Lehar, Joseph;Krueger, Andrew S.;Avery, William;Heilbut, Adrian M.;Johansen, Lisa M.;Price, E. Roydon;Rickles, Richard J.;Short, Glenn F., III;Staunton, Jane E.;Jin, Xiaowei;Lee, Margaret S.;Zimmermann, Grant R.;Borisy, Alexis A.
通讯作者：
Borisy, Alexis A.
影响因子：
45.3
作者：
Liedtke, Cornelia;Mazouni, Chafika;Pusztai, Lajos
通讯作者：
Pusztai, Lajos
影响因子：
11.5
作者：
Carey, Lisa A.;Dees, E. Claire;Perou, Charles M.
通讯作者：
Perou, Charles M.