High-throughput screening identifies idarubicin as a preferential inhibitor of smooth muscle versus endothelial cell proliferation.
High-throughput screening identifies idarubicin as a preferential inhibitor of smooth muscle versus endothelial cell proliferation.
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DOI：
10.1371/journal.pone.0089349
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kent KC
中科院分区：
文献类型：
--
作者：
Goel SA;Guo LW;Wang B;Guo S;Roenneburg D;Ananiev GE;Hoffmann FM;Kent KC
内膜增生是复发性闭塞性血管疾病（再狭窄）的原因。目前用于治疗再狭窄的药物有效抑制平滑肌细胞（SMC）增殖，但也会抑制保护性管腔内皮细胞（EC）内层的生长，导致血栓形成。为了鉴定选择性抑制 SMC 和 EC 增殖的化合物，我们开发了一种使用人类细胞的高通量筛选 (HTS) 格式，并利用它来筛选多种化合物集合（NIH 临床集合）。我们使用人主动脉 SMC 和 EC 在 96 孔板中开发了一种自动化、准确的增殖测定方法。使用这种 HTS 格式，我们筛选了包含 447 种药物的 NIH 临床图书馆。我们鉴定了 11 种抑制 SMC 增殖超过 50% 的化合物，其中伊达比星表现出优先抑制 SMC 而非 EC 增殖的独特特征。浓度响应分析表明，这种差异效应在 ∼10 nM-5 µM 窗口内最为明显。在大鼠颈动脉损伤模型中进行的伊达比星 14 天体内测试显示，内膜增生减少 80%，管腔大小增加 45%，但对再内皮化没有显着影响。总之，我们建立了人类血管细胞增殖的 HTS 测定，并确定伊达比星是体外和体内 SMC 与 EC 增殖的选择性抑制剂。筛选更大、更多样化的化合物库可能会发现下一代疗法，可以抑制内膜增生而不损害再内皮化。
Intimal hyperplasia is the cause of the recurrent occlusive vascular disease (restenosis). Drugs currently used to treat restenosis effectively inhibit smooth muscle cell (SMC) proliferation, but also inhibit the growth of the protective luminal endothelial cell (EC) lining, leading to thrombosis. To identify compounds that selectively inhibit SMC versus EC proliferation, we have developed a high-throughput screening (HTS) format using human cells and have employed this to screen a multiple compound collection (NIH Clinical Collection). We developed an automated, accurate proliferation assay in 96-well plates using human aortic SMCs and ECs. Using this HTS format we screened a 447-drug NIH Clinical Library. We identified 11 compounds that inhibited SMC proliferation greater than 50%, among which idarubicin exhibited a unique feature of preferentially inhibiting SMC versus EC proliferation. Concentration-response analysis revealed this differential effect most evident over an ∼10 nM-5 µM window. In vivo testing of idarubicin in a rat carotid injury model at 14 days revealed an 80% reduction of intimal hyperplasia and a 45% increase of lumen size with no significant effect on re-endothelialization. Taken together, we have established a HTS assay of human vascular cell proliferation, and identified idarubicin as a selective inhibitor of SMC versus EC proliferation both in vitro and in vivo. Screening of larger and more diverse compound libraries may lead to the discovery of next-generation therapeutics that can inhibit intima hyperplasia without impairing re-endothelialization.
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影响因子：
--
作者：
Sachsenmeier, Kris F.;Hay, Carl;Hollingsworth, Robert
通讯作者：
Hollingsworth, Robert
DOI：
10.1016/j.jss.2010.12.020
发表时间：
2011-05-15
期刊：
The Journal of surgical research
影响因子：
--
作者：
Suwanabol PA;Kent KC;Liu B
通讯作者：
Liu B
影响因子：
20.1
作者：
Song P;Wang S;He C;Wang S;Liang B;Viollet B;Zou MH
通讯作者：
Zou MH
影响因子：
5
作者：
Liu X;Cheng Y;Yang J;Xu L;Zhang C
通讯作者：
Zhang C
影响因子：
--
作者：
Antczak, Christophe;Shum, David;Djaballah, Hakim
通讯作者：
Djaballah, Hakim