Synergistic inhibition of endothelial cell proliferation, tube formation, and sprouting by cyclosporin A and itraconazole.
Synergistic inhibition of endothelial cell proliferation, tube formation, and sprouting by cyclosporin A and itraconazole.
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DOI：
10.1371/journal.pone.0024793
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Liu JO
中科院分区：
文献类型：
--
作者：
Nacev BA;Liu JO
病理性血管生成有助于许多疾病，包括癌症和黄斑变性。尽管血管生成抑制剂在临床上可用，但它们对大多数癌症的疗效有限，部分原因是存在替代和代偿信号通路。鉴于血管生成依赖于多种生长因子和体内广泛的信号网络，我们试图探索多种药物鸡尾酒抑制血管生成的潜力。我们筛选了741种临床药物组合来协同抑制内皮细胞增殖。我们特别关注现有的临床药物，因为与新药实体相比，临床药物的重新利用可以更快、更经济地过渡到临床研究。我们的筛选发现环孢素A (CsA)，一种免疫抑制剂，和伊曲康唑，一种抗真菌药物，作为内皮细胞增殖的协同抑制剂对。联合使用时，每种药物的IC50剂量降低了3 ~ 9倍。我们还测试了该组合抑制内皮细胞管形成和发芽的能力，这依赖于血管生成、内皮细胞迁移和分化的两个基本过程。我们发现CsA和伊曲康唑协同抑制管网大小和芽的形成。最后，我们测试了该组合对人包皮成纤维细胞活力以及Jurkat T细胞和HeLa细胞增殖的影响，发现内皮细胞有选择性靶向作用。因此，可以联合现有临床药物协同抑制体外血管生成模型。这一策略可能有助于下一代抗血管生成疗法的研究。
Pathological angiogenesis contributes to a number of diseases including cancer and macular degeneration. Although angiogenesis inhibitors are available in the clinic, their efficacy against most cancers is modest due in part to the existence of alternative and compensatory signaling pathways. Given that angiogenesis is dependent on multiple growth factors and a broad signaling network in vivo, we sought to explore the potential of multidrug cocktails for angiogenesis inhibition. We have screened 741 clinical drug combinations for the synergistic inhibition of endothelial cell proliferation. We focused specifically on existing clinical drugs since the re-purposing of clinical drugs allows for a more rapid and cost effective transition to clinical studies when compared to new drug entities. Our screen identified cyclosporin A (CsA), an immunosuppressant, and itraconazole, an antifungal drug, as a synergistic pair of inhibitors of endothelial cell proliferation. In combination, the IC50 dose of each drug is reduced by 3 to 9 fold. We also tested the ability of the combination to inhibit endothelial cell tube formation and sprouting, which are dependent on two essential processes in angiogenesis, endothelial cell migration and differentiation. We found that CsA and itraconazole synergistically inhibit tube network size and sprout formation. Lastly, we tested the combination on human foreskin fibroblast viability as well as Jurkat T cell and HeLa cell proliferation, and found that endothelial cells are selectively targeted. Thus, it is possible to combine existing clinical drugs to synergistically inhibit in vitro models of angiogenesis. This strategy may be useful in pursuing the next generation of antiangiogenesis therapy.
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影响因子：
64.5
作者：
LIU, J;FARMER, JD;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
影响因子：
14.8
作者：
Laib, Anna M.;Bartol, Arne;Augustin, Hellmut G.
通讯作者：
Augustin, Hellmut G.
影响因子：
4
作者：
Chong, Curtis R.;Xu, Jing;Liu, Jun O.
通讯作者：
Liu, Jun O.
DOI：
10.1124/jpet.111.180851
发表时间：
2011-08-01
影响因子：
3.5
作者：
Nacev, Benjamin A.;Low, Woon-Kai;Liu, Jun O.
通讯作者：
Liu, Jun O.
影响因子：
3.5
作者：
DiMasi, JA;Hansen, RW;Grabowski, HG
通讯作者：
Grabowski, HG