Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2011;6(9):e24793. doi: 10.1371/journal.pone.0024793. Epub 2011 Sep 28.
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 IC(50) 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.
病理性血管生成导致了多种疾病，包括癌症和黄斑变性。尽管临床上已经有血管生成抑制剂，但它们对大多数癌症的疗效并不显著，部分原因是存在替代和补偿性信号通路。鉴于血管生成依赖于体内的多种生长因子和广泛的信号网络，我们试图探索多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，以寻找协同抑制内皮细胞增殖的药物组合。我们特别关注现有的临床药物，因为与新的药物实体相比，重新利用临床药物可以更快速、更经济有效地将药物推向临床研究。我们的筛选确定了环孢素 A（CsA），一种免疫抑制剂，和伊曲康唑，一种抗真菌药物，作为协同抑制内皮细胞增殖的抑制剂。联合使用时，每种药物的 IC50 剂量降低了 3 到 9 倍。我们还测试了该组合抑制内皮细胞管状形成和发芽的能力，这两个过程是血管生成中两个必需的过程，依赖于内皮细胞的迁移和分化。我们发现 CsA 和伊曲康唑协同抑制管状网络大小和发芽形成。最后，我们在人包皮成纤维细胞活力以及 Jurkat T 细胞和 HeLa 细胞增殖方面测试了该组合，发现内皮细胞是被选择性靶向的。因此，有可能将现有的临床药物组合起来协同抑制血管生成的体外模型。这种策略可能有助于开发下一代抗血管生成治疗方法。
