Anti-angiogenic effects of thioridazine involving the FAK-mTOR pathway
Anti-angiogenic effects of thioridazine involving the FAK-mTOR pathway
复制标题
DOI：
10.1016/j.mvr.2012.09.006
复制
发表时间：
2012-11-01
影响因子：
3.1
通讯作者：
Rho, Seung Bae
中科院分区：
文献类型：
--
作者：
Byun, Hyun-Jung;Lee, Jeong Heon;Rho, Seung Bae
硫利达嗪是一种抗精神病药物，还具有抗肿瘤活性。在这项研究中，我们评估了硫利达嗪作为一种新型抗血管生成剂对抑制血管生成介导的细胞增殖的作用。硫利达嗪被发现可抑制卵巢癌细胞（OVCAR-3 和 2774）的生长，但对正常细胞类型（如 HOSE-E6E7、MCF-10A、MRC-5 和 BEAS-28）没有任何抑制作用。硫利达嗪还以剂量时间依赖性方式抑制血管内皮生长因子 (VEGF) 刺激的 HUVEC 迁移。我们还表明，在体外，用硫利达嗪治疗可抑制 VEGF 刺激的增殖、侵袭和毛细血管样结构管的形成。硫利达嗪通过 α v beta 3 整联蛋白抑制粘着斑激酶 (FAR) 下游信号调节因子的磷酸化，其中还包括 Akt、磷酸肌醇依赖性蛋白激酶 1 (PDK-1)、哺乳动物雷帕霉素靶标 (mTOR)、核糖体蛋白 S6 激酶 (p70S6K)，但对 VEGF 刺激的细胞外信号调节激酶 (ERK) 磷酸化没有影响。我们发现硫利达嗪的分子机制是一种新型的抗血管生成蛋白。这些结果为通过抑制 alpha v beta 3/FAK/mTOR 信号通路来调节与血管生成相关的内皮细胞功能提供了证据。 (C) 2012 Elsevier Inc. 保留所有权利。
Thioridazine is a type of anti-psychotic drug that also includes anti-tumor activity. In this study, we assessed the effects of thioridazine, as a novel anti-angiogenic agent, on the suppression of angiogenesis-mediated cell proliferation. Thioridazine was found to inhibit growth in ovarian cancer cells (OVCAR-3 and 2774), but did not possess any inhibitory effects on normal cell types such as HOSE-E6E7, MCF-10A, MRC-5, and BEAS-28. Thioridazine also suppressed vascular endothelial growth factor (VEGF)-stimulated HUVEC migration in a dose-time-dependent manner. We also showed that being treated with thioridazine inhibited VEGF-stimulated proliferation, invasion, and capillary-like structure tube formation in vitro. Thioridazine suppressed phosphorylation of the signaling regulators downstream of the focal adhesion kinase (FAR) through alpha v beta 3 integrin, which also include Akt, phosphoinositide-dependent protein kinase 1 (PDK-1), mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), but had no effect on VEGF-stimulated extracellular signal-regulated kinase (ERK) phosphorylation. We found the molecular mechanism of thioridazine to be a novel anti-angiogenic protein. These results provide evidence for the regulation of endothelial cell functions that are relevant to angiogenesis through the suppression of the alpha v beta 3/FAK/mTOR signaling pathway. (C) 2012 Elsevier Inc. All rights reserved.