Preclinical Effectiveness of Selective Inhibitor of IRS-1/2 NT157 in Osteosarcoma Cell Lines.
Preclinical Effectiveness of Selective Inhibitor of IRS-1/2 NT157 in Osteosarcoma Cell Lines.
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骨肉瘤细胞系中IRS-1/2 NT157选择性抑制剂的临床前有效性。
DOI：
10.3389/fendo.2015.00074
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发表时间：
2015
影响因子：
5.2
通讯作者：
Scotlandi K
中科院分区：
文献类型：
--
作者：
Garofalo C;Capristo M;Mancarella C;Reunevi H;Picci P;Scotlandi K
骨肉瘤（OS）是儿童和年轻人最常见的原发性骨肿瘤。一些研究已经证实胰岛素样生长因子（IGF）系统参与OS细胞增殖和分化的调节以及保护细胞免受化疗。胰岛素受体底物（IRS）-1是IGF-1 R信号传导的关键介质，我们最近报道了其在OS细胞中的过表达增加了体外和体内的增殖、迁移和转移。在这项研究中，我们评估了NT 157，IRS-1/2的选择性抑制剂，在OS细胞的面板的疗效。在MG-63、OS-19和U-2 OS OS细胞系中观察到强烈的剂量依赖性生长抑制，显示处理72小时后亚微摩尔剂量的IC 50值。暴露于NT 157引起IRS-1水平的剂量和时间依赖性降低。此外，蛋白质分析表明，IRS-1的降解抑制IGF途径的主要下游介质的激活。NT 157显著影响细胞的迁移能力，如通过伤口愈合测定所证实的。抑制剂诱导的细胞生长抑制作用，证明了G2/M细胞周期阻滞，并不影响凋亡。因此，NT 157与用于治疗OS的药物组合以利用其治疗潜力。以固定比例联合化疗药物同时处理72 h，MTT法测定细胞增殖。相对于单一药剂的协同或成瘾效应表示为组合指数。使用几种靶向药物获得了显著的协同效应，如依维莫司（一种哺乳动物雷帕霉素靶点（mTOR）抑制剂）和NVP-BEZ 235（一种PI-3 K/mTOR双重抑制剂）。总体而言，这些发现为选定的IRS-1/2 NT 157抑制剂在OS细胞中的有效性提供了证据，显示了基于IRS-1靶向结合其他疗法治疗这种儿科实体瘤的有希望的方法。
Osteosarcoma (OS) is the most common primary bone tumor in children and young adults. Several studies have confirmed the involvement of the insulin-like growth factor (IGF) system in the regulation of OS cell proliferation and differentiation as well as in the protection of cells from chemotherapy. Insulin receptor substrate (IRS)-1 is a critical mediator of IGF-1R signaling, and we recently reported that its overexpression in OS cells increases proliferation, migration, and metastasis both in vitro and in vivo. In this study, we evaluated the efficacy of NT157, a selective inhibitor of IRS-1/2, in a panel of OS cells. A strong dose-dependent inhibition of growth was observed in the MG-63, OS-19, and U-2OS OS cell lines, displaying IC50 values at sub-micromolar doses after 72 h of treatment. Exposure to NT157 elicited dose- and time-dependent decreases in IRS-1 levels. Moreover, a protein analysis showed that the degradation of IRS-1 inhibited the activation of principal downstream mediators of the IGF pathway. NT157 significantly affected the cells’ migratory ability, as confirmed by a wound-healing assay. The inhibitor induced cytostatic effects, as evidenced by G2/M cell cycle arrest, and did not affect apoptosis. Consequently, NT157 was combined with drugs used to treat OS in order to capitalize on its therapeutic potential. Simultaneous treatments were made in association with chemotherapeutic agents in a fixed ratio for 72 h and cell proliferation was determined by MTT assay. Synergistic or addictive effects with respect to single agents are expressed as the combination index. Significant synergistic effects were obtained with several targeted drugs, such as Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, and NVP-BEZ235, a dual inhibitor of PI-3K/mTOR. Overall, these findings provide evidence for the effectiveness of a selected inhibitor of IRS-1/2 NT157 in OS cells, displaying a promising approach based on the targeting of IRS-1 combined with other therapies for the treatment of this pediatric solid tumor.
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影响因子：
4.8
作者：
Chen, J;Wu, A;Baserga, R
通讯作者：
Baserga, R
影响因子：
50.5
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Bielack, S.;Carrle, D.;Casali, P. G.
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Buck, Elizabeth;Gokhale, Prafulla C.;Miglarese, Mark R.
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Garofalo, C.;Manara, M. C.;Scotlandi, K.
通讯作者：
Scotlandi, K.
影响因子：
51.1
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Grignani, Giovanni;Palmerini, Emanuela;Aglietta, Massimo
通讯作者：
Aglietta, Massimo