摘要
恶性胸膜间皮瘤(MPM)是一种缺乏治疗选择的致命性疾病,新的靶向药物的临床前研究是必要的。因为以前的研究报道了在大多数的MPM病例中的微管网络中的高的c-Met表达和变化,我们对tivantinib的活性进行了评价,tivantinib最近被发现具有影响除了抑制c-Met以外的微管聚合。在四种MPM细胞系中,tivantinib抑制c-Met活性和微管聚合,导致抑制细胞生长在IC50s介于0.3 µM (MSTO-211H)和 2.4 µM (H2052)之间。此外,由蛋白标记试剂盒B试验和流式细胞术检测到tivantinib协同地增强培美曲塞的抗恶性细胞增生活性和凋亡活性。协同交互作用与减少胸苷酸合成酶表达和抑制迁移活性相关。总的来说,这些数据显示了tivantinib特别的MPM细胞的靶向关键通路活性和与培美曲塞的协同相互作用,这支持进一步的临床方法的研究。
关键词: c-Met,恶性胸膜间皮瘤,转移,培美曲塞,协同交互作用,tivantinib,微管蛋白
Current Drug Targets
Title:Synergistic Activity of the c-Met and Tubulin Inhibitor Tivantinib (ARQ197) with Pemetrexed in Mesothelioma Cells
Volume: 15 Issue: 14
Author(s): Leticia G. Leon, Maria Gemelli, Rocco Sciarrillo, Amir Avan, Niccola Funel and Elisa Giovannetti
Affiliation:
关键词: c-Met,恶性胸膜间皮瘤,转移,培美曲塞,协同交互作用,tivantinib,微管蛋白
摘要: Malignant pleural mesothelioma (MPM) is a lethal disease with scarce therapeutic options, and preclinical studies on new targeted-agents are warranted. Because previous studies reported high c-Met expression and alterations in the microtubules network in most MPM samples, we evaluated the activity of tivantinib, which has been recently suggested to affect microtubule polymerization in addition to inhibiting c-Met. In four MPM cell lines tivantinib inhibited both c-Met activity and microtubule polymerization, resulting in inhibition of cell-growth with IC50s ranging between 0.3 µM (MSTO-211H) and 2.4 µM (H2052). Furthermore tivantinib synergistically enhanced the antiproliferative and proapoptotic activity of pemetrexed, as detected by sulforhodamine-B-assay and flow cytometry. The synergistic interaction was associated with reduction of thymidylate synthase expression and inhibition of migratory activity. In aggregate, these data show the ability of tivantinib to specifically target key pathways in MPM cells and synergistically interact with pemetrexed, supporting further studies on this therapeutic approach.
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Leticia G. Leon, Maria Gemelli, Rocco Sciarrillo, Amir Avan, Niccola Funel and Elisa Giovannetti , Synergistic Activity of the c-Met and Tubulin Inhibitor Tivantinib (ARQ197) with Pemetrexed in Mesothelioma Cells, Current Drug Targets 2014; 15 (14) . https://dx.doi.org/10.2174/1389450116666141205160924
DOI https://dx.doi.org/10.2174/1389450116666141205160924 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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