摘要
骨肉瘤(OS)是最常见的具有肺转移高倾向性的原发性恶性肿瘤。尽管在过去的几十年中外科手术技术和化疗方案已取得显著的进步,然而对于OS患者的存活率却没有多大的提升。因此,开发新的抗肿瘤药物来治疗人类骨肉瘤已刻不容缓。重新利用临床药物的作用是一个既快速又有效的开发新抗癌药物的方式。驱虫药氯硝柳胺最近已被认为是人类癌症中的潜在抗癌剂。在这里,我们做了关于氯硝柳胺是否可以被开发作为抗骨肉瘤药物的调查。我们发现低微摩尔浓度的氯硝柳胺能有效地抑制OS细胞的增殖和存活。氯硝柳胺可以显著抑制细胞迁移和闭合性损伤。氯硝柳胺诱导细胞凋亡并且抑制OS细胞的细胞周期。氯硝柳胺对11种癌症相关的信号通路受体的作用分析表明,可以显著抑制其中三个受体:E2F1,AP1和c-Myc应答蛋白。在较小程度上,也可以抑制 HIF1α, TCF/LEF, CREB, NFκB, Smad/TGFβ,和Rbpj/Notch通路受体,而氯硝柳胺治疗却没有影响NFAT和Wnt/β-链蛋白受体。我们发现氯硝柳胺可以有效抑制c-Fos, c-Jun, E2F1和c-Myc的表达。此外,在人骨肉瘤细胞的小鼠异种移植肿瘤模型中,显示氯硝柳胺能有效地抑制肿瘤生长。总之,这些结果强烈表明氯硝柳胺可能通过靶向多种信号通路来发挥其对骨肉瘤细胞的抗癌活性。未来的研究方向应该是探索临床相关骨肉瘤模型中的抗肿瘤活性以及最终在临床上的试验。
关键词: 抗癌药,骨肿瘤,药物再利用,氯硝柳胺,骨肉瘤,肉瘤
图形摘要
Current Cancer Drug Targets
Title:The Anthelmintic Drug Niclosamide Inhibits the Proliferative Activity of Human Osteosarcoma Cells by Targeting Multiple Signal Pathways
Volume: 15 Issue: 8
Author(s): Zhan Liao, Guoxin Nan, Zhengjian Yan, Liyi Zeng, Youlin Deng, Jixing Ye, Zhonglin Zhang, Min Qiao, Ruifang Li, Sahitya Denduluri, Jing Wang, Qiang Wei, Nisha Geng, Lianggong Zhao, Shun Lu, Xin Wang, Guolin Zhou and Hue H. Luu, Rex C. Haydon, Tong-Chuan He and Zhongliang Wang
Affiliation:
关键词: 抗癌药,骨肿瘤,药物再利用,氯硝柳胺,骨肉瘤,肉瘤
摘要: Osteosarcoma (OS) is the most common primary malignant tumor of bone with a high propensity for lung metastasis. Despite significant advances in surgical techniques and chemotherapeutic regimens over the past few decades, there has been minimal improvement in OS patient survival. There is an urgent need to identify novel antitumor agents to treat human OS. Repurposing the clinically-used drugs represents a rapid and effective approach to the development of new anticancer agents. The anthelmintic drug niclosamide has recently been identified as a potential anticancer agent in human cancers. Here, we investigate if niclosamide can be developed as an anti-OS drug. We find that niclosamide can effectively inhibit OS cell proliferation and survival at low micromolar concentrations. Cell migration and wounding closure are significantly inhibited by niclosamide. Niclosamide induces cell apoptosis and inhibits cell cycle progression in OS cells. Analysis of niclosamide’s effect on 11 cancer-related signal pathway reporters reveals that three of them, the E2F1, AP1, and c-Myc-responsive reporters, are significantly inhibited. To a lesser extent, the HIF1α, TCF/LEF, CREB, NFκB, Smad/TGFβ, and Rbpj/Notch pathway reporters are also inhibited, while the NFAT and Wnt/β-catenin reporters are not significantly affected by niclosamide treatment. We demonstrate that the expression of c-Fos, c-Jun. E2F1, and c-Myc in OS cells is effectively inhibited by niclosamide. Furthermore, niclosamide is shown to effectively inhibit tumor growth in a mouse xenograft tumor model of human osteosarcoma cells. Taken together, these results strongly suggest that niclosamide may exert its anticancer activity in OS cells by targeting multiple signaling pathways. Future investigations should be directed to exploring the antitumor activity in clinically relevant OS models and ultimately in clinical trials.
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Cite this article as:
Zhan Liao, Guoxin Nan, Zhengjian Yan, Liyi Zeng, Youlin Deng, Jixing Ye, Zhonglin Zhang, Min Qiao, Ruifang Li , Sahitya Denduluri, Jing Wang, Qiang Wei, Nisha Geng, Lianggong Zhao, Shun Lu, Xin Wang, Guolin Zhou and Hue H. Luu, Rex C. Haydon, Tong-Chuan He and Zhongliang Wang , The Anthelmintic Drug Niclosamide Inhibits the Proliferative Activity of Human Osteosarcoma Cells by Targeting Multiple Signal Pathways, Current Cancer Drug Targets 2015; 15 (8) . https://dx.doi.org/10.2174/1568009615666150629132157
DOI https://dx.doi.org/10.2174/1568009615666150629132157 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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