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.