The Anthelmintic Drug Niclosamide Inhibits the Proliferative Activity of Human Osteosarcoma Cells by Targeting Multiple Signal Pathways.

Abstract

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.

• Authors: 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, Hue H Luu, Rex C Haydon, Tong-Chuan He, Zhongliang Wang
• Journal: Current cancer drug targets (Curr Cancer Drug Targets) Vol. 15 Issue 8 Pg. 726-38 ( 2015) ISSN: 1873-5576 [Electronic] Netherlands
• PMID: 26118906 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anthelmintics
• Antineoplastic Agents
• Biomarkers, Tumor
• Niclosamide

Topics

• Animals
• Anthelmintics (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers, Tumor (metabolism)
• Bone Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Delivery Systems
• Female
• Humans
• Mice
• Mice, Nude
• Niclosamide (pharmacology)
• Osteosarcoma (drug therapy, pathology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays