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.

Low-dose paclitaxel downregulates MYC proto-oncogene bHLH transcription factor expression in colorectal carcinoma cells

“…Other anticancer drugs, including fluorouracil and niclosamide, have been reported to directly downregulate c-Myc expression in human colon cancer KM12C cells and human osteosarcoma cells, respectively (24,25). PTX treatment of HT29-4D colon carcinoma cells, HL-60 promyelocytic leukemic cells and ovarian cancer cells has been suggested to indirectly downregulate c-Myc expression (26)(27)(28).…”

Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs)

“…293pTP cells were derived from HEK-293 cells and overexpression of human Ad5 pTP gene as previously characterized [50]. The cell lines are maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS, Gemini Bio-Products, West Sacramento, CA), containing 100 U/ml penicillin and 100 mg/ml streptomycin, at 37°C in 5% CO 2 as described [51-53]. Unless indicated otherwise, all other reagents were purchased from Sigma-Aldrich (St. Louis, MO) or Thermo-Fisher Scientific (Waltham, MA).…”

Osteogenic Sarcoma: A 21st Century Review

“…It was, recently, reported that the antihelmintic drug niclosamide has anticancer potential in humans: it inhibits cell migration and wound closure and induces apoptosis and inhibits cell-cycle progression in BOS cells. Niclosamide is said to significantly inhibit the transcription factors E2F1, AP1, and c-MYC-responsive reporters, and it mildly inhibits the HIF1α, TCF/LEF, CREB, NFĸB, SMAD/TGFβ, and RBPJ/NOTCH pathway reporters (35). This further underscores the significant role of transcription factors in the pathogenesis of BOS.…”