Niclosamide enhances ROS-mediated cell death through c-Jun activation

Lee, Sae-lo-oom; Son, Arang; Ahn, Joon-Woo; Song, Jie‐Young

doi:10.1016/j.biopha.2014.03.018

Cited by 45 publications

(41 citation statements)

References 22 publications

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“…It is well known that niclosamide inhibits oxidative phosphorylation in the mitochondria of cestodes. Niclosamide affects cancer cells in several different pathways, including Wnt/β-catenin (24,25), mTORC1 signaling (26,27), STAT 3 (10), and ROS (28). Further studies are required to determine the exact mechanism in osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

Niclosamide inhibits the proliferation of human osteosarcoma cell lines by inducing apoptosis and cell cycle arrest

Sun

et al. 2015

Oncology Reports

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Abstract. Niclosamide, used as an antihelminthic, has demonstrated some properties of anticancer effects. However, its role in osteosarcoma remains to be determined. The aim of this study was to determine the effect of niclosamide on human osteosarcoma cell lines. The human MG-63 and U2OS osteosarcoma cell lines were treated with different concentrations of niclosamide. The cell inhibitory rate was calculated by CCK-8 assay. Cell cycle was detected by flow cytometry. Cell apoptosis was determined by Hoechst 33324 staining, flow cytometry and fluorescence microscope, respectively. The expression of bcl-2, bax and pro-caspase-3 were measured by western blotting. Niclosamide exerted an inhibitory effect on the two cell lines in a time-and dose-dependent manner. Niclosamide was found to induce the arrest of S and G2/M phase in U2OS cells and G2/M in MG-63 cells. Moreover, niclosamide induced apoptosis in MG-63 and U2OS cells. The bax/bcl-2 ratio increased while the expression of pro-caspase-3 decreased significantly in the two cell lines. The results indicated that niclosamide inhibits proliferation, and induces apoptosis and cell cycle arrest in human osteosarcoma cell lines.

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Section: Discussionmentioning

confidence: 99%

Niclosamide inhibits the proliferation of human osteosarcoma cell lines by inducing apoptosis and cell cycle arrest

Sun

et al. 2015

Oncology Reports

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“…One of the compounds that elevate ROS levels in cancer cells is niclosamide. ROS generation plays an important role in the anticancer activity of niclosamide in acute myeloid leukemia and lung cancer cells (Wartenberg et al, 2005; Jin et al, 2010; Lee et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Drug Repurposing of the Anthelmintic Niclosamide to Treat Multidrug-Resistant Leukemia

2017

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Multidrug resistance, a major problem that leads to failure of anticancer chemotherapy, requires the development of new drugs. Repurposing of established drugs is a promising approach for overcoming this problem. An example of such drugs is niclosamide, a known anthelmintic that is now known to be cytotoxic and cytostatic against cancer cells. In this study, niclosamide showed varying activity against different cancer cell lines. It revealed better activity against hematological cancer cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines MDA-MB-231, A549, and HT-29. The multidrug resistant CEM/ADR5000 cells were similar sensitive as their sensitive counterpart CCRF-CEM (resistance ration: 1.24). Furthermore, niclosamide caused elevations in reactive oxygen species and glutathione (GSH) levels in leukemia cells. GSH synthetase (GS) was predicted as a target of niclosamide. Molecular docking showed that niclosamide probably binds to the ATP-binding site of GS with a binding energy of -9.40 kcal/mol. Using microscale thermophoresis, the binding affinity between niclosamide and recombinant human GS was measured (binding constant: 5.64 μM). COMPARE analyses of the NCI microarray database for 60 cell lines showed that several genes, including those involved in lipid metabolism, correlated with cellular responsiveness to niclosamide. Hierarchical cluster analysis showed five major branches with significant differences between sensitive and resistant cell lines (p = 8.66 × 105). Niclosamide significantly decreased nuclear factor of activated T-cells (NFAT) activity as predicted by promoter binding motif analysis. In conclusion, niclosamide was more active against hematological malignancies compared to solid tumors. The drug was particularly active against the multidrug-resistant CEM/ADR5000 leukemia cells. Inhibition of GSH synthesis and NFAT signaling were identified as relevant mechanisms for the anticancer activity of niclosamide. Gene expression profiling predicted the sensitivity or resistance of cancer cells to niclosamide.

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“…Mebendazole can be administered with the non-steroidal anti-inflammatory drug sulindac for prevention of tumor initiation in a colon cancer model [33]. Colon Cancer [52] Breast Cancer Triple [29] Breast Cancer [53] Adrenocortical Cancer [19] Adrenocortical Cancer [39] Leukemia/Myeloma [25] Leukemia/Myeloma [34] Leukemia/Myeloma [59,64] NSCLC [20] NSCLC [36] Lung Cancer CSC [57] Cell Lines [9] Cancer stem cells [46] Cancer [61] Gastric Cancer [22] Osteosarcoma [37] Medulloblastoma [23] Prostate Cancer [36] Melanoma [21,29] Ovarian Cancer/ TICs [41 -44] Ovarian cancer [62] Breast CSC-like Cells [26] Breast CSC-like Cells [40] Breast CSC-like Cells [56] Glioblastoma [24,32] Glioblastoma [33] Glioblastoma CD133 + [60] This table lists reports on investigations employing mebendazole, niclosamide and pyrvinium (pamoate) as anticancer agents against cell lines or in experimental animal models.…”

Section: Anticancer Activity Of Mebendazolementioning

confidence: 99%

“…Signaling pathways were inhibited in osteosarcoma and, especially, Wnt/β-catenin signal transduction in ovarian cancer cells and via GSK3 and STAT3 in CSCs and colon cancer [41,47,50,52,53]. In prostate cancer cells the STAT3 -androgen receptor (AR) axis was inhibited by niclosamide and cell death in NSCLC was effected via c-JUN stress kinase and generation of ROS [39,40]. Transcription factors NFκB and ATF3 were targeted by niclosamide in hepatocellular carcinoma (HCC) and leukemia, respectively [36,38].…”

Section: Glycolysismentioning

confidence: 99%