Niclosamide Analogs for Treatment of Ovarian Cancer

Haygood, C.L. Walters; Arend, Rebecca C.; Gangrade, Abhishek; Chettiar, Somsundaram; Regan, Nicholas; Hassmann, Christopher J.; Li, Pui-Kai; Hidalgo, Bertha; Straughn, J. Michael; Buchsbaum, Donald J.

doi:10.1097/igc.0000000000000506

Cited by 22 publications

(20 citation statements)

References 22 publications

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“…In accordance with these findings, our previous results revealed the same relation between the toxicity of ring-substituted hydroxynaphthanilides to the THP-1 cancer cells and the presence of substituents with electron-withdrawing properties [3,4,5]. The SAR studies also found the presence of an electron-withdrawing nitro group to be one of the essential requirements for the anticancer effect of niclosamide [21]. Based on these findings, the substitution by a nitro moiety was determined to be appropriate for the potent anticancer effect of newly-designed hydroxynaphthanilides.…”

Section: Introductionsupporting

confidence: 77%

Antiproliferative and Pro-Apoptotic Effect of Novel Nitro-Substituted Hydroxynaphthanilides on Human Cancer Cell Lines

Kauerova

Kos

Goněc

et al. 2016

IJMS

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Ring-substituted hydroxynaphthanilides are considered as cyclic analogues of salicylanilides, compounds possessing a wide range of pharmacological activities, including promising anticancer properties. The aim of this study was to evaluate the potential anticancer effect of novel nitro-substituted hydroxynaphthanilides with a special focus on structure-activity relationships. The antiproliferative effect was assessed by Water Soluble Tetrazolium Salts-1 (WST-1) assay, and cytotoxicity was evaluated via dye exclusion test. Flow cytometry was used for cell cycle analysis and detection of apoptosis using Annexin V-FITC/PI assay. Protein expression was estimated by Western blotting. Our data indicate that the potential to cause the antiproliferative effect increases with the shift of the nitro substituent from the ortho- to the para-position. The most potent compounds, 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide (2), and 2-hydroxy-N-(4-nitrophenyl)-naphthalene-1-carboxamide (6) showed antiproliferative activity against THP-1 and MCF-7 cancer cells without affecting the proliferation of 3T3-L1 non-tumour cells. Compounds 2 and 6 induced the accumulation of THP-1 and MCF-7 cells in G1 phase associated with the downregulation of cyclin E1 protein levels, while the levels of cyclin B1 were not affected. Moreover, compound 2 was found to exert the pro-apoptotic effect on the THP-1 cells. These results suggest that hydroxynaphthanilides might represent a potential model structure for the development of novel anticancer agents.

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Section: Introductionsupporting

confidence: 77%

Antiproliferative and Pro-Apoptotic Effect of Novel Nitro-Substituted Hydroxynaphthanilides on Human Cancer Cell Lines

Kauerova

Kos

Goněc

et al. 2016

IJMS

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“…Several other groups have also shown that niclosamide and niclosamide derivatives can inhibit mTOR and STAT3 signaling in various tumor types [13–19]. We previously showed that niclosamide and its analogs were anti-proliferative and targeted the Wnt pathway in >30 primary ovarian cancer patient ascites samples, some of which were clinically platinum resistant [12, 20]. In addition, we found that niclosamide specifically decreased the stem cell marker ALHD1A1 and the Wnt pathway surface receptor LRP6.…”

Section: Introductionmentioning

confidence: 77%

“…A schematic is shown in Figure 1 of the Haygood et al . manuscript [12]. Carboplatin was purchased from Sigma-Aldrich (St. Louis, MO), dissolved in water at concentration of 25 mM, and stored at 4°C.…”

Section: Methodsmentioning

confidence: 99%

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Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer

et al. 2016

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Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of cancer stem cells (CSCs) include Wnt/β-catenin, mTOR, and STAT3. The major objective of our study was to investigate the treatment of ovarian cancer with targeted agents that inhibit these three pathways. Here we demonstrate that niclosamide, a salicylamide derivative, and two synthetically manufactured niclosamide analogs (analog 11 and 32) caused significant inhibition of proliferation of two chemoresistant ovarian cancer cell lines (A2780cp20 and SKOV3Trip2), tumorspheres isolated from the ascites of EOC patients, and cells from a chemoresistant patient-derived xenograft (PDX). This work shows that all three agents significantly decreased the expression of proteins in the Wnt/β-catenin, mTOR and STAT3 pathways and preferentially targeted cells that expressed the ovarian CSC surface protein CD133. It also illustrates the potential of drug repurposing for chemoresistant EOC and can serve as a basis for pathway-oriented in vivo studies.

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“…Another study indicates that Niclosamide may also exert its anticancer activity through inhibition of Wnt/β-catenin target gene FGF1 in ovarian cancer [32]. More recently, efforts have been devoted to developing Niclosamide analogs with higher bioavailability [77] and/or designing more efficacious formulations for preclinical and eventually clinical studies [78].…”

Section: Discussionmentioning

confidence: 99%

A Blockade of IGF Signaling Sensitizes Human Ovarian Cancer Cells to the Anthelmintic Niclosamide-Induced Anti-Proliferative and Anticancer Activities

Deng

Wang²,

Zhang³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Ovarian cancer is the most lethal gynecologic malignancy, and there is an unmet clinical need to develop new therapies. Although showing promising anticancer activity, Niclosamide may not be used as a monotherapy. We seek to investigate whether inhibiting IGF signaling potentiates Niclosamide's anticancer efficacy in human ovarian cancer cells. Methods: Cell proliferation and migration are assessed. Cell cycle progression and apoptosis are analyzed by flow cytometry. Inhibition of IGF signaling is accomplished by adenovirus-mediated expression of siRNAs targeting IGF-1R. Cancer-associated pathways are assessed using pathway-specific reporters. Subcutaneous xenograft model is used to determine anticancer activity. Results: We find that Niclosamide is highly effective on inhibiting cell proliferation, cell migration, and cell cycle progression, and inducing apoptosis in human ovarian cancer cells, possibly by targeting multiple signaling pathways involved in ELK1/SRF, AP-1, MYC/MAX and NFkB. Silencing IGF-1R exert a similar but weaker effect than that of Niclosamide's. However, silencing IGF-1R significantly sensitizes ovarian cancer cells to Niclosamide-induced anti-proliferative and anticancer activities both in vitro and in vivo. Conclusion: Niclosamide as a repurposed anticancer agent may be more efficacious when combined with agents that target other signaling pathways such as IGF signaling in the treatment of human cancers including ovarian cancer.

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Niclosamide Analogs for Treatment of Ovarian Cancer

Cited by 22 publications

References 22 publications

Antiproliferative and Pro-Apoptotic Effect of Novel Nitro-Substituted Hydroxynaphthanilides on Human Cancer Cell Lines

Antiproliferative and Pro-Apoptotic Effect of Novel Nitro-Substituted Hydroxynaphthanilides on Human Cancer Cell Lines

Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer

A Blockade of IGF Signaling Sensitizes Human Ovarian Cancer Cells to the Anthelmintic Niclosamide-Induced Anti-Proliferative and Anticancer Activities

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