Antihelminth Compound Niclosamide Downregulates Wnt Signaling and Elicits Antitumor Responses in Tumors with Activating APC Mutations

Osada, Takuya; Chen, Minyong; Yang, Xiao Yi; Spasojević, Ivan; VanDeusen, Jeffrey; Hsu, David S.; Clary, Bryan M.; Clay, Timothy M.; Chen, Wei; Morse, Michael A.; Lyerly, H. Kim

doi:10.1158/0008-5472.can-10-3978

Cited by 235 publications

(271 citation statements)

References 31 publications

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“…The anthelmintic activity of niclosamide seems to rely on its ability to uncouple mitochondrial oxidative phosphorylation (61). More recently, it has been found to inhibit proliferation of some tumor cells by hampering different regulatory pathways, without relevant effects on normal nontumor cells (62)(63)(64). Notably, niclosamide has also been reported to act as an antimycobacterial agent (64), plausibly disrupting Mycobacterium membrane potential and pH homeostasis (65).…”

Section: Discussionmentioning

confidence: 99%

New Life for an Old Drug: the Anthelmintic Drug Niclosamide Inhibits Pseudomonas aeruginosa Quorum Sensing

Imperi

Massai

Pillai

et al. 2013

Antimicrob Agents Chemother

176

141

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The need for novel antibacterial strategies and the awareness of the importance of quorum sensing (QS) in bacterial infections have stimulated research aimed at identifying QS inhibitors (QSIs). However, clinical application of QSIs identified so far is still distant, likely due to their unsuitability for use in humans. A promising way to overcome this problem is searching for anti-QS side activity among the thousands of drugs approved for clinical use in the treatment of different diseases. Here, we applied this strategy to the search for QSIs, by screening a library of FDA-approved compounds for their ability to inhibit the QS response in the Gram-negative pathogen Pseudomonas aeruginosa. We found that the anthelmintic drug niclosamide strongly inhibits the P. aeruginosa QS response and production of acyl-homoserine lactone QS signal molecules. Microarray analysis showed that niclosamide affects the transcription of about 250 genes, with a high degree of target specificity toward the QS-dependent regulon. Phenotypic assays demonstrated that niclosamide suppresses surface motility and production of the secreted virulence factors elastase, pyocyanin, and rhamnolipids, and it reduces biofilm formation. In accordance with the strong antivirulence activity disclosed in vitro, niclosamide prevented P. aeruginosa pathogenicity in an insect model of acute infection. Besides the finding that an FDA-approved drug has a promising antivirulence activity against one of the most antibiotic-resistant bacterial pathogens, this work provides a proof of concept that a lateral anti-QS activity can be detected among drugs already used in humans, validating a new approach to identify QSIs that could easily move into clinical applications.

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Section: Discussionmentioning

confidence: 99%

New Life for an Old Drug: the Anthelmintic Drug Niclosamide Inhibits Pseudomonas aeruginosa Quorum Sensing

Imperi

Massai

Pillai

et al. 2013

Antimicrob Agents Chemother

176

141

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“…1E). Niclosamide is an established antihelminthic drug for which recent work in extra-neural, for example, preclinical colorectal cancer models had already suggested antineoplastic activity (21,22). This encouraged further assessment as a candidate compound for glioblastoma therapy.…”

Section: Niclosamide Is a Previously Unrecognized Candidate For Gliobmentioning

confidence: 99%

“…Evidence from previous studies had suggested that niclosamide interfered with several of these in non-neural cancer cells, specifically affecting the NOTCH-, mTOR-, WNT-/CTNNB1-, and NF-kB signaling cascades (21,22,(31)(32)(33). We focused on these cascades for mechanism of action analysis.…”

Section: Niclosamide Interferes With Cancer-driving Signaling Cascadesmentioning

confidence: 99%

Anticancer Effects of Niclosamide in Human Glioblastoma

Wieland

Trageser

Gogolok

et al. 2013

Clinical Cancer Research

137

121

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Purpose: Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pharmacotherapy remains an unmet medical need.Experimental Design: Screening of a compound library of 160 synthetic and natural toxic substances identified the antihelmintic niclosamide as a previously unrecognized candidate for clinical development. Considering the cellular and interindividual heterogeneity of glioblastoma, a portfolio of short-term expanded primary human glioblastoma cells (pGBM; n ¼ 21), common glioma lines (n ¼ 5), and noncancer human control cells (n ¼ 3) was applied as a discovery platform and for preclinical validation. Pharmacodynamic analysis, study of cell-cycle progression, apoptosis, cell migration, proliferation, and on the frequency of multipotent/self-renewing pGBM cells were conducted in vitro, and orthotopic xenotransplantation was used to confirm anticancer effects in vivo.Results: Niclosamide led to cytostatic, cytotoxic, and antimigratory effects, strongly reduced the frequencies of multipotent/self-renewing cells in vitro, and after exposure significantly diminished the pGBMs' malignant potential in vivo. Mechanism of action analysis revealed that niclosamide simultaneously inhibited intracellular WNT/CTNNB1-, NOTCH-, mTOR-, and NF-kB signaling cascades. Furthermore, combinatorial drug testing established that a heterozygous deletion of the NFKBIA locus in glioblastoma samples could serve as a genomic biomarker for predicting a synergistic activity of niclosamide with temozolomide, the current standard in glioblastoma therapy.Conclusions: Together, our data advocate the use of pGBMs for exploration of compound libraries to reveal unexpected leads, for example, niclosamide that might be suited for further development toward personalized clinical application. Clin Cancer Res; 19(15); 4124-36. Ó2013 AACR.

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“…Amongst other functions, Niclosamide was found to inhibit Wnt/Frizzled-1 signaling with an IC 50 of 0.5 ± 0.05 μM [253][254][255]. It also downregulates Dishevelled-2 (Dvl-2) [256] and induces LRP6 degradation in prostate and breast cancer cells [254]. Interestingly, Niclosamide has no reported toxicity against non-cancer cells [256].…”

Section: The Wnt Receptor Complexmentioning

confidence: 99%

“…It also downregulates Dishevelled-2 (Dvl-2) [256] and induces LRP6 degradation in prostate and breast cancer cells [254]. Interestingly, Niclosamide has no reported toxicity against non-cancer cells [256].…”

Section: The Wnt Receptor Complexmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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Antihelminth Compound Niclosamide Downregulates Wnt Signaling and Elicits Antitumor Responses in Tumors with Activating APC Mutations

Cited by 235 publications

References 31 publications

New Life for an Old Drug: the Anthelmintic Drug Niclosamide Inhibits Pseudomonas aeruginosa Quorum Sensing

New Life for an Old Drug: the Anthelmintic Drug Niclosamide Inhibits Pseudomonas aeruginosa Quorum Sensing

Anticancer Effects of Niclosamide in Human Glioblastoma

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

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