The impact of pyrvinium pamoate on colon cancer cell viability

Wiegering, Armin; Uthe, Friedrich-Wilhelm; Hüttenrauch, Melanie; Mühling, Bettina; Linnebacher, Michael; Krummenast, Franziska; Germer, Christoph‐Thomas; Thalheimer, Andreas; Otto, Christoph

doi:10.1007/s00384-014-1975-y

Cited by 31 publications

(37 citation statements)

References 29 publications

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“…Furthermore, it promoted the degradation of pygopus, a nuclear factor that is required by β-catenin for transcription of downstream Wnt targets (Thorne et al, 2010). Pyrivinium has recently been shown to target Wnt signaling in colon cancer cells, resulting in increased cell death, inhibition of cell migration and delaying liver metastasis growth in vivo (Wiegering et al, 2014). Another FDA-approved drug termed niclosamide, routinely used in the treatment of tapeworm, inhibited Wnt signaling by causing Fzd1 receptor internalization and decreased Dvl2 protein levels in human osteosarcoma cells (Figure 1 [Chen et al, 2009b]).…”

Section: Targeting the Wnt Pathwaymentioning

confidence: 99%

Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28

McDermott

Jimeno

2015

Pharmacology & Therapeutics

209

167

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The Wnt signaling pathways are a group of signal transduction pathways that play an important role in cell fate specification, cell proliferation and cell migration. Aberrant signaling in these pathways has been implicated in the development and progression of multiple cancers by allowing increased proliferation, angiogenesis, survival and metastasis. Activation of the Wnt pathway also contributes to the tumorigenicity of cancer stem cells (CSCs). Therefore, inhibiting this pathway has been a recent focus for cancer research with multiple targetable candidates in development. OMP-54F28 is a fusion protein that combines the cysteine-rich domain of frizzled family receptor 8 (Fzd8) with the immunoglobulin Fc domain that competes with the native Fzd8 receptor for its ligands and antagonizes Wnt signaling. Preclinical models with OMP-54F28 have shown reduced tumor growth and decreased CSC frequency as a single agent and in combination with other chemotherapeutic agents. Due to these findings, a phase 1a study is nearing completion with OMP-54F28 in advanced solid tumors and 3 phase 1b studies have been opened with OMP-54F28 in combination with standard of care chemotherapy backbones in ovarian, pancreatic and hepatocellular cancers. This article will review the Wnt signaling pathway, preclinical data on OMP-54F28 and other Wnt pathway inhibitors and ongoing clinical trials.

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Section: Targeting the Wnt Pathwaymentioning

confidence: 99%

Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28

McDermott

Jimeno

2015

Pharmacology & Therapeutics

209

167

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“…Pyrvinium pamoate inhibits the AR activity by inhibiting androgen receptor-dependent gene expression via a distinct signaling mechanism [29]. It does not block DNA occupancy by the AR or binding to the ligand-binding domain of the androgen receptor [30]. Pyrvinium pamoate binds to the DNA binding domain of AR at the interface to the minor groove [31].…”

Section: Methodsmentioning

confidence: 99%

Androgen inhibits key atherosclerotic processes by directly activating ADTRP transcription

Luo¹,

Pook²,

Tang³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Low androgen levels are associated with an increased risk of coronary artery disease (CAD), thrombosis and myocardial infarction (MI), suggesting that androgen has a protective role. However, little is known about the underlying molecular mechanism. Our genome-wide association study identified the ADTRP gene encoding the androgen-dependent TFPI regulating protein as a susceptibility gene for CAD and MI. The expression level of ADTRP was regulated by androgen, but the molecular mechanism is unknown. In this study, we identified the molecular mechanism by which androgen regulates ADTRP expression and tested the hypothesis that androgen plays a protective role in cardiovascular disease by activating ADTRP expression. Luciferase assays with an ADTRP promoter luciferase reporter revealed that androgen regulated ADTRP transcription in a dose- and time-dependent manner, and the effect was abolished by three different androgen inhibitors, including pyrvinium pamoate, bicalutamide, and cyproterone acetate. Chromatin-immunoprecipitation showed that the androgen receptor bound to a half androgen response element (ARE, TGTTCT) located at + 324 bp from the ADTRP transcription start site. The ARE is required for concentration-dependent transcriptional activation of ADTRP. HL-60 monocyte adhesion to EAhy926 endothelial cells (ECs) and transmigration across the EC layer, the two processes critical to development of CAD and MI, were inhibited by androgen, but the effect was rescued by ADTRP siRNA and exacerbated by overexpression of ADTRP and its downstream genes PIK3R3 and MIA3. These data suggest that one molecular mechanism by which androgen confers protection against CAD is stimulation of ADTRP expression.

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“…This drug showed cytotoxicity against colon cancer cells, intestinal polyposis and lymphoma cells via JAK2/STAT5 signaling and impairment of mitochondrial functions [58,60,61]. Additionally, PPAM inhibited PI3K-dependent signaling via decreased phosphorylation of both downstream targets of PI3K, AKT and P70S6K [58,62].…”

Section: Anticancer Activity Of Pyrvinium Pamoatementioning

confidence: 98%

“…PPAM inhibited mammosphere formation of aggressive breast cancer cells and decreased expression of the CSC surrogate marker aldehyde dehydrogenase (ALDH1) as well as of the epithelial-mesenchymal transition (EMT) phenotype [59]. This drug showed cytotoxicity against colon cancer cells, intestinal polyposis and lymphoma cells via JAK2/STAT5 signaling and impairment of mitochondrial functions [58,60,61]. Additionally, PPAM inhibited PI3K-dependent signaling via decreased phosphorylation of both downstream targets of PI3K, AKT and P70S6K [58,62].…”

Section: Anticancer Activity Of Pyrvinium Pamoatementioning

confidence: 99%

“…Furthermore, the drug was characterized as agonist of casein kinases 1 (CK1); however, this effect was not confirmed and in colon cancer cells there was no correlation between PPAM toxicity and mutations in Wnt signaling mediators [57,58]. PPAM inhibited mammosphere formation of aggressive breast cancer cells and decreased expression of the CSC surrogate marker aldehyde dehydrogenase (ALDH1) as well as of the epithelial-mesenchymal transition (EMT) phenotype [59].…”

Section: Anticancer Activity Of Pyrvinium Pamoatementioning

confidence: 99%

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Repurposing of Anthelminthics as Anticancer Drugs

Hamilton¹,

Rath²

2018

Oncomedicine

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The impact of pyrvinium pamoate on colon cancer cell viability

Abstract: PP displays promising anticancer activity against a broad panel of human colon cancer cell lines, as well as primary colon cancer samples. However, our findings do not demonstrate a predominant cytotoxic effect of PP on colon cancer cells with mutations in WNT signaling.

Cited by 31 publications

References 29 publications

Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28

Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28

Androgen inhibits key atherosclerotic processes by directly activating ADTRP transcription

Repurposing of Anthelminthics as Anticancer Drugs

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