Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Schultz, Christopher W.

doi:10.3390/biomedicines10123249

Cited by 16 publications

(18 citation statements)

References 141 publications

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“…In preclinical models, PP exhibited strong efficacy in protecting against both tauopathy and retinal degeneration at nanomolar concentration. We further demonstrated that the previously known anti-YAP/WNT activity of PP [21][22][23] could be explained by the expanded proteostasis framework and is also required for its ability to ameliorate proteinopathies. Lastly, we showed that both the reduction of proteostasis gene expression and increase of YAP1 transcriptional activity is associated with retinal degeneration in mice and tauopathy in humans.…”

Section: Introductionmentioning

confidence: 71%

“…Interestingly, pyrvinium is enriched with cationic amines and aromatic motifs, chemical features that were predicted to partition into various nuclear condensates 99 . PP was originally developed as an anthelmintic drug effective for treating pinworm infections 100 . Moreover, it has gained strong recent interest as an anti-cancer reagent due to its ability to inhibit WNT signaling 100 .…”

Section: Discussionmentioning

confidence: 99%

“…PP was originally developed as an anthelmintic drug effective for treating pinworm infections 100 . Moreover, it has gained strong recent interest as an anti-cancer reagent due to its ability to inhibit WNT signaling 100 . Our current study further expands its therapeutic values to proteinopathies, including both reducing tauopathy in neurons and flies and protecting against retina degeneration in an ex vivo mouse RP model.…”

Section: Discussionmentioning

confidence: 99%

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Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Dion,

Tao,

Chambers

et al. 2024

Preprint

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Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as pivotal organelles responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, pyrvinium pamoate reduced tauopathy and alleviated retina degeneration by promoting autophagy and ubiquitin-proteasome system. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were also observed in human tauopathies. Our study uncovers novel therapeutic targets for tackling protein misfolding disorders within an expanded proteostasis framework encompassing nuclear speckles and YAP1.

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Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Dion,

Tao,

Chambers

et al. 2024

Preprint

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“…Pyrvinium pamoate (PP): The antifungal and anthelmintic PP, approved by the FDA ( Li et al, 2022 ), was investigated as an anti-cancer drug and found to act via multiple pathways such as WNT signaling, inhibition of mitochondrial NADH-fumarate, tumor stemness, the unfolded protein response and hedgehog signaling ( Schultz and Nevler, 2022 ). In our screen, PP caused a significant decrease in HR in both heart chambers (−8.54; n = 5).…”

Section: Resultsmentioning

confidence: 99%

pyHeart4Fish: Chamber-specific heart phenotype quantification of zebrafish in high-content screens

Vedder¹,

Reinberger²,

Haider³

et al. 2023

Front. Cell Dev. Biol.

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Cardiovascular diseases (CVDs) are the leading cause of death. Of CVDs, congenital heart diseases are the most common congenital defects, with a prevalence of 1 in 100 live births. Despite the widespread knowledge that prenatal and postnatal drug exposure can lead to congenital abnormalities, the developmental toxicity of many FDA-approved drugs is rarely investigated. Therefore, to improve our understanding of drug side effects, we performed a high-content drug screen of 1,280 compounds using zebrafish as a model for cardiovascular analyses. Zebrafish are a well-established model for CVDs and developmental toxicity. However, flexible open-access tools to quantify cardiac phenotypes are lacking. Here, we provide pyHeart4Fish, a novel Python-based, platform-independent tool with a graphical user interface for automated quantification of cardiac chamber-specific parameters, such as heart rate (HR), contractility, arrhythmia score, and conduction score. In our study, about 10.5% of the tested drugs significantly affected HR at a concentration of 20 µM in zebrafish embryos at 2 days post-fertilization. Further, we provide insights into the effects of 13 compounds on the developing embryo, including the teratogenic effects of the steroid pregnenolone. In addition, analysis with pyHeart4Fish revealed multiple contractility defects induced by seven compounds. We also found implications for arrhythmias, such as atrioventricular block caused by chloropyramine HCl, as well as (R)-duloxetine HCl-induced atrial flutter. Taken together, our study presents a novel open-access tool for heart analysis and new data on potentially cardiotoxic compounds.

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“…Our results suggest that, although p53 activation plays a significant role in cell apoptosis during pyrvinium treatment, there are also p53-independent pro-apoptotic mechanisms that provide pyrvinium with an advantage as a novel therapy for treating p53 mut or p53 -/-MCC. Pyrvinium has been previously identified as a mitochondrial inhibitor and has demonstrated even greater potency in nutrient-deficient conditions (36,37,70). To assess the extent of oxidative phosphorylation inhibition by pyrvinium in MCC cells, we conducted an FCCP-OCR analysis using the Seahorse XF96 Analyzer.…”

Section: Pyrvinium Pamoate Impacts Canonical and Non-canonical Wnt Si...mentioning

confidence: 99%

Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma

Yang,

Lim,

Victor

et al. 2023

Preprint

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Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. It is the only known neuroendocrine tumor (NET) with a virus etiology. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens into normal human fibroblasts by performing RNA sequencing. Our findings suggested that the WNT signaling pathway plays a critical role in the development of MCC. To test this model, we bioinformatically evaluated various perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its anti-tumor potential in multiple cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium effectively targets multiple MCC vulnerabilities. Specifically, pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and non-canonical WNT signaling pathways but also inhibits cancer cell growth by activating the p53-mediated apoptosis pathway, disrupting mitochondrial function, and inducing endoplasmic reticulum (ER) stress. Pyrvinium also effectively inhibits tumor growth in an MCC mouse xenograft model. These findings offer new avenues for the development of therapeutic strategies for neuroendocrine cancer and highlight the utility of pyrvinium as a potential treatment for MCC.SignificanceOur study sheds light on the role of the WNT signaling pathway in MCC transformation and characterizes pyrvinium pamoate as a potent anti-tumor reagent that targets multiple vulnerabilities of MCC.

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Pyrvinium Pamoate: Past, Present, and Future as an Anti-Cancer Drug

Cited by 16 publications

References 141 publications

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

pyHeart4Fish: Chamber-specific heart phenotype quantification of zebrafish in high-content screens

Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma

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