The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Jingxuan Pan - One of the best experts on this subject based on the ideXlab platform.
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inhibitory effect of the anthelmintic drug Pyrvinium pamoate on t315i bcr abl positive cml cells
Molecular Medicine Reports, 2017Co-Authors: Jing Zhang, Yanli Jin, Jingxuan PanAbstract:Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a chromosome translocation that generates the BCR‑ABL oncogene, which encodes a constitutively activated tyrosine kinase. Despite progress in controlling CML at the chronic phase by first and second generations of BCR‑ABL tyrosine kinase inhibitors (TKIs), effective drugs with good safety are not available for CML patients harboring T315I BCR‑ABL and those in advanced stages of CML. Therefore, there is an urgent requirement for the development of effective therapies against T315I BCR‑ABL. In the present study, it was demonstrated that Pyrvinium pamoate, an anthelmintic drug approved by the Food and Drug Administration had potent inhibitory effects on growth and survival in CML cells with T315I BCR‑ABL. In addition, this agent was equally effective in inhibiting the Wnt/β‑catenin signaling in wild‑type and T315I BCR‑ABL CML cells. Thus, the clinical efficacy of Pyrvinium pamoate in treating patients with CML bearing T315I BCR‑ABL should be further investigated.
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Inhibitory effect of the anthelmintic drug Pyrvinium pamoate on T315I BCR‑ABL‑positive CML cells
Molecular medicine reports, 2017Co-Authors: Jing Zhang, Yanli Jin, Jingxuan PanAbstract:Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a chromosome translocation that generates the BCR‑ABL oncogene, which encodes a constitutively activated tyrosine kinase. Despite progress in controlling CML at the chronic phase by first and second generations of BCR‑ABL tyrosine kinase inhibitors (TKIs), effective drugs with good safety are not available for CML patients harboring T315I BCR‑ABL and those in advanced stages of CML. Therefore, there is an urgent requirement for the development of effective therapies against T315I BCR‑ABL. In the present study, it was demonstrated that Pyrvinium pamoate, an anthelmintic drug approved by the Food and Drug Administration had potent inhibitory effects on growth and survival in CML cells with T315I BCR‑ABL. In addition, this agent was equally effective in inhibiting the Wnt/β‑catenin signaling in wild‑type and T315I BCR‑ABL CML cells. Thus, the clinical efficacy of Pyrvinium pamoate in treating patients with CML bearing T315I BCR‑ABL should be further investigated.
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inhibitory effect of Pyrvinium pamoate on uveal melanoma cells involves blocking of wnt β catenin pathway
Acta Biochimica et Biophysica Sinica, 2017Co-Authors: Lei Zheng, Yizhi Liu, Jingxuan PanAbstract:Uveal melanoma is the most common primary intraocular malignancy in adults. And there is an absence of targeted agents for patients with uveal melanoma. Pyrvinium pamoate is an old anthelminthic medicine approved by FDA for the treatment of enterobiasis in 1955, which recently re-attracts attention as an anti-cancer drug due to its inhibition of Wnt/β-catenin pathway in some types of cancer. But the role of Pyrvinium pamoate in uveal melanoma and the potential underlying mechanism remains unknown. In this study, we tested the anti-tumor effects of Pyrvinium pamoate on four uveal melanoma cell lines (92.1, Mel270, Omm1, and Omm2.3) and evaluated the Wnt/β-catenin signaling transduction, cell growth, cell death, cell migration, and invasion accordingly. The results revealed that Pyrvinium pamoate treatment repressed the phosphorylation of GSK3β at S9 which might be mediated by AKT, and decreased the protein levels of β-catenin and its downstream targets (c-Myc, cyclin D1). Pyrvinium pamoate remarkably inhibited cell viability and colony formation ability. Treatment with Pyrvinium pamoate induced intrinsic pathway-dependent apoptosis accompanied with a decline of anti-apoptotic XIAP and Survivin, and an overt increase of pro-apoptotic Bax. In addition, Pyrvinium pamoate significantly inhibited the migration and invasion in vitro. Our studies suggest that Pyrvinium pamoate may be a potential therapeutic agent for uveal melanoma.
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Inhibitory effect of Pyrvinium pamoate on uveal melanoma cells involves blocking of Wnt/β-catenin pathway
Acta biochimica et biophysica Sinica, 2017Co-Authors: Lei Zheng, Yizhi Liu, Jingxuan PanAbstract:Uveal melanoma is the most common primary intraocular malignancy in adults. And there is an absence of targeted agents for patients with uveal melanoma. Pyrvinium pamoate is an old anthelminthic medicine approved by FDA for the treatment of enterobiasis in 1955, which recently re-attracts attention as an anti-cancer drug due to its inhibition of Wnt/β-catenin pathway in some types of cancer. But the role of Pyrvinium pamoate in uveal melanoma and the potential underlying mechanism remains unknown. In this study, we tested the anti-tumor effects of Pyrvinium pamoate on four uveal melanoma cell lines (92.1, Mel270, Omm1, and Omm2.3) and evaluated the Wnt/β-catenin signaling transduction, cell growth, cell death, cell migration, and invasion accordingly. The results revealed that Pyrvinium pamoate treatment repressed the phosphorylation of GSK3β at S9 which might be mediated by AKT, and decreased the protein levels of β-catenin and its downstream targets (c-Myc, cyclin D1). Pyrvinium pamoate remarkably inhibited cell viability and colony formation ability. Treatment with Pyrvinium pamoate induced intrinsic pathway-dependent apoptosis accompanied with a decline of anti-apoptotic XIAP and Survivin, and an overt increase of pro-apoptotic Bax. In addition, Pyrvinium pamoate significantly inhibited the migration and invasion in vitro. Our studies suggest that Pyrvinium pamoate may be a potential therapeutic agent for uveal melanoma.
David J Sullivan - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of oocyst development of top compounds from JHU FDA-approved clinical compound library.
2014Co-Authors: Natalie G. Sanders, David J Sullivan, Godfree Mlambo, George Dimopoulos, Abhai K. TripathiAbstract:Dose dependent transmission blocking activity of clotrimazole (CLTZ), Pyrvinium pamoate (PP), methylene blue (MB) and cetalkonium chloride (CCl) measured by number of oocysts per mosquito midgut.
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Inhibition by MMV Malaria Box.
2014Co-Authors: Natalie G. Sanders, David J Sullivan, Godfree Mlambo, George Dimopoulos, Abhai K. TripathiAbstract:SYBR Green I assay results for the MMV box screened at 10 µM. Plot of percentage of gametocytocidal activity of 400 compounds compared to Pyrvinium pamoate control.
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in vitro activity of Pyrvinium pamoate against entamoeba histolytica and giardia intestinalis using radiolabelled thymidine incorporation and an sybr green i based fluorescence assay
Journal of Antimicrobial Chemotherapy, 2009Co-Authors: Autumn S Downey, Thaddeus K Graczyk, David J SullivanAbstract:Objectives: To assess the in vitro activity of the FDA-approved antihelminthic drug Pyrvinium pamoate against Entamoeba histolytica and Giardia intestinalis. Methods: A head-to-head comparison of a standard radiolabelled thymidine incorporation assay and the SYBR Green I-based fluorescence assay for determination of in vitro inhibition by Pyrvinium and metronidazole was performed. Results: The 50% inhibitory concentration (IC50) for treatment of E. histolytica with Pyrvinium was 4‐5mM for both assays compared with 1‐2 mM for metronidazole. For Pyrvinium treatment of G. intestinalis ,a n IC50 of 12 mM was determined by the radiolabelled thymidine assay alone, with maximum inhibition around 60%. In contrast, the IC50 for metronidazole treatment using this assay was 2 mM.
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in vitro activity of Pyrvinium pamoate against entamoeba histolytica and giardia intestinalis using radiolabelled thymidine incorporation and an sybr green i based fluorescence assay
Journal of Antimicrobial Chemotherapy, 2009Co-Authors: Autumn S Downey, Thaddeus K Graczyk, David J SullivanAbstract:Objectives: To assess the in vitro activity of the FDA-approved antihelminthic drug Pyrvinium pamoate against Entamoeba histolytica and Giardia intestinalis. Methods: A head-to-head comparison of a standard radiolabelled thymidine incorporation assay and the SYBR Green I-based fluorescence assay for determination of in vitro inhibition by Pyrvinium and metronidazole was performed. Results: The 50% inhibitory concentration (IC50) for treatment of E. histolytica with Pyrvinium was 4‐5mM for both assays compared with 1‐2 mM for metronidazole. For Pyrvinium treatment of G. intestinalis ,a n IC50 of 12 mM was determined by the radiolabelled thymidine assay alone, with maximum inhibition around 60%. In contrast, the IC50 for metronidazole treatment using this assay was 2 mM.
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Efficacy of Pyrvinium Pamoate against Cryptosporidium parvum Infection In Vitro and in a Neonatal Mouse Model
Antimicrobial agents and chemotherapy, 2008Co-Authors: Autumn S Downey, Thaddeus K Graczyk, Curtis R. Chong, David J SullivanAbstract:No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients. Here we investigated the nonabsorbed anthelmintic drug Pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of Pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 μM paromomycin or 27 μM chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of Pyrvinium pamoate in vivo. Beginning 3 days after infection, Pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a >90% reduction in infection intensity in Pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, Pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.
Curtis A Thorne - One of the best experts on this subject based on the ideXlab platform.
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Pyrvinium a potent small molecule wnt inhibitor promotes wound repair and post mi cardiac remodeling
PLOS ONE, 2010Co-Authors: Sarika Saraswati, Curtis A Thorne, Ethan Lee, Maria P Alfaro, James B Atkinson, Pampee P. YoungAbstract:Wnt signaling plays an important role in developmental and stem cell biology. To test the hypothesis that temporary inhibition of Wnt signaling will enhance granulation tissue and promote angiogenesis in tissue repair, we employed a recently characterized small molecule Wnt inhibitor. Pyrvinium is an FDA-approved drug that we identified as a Wnt inhibitor in a chemical screen for small molecules that stabilize β-catenin and inhibit Axin degradation. Our subsequent characterization of Pyrvinium has revealed that its critical cellular target in the Wnt pathway is Casein Kinase 1α. Daily administration of Pyrvinium directly into polyvinyl alcohol (PVA) sponges implanted subcutaneously in mice generated better organized and vascularized granulation tissue; this compound also increased the proliferative index of the tissue within the sponges. To evaluate its effect in myocardial repair, we induced a myocardial infarction (MI) by coronary artery ligation and administered a single intramyocardial dose of Pyrvinium. Mice were evaluated by echocardiography at 7 and 30 days post-MI and treatment; post mortem hearts were evaluated by histology at 30 days. Pyrvinium reduced adverse cardiac remodeling demonstrated by decreased left ventricular internal diameter in diastole (LVIDD) as compared to a control compound. Increased Ki-67+ cells were observed in peri-infarct and distal myocardium of Pyrvinium-treated animals. These results need to be further followed-up to determine if therapeutic inhibition of canonical Wnt may avert adverse remodeling after ischemic injury and its impact on myocardial repair and regeneration.
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Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α
Nature Chemical Biology, 2010Co-Authors: Curtis A Thorne, Darren Orton, Brian I. Hang, Alison J Hanson, Judsen Schneider, Emilios Tahinci, Christopher S Cselenyi, Kristin K Jernigan, Kelly C Meyers, Alex G WatersonAbstract:Wnt/β-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote β-catenin turnover, we identified an FDA-approved drug, Pyrvinium, as a potent inhibitor of Wnt signaling (EC_50 of ∼10 nM). We show Pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and Pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of Pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, Pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway. A Xenopus laevis two-reporter screen identifies the antihelminthic drug Pyrvinium as an inhibitor of the Wnt/β-catenin signaling pathway that works by activating CK1α, which is likely working at the level of Pygopus, a core transcriptional component of the Wnt pathway.
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small molecule inhibition of wnt signaling through activation of casein kinase 1α
Nature Chemical Biology, 2010Co-Authors: Curtis A Thorne, Darren Orton, Brian I. Hang, Alison J Hanson, Judsen Schneider, Emilios Tahinci, Christopher S Cselenyi, Kristin K Jernigan, Kelly C Meyers, Alex G WatersonAbstract:A Xenopus laevis two-reporter screen identifies the antihelminthic drug Pyrvinium as an inhibitor of the Wnt/β-catenin signaling pathway that works by activating CK1α, which is likely working at the level of Pygopus, a core transcriptional component of the Wnt pathway.
W.a. Woodward - One of the best experts on this subject based on the ideXlab platform.
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P1-04-01: The Mechanism of Anti-Breast Cancer TICs Effect of Pyrvinium Pamoate Is through WNT/beta-Catenin Signaling.
Poster Session Abstracts, 2011Co-Authors: Bisrat G. Debeb, A De Lacerda, Richard A. Larson, Jm Reuben, Nt Ueno, W.a. WoodwardAbstract:We have previously shown that Pyrvinium pamoate can decrease breast cancer TICs in vitro and shrink the tumor size in vivo. Although Pyrvinium pamoate has been shown to target beta-catenin through activating CK-1alpha in a vitro model, the mechanism of its anti-breast cancer TICs effect is unknown. Herein, we use a constitutively active WNT/beta-catenin signaling construct EBETAP (ref) to determine if the anti-breast TIC effect of Pyrvinium pamoate is through WNT/beta-catenin signaling. Using aldefluor expression and mammosphere formation efficiency as TIC surrogate assays, we found that TICs of SUM-159 transfected with EBETAP construct are resistant to Pyrvinium pamoate treatment compared to control cells. Moreover, microarray analysis reveals a series of genes and signaling downstream of WNT-catenin were down-regulated in SUM-159 cells treated with Pyrvinium pamoate. In summary, mechanism of anti-breast cancer TICs effect of Pyrvinium pamoate is through WNT/beta-catenin signaling. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-01.
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p1 04 01 the mechanism of anti breast cancer tics effect of Pyrvinium pamoate is through wnt beta catenin signaling
Cancer Research, 2011Co-Authors: Bisrat G. Debeb, A De Lacerda, Richard A. Larson, Jm Reuben, Nt Ueno, W.a. WoodwardAbstract:We have previously shown that Pyrvinium pamoate can decrease breast cancer TICs in vitro and shrink the tumor size in vivo. Although Pyrvinium pamoate has been shown to target beta-catenin through activating CK-1alpha in a vitro model, the mechanism of its anti-breast cancer TICs effect is unknown. Herein, we use a constitutively active WNT/beta-catenin signaling construct EBETAP (ref) to determine if the anti-breast TIC effect of Pyrvinium pamoate is through WNT/beta-catenin signaling. Using aldefluor expression and mammosphere formation efficiency as TIC surrogate assays, we found that TICs of SUM-159 transfected with EBETAP construct are resistant to Pyrvinium pamoate treatment compared to control cells. Moreover, microarray analysis reveals a series of genes and signaling downstream of WNT-catenin were down-regulated in SUM-159 cells treated with Pyrvinium pamoate. In summary, mechanism of anti-breast cancer TICs effect of Pyrvinium pamoate is through WNT/beta-catenin signaling. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-01.
Brian I. Hang - One of the best experts on this subject based on the ideXlab platform.
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Repurposing the FDA-Approved Pinworm Drug Pyrvinium as a Novel Chemotherapeutic Agent for Intestinal Polyposis
2016Co-Authors: Colin A. Flaveny, Dennis Liang Fei, Feng Bai, Xin Hai Pei, Brian I. Hang, Camilla Giambelli, Lu Han, Vania Nose, Oname BurlingameAbstract:Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85 % of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1a. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1a agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC
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Repurposing the FDA-approved pinworm drug Pyrvinium as a novel chemotherapeutic agent for intestinal polyposis.
PloS one, 2014Co-Authors: Colin A. Flaveny, Dennis Liang Fei, Feng Bai, Xin Hai Pei, Brian I. Hang, Camilla Giambelli, Lu Han, Vania Nose, Oname BurlingameAbstract:Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes.
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Pyrvinium attenuates Hedgehog signaling downstream of Smoothened
Cancer research, 2014Co-Authors: Dennis Liang Fei, Colin A. Flaveny, Nadia Dahmane, Valerie Baubet, Zhiqiang Wang, Feng Bai, Xin Hai Pei, Jezabel Rodriguez-blanco, Brian I. HangAbstract:The Hedgehog (HH) signaling pathway represents an important class of emerging developmental signaling pathways that play critical roles in the genesis of a large number of human cancers. The pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that regulates the levels and activity of the Gli family of transcription factors. Although one of these compounds vismodegib is now FDA-approved for advanced basal cell carcinoma patients, acquired mutations in Smo can result in rapid relapse. Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observation that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of cancer. Thus, there remains a critical need for HH inhibitors with different mechanisms of action, in particularly those that act downstream of Smo. Recently, we identified the FDA-approved anti-pinworm compound Pyrvinium as a novel, potent (IC50 ~ 10nM) Casein Kinase-1α (CK1α) agonist. We show here that Pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the stability of the Gli family of transcription factors. Consistent with CK1α agonists acting on these most distal components of the HH signaling pathway, Pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib resistant Smo mutant, as well as the Gli activity resulting from loss of the negative regulator Suppressor of fused. We go on to demonstrate the utility of this small-molecule in vivo, against the HH dependent cancer medulloblastoma, attenuating its growth and reducing the expression of HH biomarkers.
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Pyrvinium inhibits WNT signaling in CRC cells.
2014Co-Authors: Colin A. Flaveny, Dennis Liang Fei, Feng Bai, Xin Hai Pei, Brian I. Hang, Camilla Giambelli, Lu Han, Vania Nose, Oname BurlingameAbstract:A. Pyrvinium inhibits WNT reporter gene activity in CRC cells. Cells were treated with Pyrvinium at the indicated concentrations and relative WNT reporter luciferase activity determined. Immunoblots show that Pyrvinium decreases PYGOPUS2 levels in both SW480 and HCT116 WTKO cells in a dose-dependent manner. Error bars indicate ± S.E.M of three experiments. B. Expression of WNT regulated genes AXIN2, DKK1, CCND1 and LGR5 in CRC cell lines treated with 100 nM Pyrvinium or vehicle control was determined using real-time RT-PCR. Error bars indicate ± S.E.M of three experiments. *p
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Pyrvinium reduces CRC cell viability.
2014Co-Authors: Colin A. Flaveny, Dennis Liang Fei, Feng Bai, Xin Hai Pei, Brian I. Hang, Camilla Giambelli, Lu Han, Vania Nose, Oname BurlingameAbstract:A. Structure of Pyrvinium. B. MTT assay of various CRC cells treated with increasing amounts of Pyrvinium or vehicle control (V). Treated plates were incubated with 10% MTT, lysed and MTT reduction assessed. C. Similar assay as B was performed using WT MEF cells. D. Clonogenic assay of Pyrvinium treated CRC cell lines. The CRC cell lines SW480, SW620, HT29 and HCT116 were treated with increasing concentrations of Pyrvinium or vehicle control for 2 weeks. Colonies were fixed with gluteraldehyde and stained with crystal violet. Mean number of colonies was quantitated relative to vehicle controls. Error bars indicate ± S.E.M of three experiments.
