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           Search results for: NVP-LDE-225 Mechanisms: Hedgehog inhibitor   

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Strategies to target the Hedgehog signaling pathway for cancer therapy.

Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first-in-class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma. The clinical success of vismodegib and sonidegib provided strong support for the development of Hh signaling pathway inhibitors via targeting the smoothened (Smo) receptor. Moreover, Hh signaling pathway inhibitors aimed to target proteins, which are downstream or upstream of Smo, have also been pursued based on the identification of additional therapeutic benefits. Recently, much progress has been made in Hh singling and inhibitors of this pathway. Herein, medicinal chemistry strategies, especially the structural optimization process of different classes of Hh inhibitors, are comprehensively summarized. Further therapeutic potentials and challenges are also discussed.

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DiscoveryPak™ Hedgehog MOUSE ANTI BOVINE ROTAVIR MOUSE ANTI BORRELIA BURGD Hh Signaling Pathway Anta AP-1 Reporter – HEK293 Gli Reporter – NIH3T3 C Wnt Signaling Pathway TCF NATIVE HUMAN PROLACTIN, P AKT PKB Signaling Phospho AMPK Signaling Phospho-Sp Cancer Apoptosis Phospho- ErbB Her Signaling Phosph

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Relationship between Hedgehog Signaling Pathway and Drug Resistance of Poorly Differentiated Gliomas.

The effects of Hedgehog signaling inhibitor (cyclopamine) and activator (Shh) on drug resistance of U251-MG human glioma cells and human astrocyte culture to cisplatin, temozolomide, and doxorubicin were studied. Cyclopamine and Shh modified the drug resistance of U251-MG cells but not of human astrocytes. Experiments with cyclopamine, Shh, and chemical drugs can contribute to detection of the mechanisms of signaling effects on the drug resistance processes, while the experimental data can serve as one of the criteria for choosing individual chemotherapy for patients.

1564 related Products with: Relationship between Hedgehog Signaling Pathway and Drug Resistance of Poorly Differentiated Gliomas.

DiscoveryPak™ Hedgehog Hh Signaling Pathway Anta AP-1 Reporter – HEK293 Gli Reporter – NIH3T3 C Wnt Signaling Pathway TCF AKT PKB Signaling Phospho AMPK Signaling Phospho-Sp ErbB Her Signaling Phosph ERK Signaling Phospho-Spe GPCR Signaling to MAPK ER IGF-1R Signaling Phospho- NF-kB II Phospho-Specific

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Bisphenol A stimulates adrenal cortical cell proliferation via ERβ-mediated activation of the sonic hedgehog signalling pathway.

We previously demonstrated that prenatal exposure to bisphenol A (BPA) resulted in increased adrenal gland weight independent of changes in plasma ACTH levels in adult mouse offspring. This finding suggested that BPA exposure likely had a direct effect on adrenal development. Given that (1) sonic hedgehog (Shh) signaling is essential for adrenal development; (2) deletion of the Shh gene in mice results in adrenal hypoplasia; (3) BPA is known to signal through estrogen receptor β (ERβ); and (4) ERβ is highly expressed in adrenal glands; we hypothesized that BPA stimulates adrenal cell proliferation via ERβ-mediated activation of the Shh pathway. To test this hypothesis, the human adrenal cell line, H295A cells, was used as an in vitro model system. Our main findings were: (1) BPA increased cell number and protein levels of proliferating cell nuclear antigen (PCNA; a universal marker of cell proliferation), cyclin D1 and D2 (key proliferation factors), as well as Shh and its key transcriptional regulator Gli1; (2) cyclopamine, a Shh pathway inhibitor, blocked these stimulatory effects of BPA on cell proliferation; (3) BPA increased the nuclear translocation of ERβ; and (4) the ERβ-specific agonist DPN mimicked while the ERβ-specific antagonist PHTPP abrogated the stimulatory effects of BPA on cell proliferation and Shh signaling. Taken together, these findings demonstrate that BPA stimulates adrenal cell proliferation likely through ERβ-mediated activation of the Shh signaling pathway. Thus, the present study provides novel insights into the molecular mechanisms underlying our previously reported BPA-induced aberrant adrenal phenotype.

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Marker Gene™ Non-Radioa Epidermal Growth Factor ( Epidermal Growth Factor ( Cell Meter™ Cell Viabil Cell Meter™ Cell Viabil Cell Meter™ Cell Viabil Cell Meter™ Cell Viabil Cell Meter™ Cell Viabil MTT Cell Proliferation As anti CD7 All T cells Reco anti Transferrin receptor anti Cortical thymocytes

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Coordinated d-cyclin/Foxd1 activation drives mitogenic activity of the Sonic Hedgehog signaling pathway.

Sonic Hedgehog (Shh) signaling plays key regulatory roles in embryonic development and postnatal homeostasis and repair. Modulation of the Shh pathway is known to cause malformations and malignancies associated with dysregulated tissue growth. However, our understanding of the molecular mechanisms by which Shh regulates cellular proliferation is incomplete. Here, using mouse embryonic fibroblasts, we demonstrate that the Forkhead box gene Foxd1 is transcriptionally regulated by canonical Shh signaling and required for downstream proliferative activity. We show that Foxd1 deletion abrogates the proliferative response to SHH ligand while FOXD1 overexpression alone is sufficient to induce cellular proliferation. The proliferative response to both SHH ligand and FOXD1 overexpression was blocked by pharmacologic inhibition of cyclin-dependent kinase signaling. Time-course experiments revealed that Shh pathway activation of Foxd1 is followed by downregulation of Cdkn1c, which encodes a cyclin-dependent kinase inhibitor. Consistent with a direct transcriptional regulation mechanism, we found that FOXD1 reduces reporter activity of a Fox enhancer sequence in the second intron of Cdkn1c. Supporting the applicability of these findings to specific biological contexts, we show that Shh regulation of Foxd1 and Cdkn1c is recapitulated in cranial neural crest cells and provide evidence that this mechanism is operational during upper lip morphogenesis. These results reveal a novel Shh-Foxd1-Cdkn1c regulatory circuit that drives the mitogenic action of Shh signaling and may have broad implications in development and disease.

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DiscoveryPak™ Hedgehog Human Sonic Hedgehog SHH Hh Signaling Pathway Anta Mouse Sonic Hedgehog SHH Sonic Hedgehog (SHH), hum Sonic Hedgehog (SHH), hum Sonic Hedgehog (SHH), hum Sonic Hedgehog (SHH), mur Sonic Hedgehog (SHH), mur Sonic Hedgehog (SHH), mur AP-1 Reporter – HEK293 Gli Reporter – NIH3T3 C

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Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling.

Hypoxic microenvironment, a common feature of hepatocellular carcinoma (HCC), can induce HIF-1α expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, the underlying molecular mechanisms have not fully elucidated.

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OXI TEK (Oxidative Stress Rat Mesenchymal Cells AP-1 Reporter – HEK293 Wnt Signaling Pathway TCF 8 Isoprostane oxidative s Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma Mouse Anti-Human Fibrobla Mouse Anti-Human Fibrobla Transcription factors: O DiscoveryPak™ Hedgehog

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GANT-61 and GDC-0449 induce apoptosis of prostate cancer stem cells through a GLI-dependent mechanism.

Aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway promotes prostate cancer (PC) growth and progression by regulating cancer-related genes through its downstream effectors GLI1 and GLI2. Therefore, targeting the SHH-GLI pathway provides an alternative approach to avoid cancer progression. The aim of this study was to delineate the underlying molecular mechanisms by which GDC-0449 (a SMO receptor inhibitor) and GANT-61 (a GLI transcription factor inhibitor) regulate cellular proliferation and self-renewal in human PC stem cells (ProCSCs). Inhibition of the SHH signaling pathway by GANT-61 induced apoptosis with more efficacy than by GDC-0449 in ProCSCs and PC cell lines. GLI1 and GLI2 expression, promoter-binding activity and GLI-responsive luciferase reporter activity were all decreased with either GDC-0449 or GANT-61 treatment. Expression of Fas, DR4, DR5, and cleavage of caspase-3 and PARP were increased, whereas levels of PDGFR-α and Bcl-2 were reduced. Double knockout of GLI1 and GLI2 using shRNA abolished the effects observed with either GDC-0449 or GANT-61 treatment. Collectively, our results showed that GANT-61 and GDC-0449 induced ProCSC apoptosis by directly or indirectly inhibiting the activities of the GLI family transcription factors, may enhance the efficacy of PC treatment.

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17β-Acetoxy-2α-bromo-5 3-O-Acetyl 5,14-Androstad 3-O-Acetyl-17-O-tert-buty Cancer Apoptosis Phospho- Prostate cancer and hyper Prostate cancer, adjacent High density breast cance High density colon cancer High density uterine cerv Dog Receptor-binding canc Ready to use Apoptosis In High density renal cancer

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The Injury-Related Activation of Hedgehog Signaling Pathway Modulates the Repair-Associated Inflammation in Liver Fibrosis.

Liver fibrosis is a wound healing response initiated by inflammation responding for different iterative parenchymal damages caused by diverse etiologies. Immune cells, which exert their ability of either inducing injury or promoting repair, have been regarded as crucial participants in the fibrogenic response. A characteristic feature of the fibrotic microenvironment associated with chronic liver injury is aberrant activation of hedgehog (Hh) signaling pathway. Growing evidence from a number of different studies in vivo and in vitro has indicated that immune-mediated events involved in liver fibrogenesis are regulated by Hh signaling pathway. In this review, we emphasize the impacts of injury-activated Hh signaling on liver fibrogenesis through modulating repair-related inflammation and focus on the regulatory action of aberrant Hh signaling on repair-related inflammatory responses mediated by hepatic classical and non-classical immune cell populations in the progression of liver fibrosis. Moreover, we also assess the potentiality of Hh pathway inhibitors as good candidates for anti-fibrotic therapeutic agents because of their immune regulation actions for fibrogenic liver repair. The identification of immune-modulatory mechanisms of Hh signaling pathway underlying the fibrotic process of chronic liver diseases might provide a basis for Hh-centered therapeutic strategies for liver fibrosis.

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GPCR Signaling to MAPK ER DiscoveryPak™ Hedgehog AKT PKB Signaling Phospho AMPK Signaling Phospho-Sp ErbB Her Signaling Phosph ERK Signaling Phospho-Spe IGF-1R Signaling Phospho- NF-kB II Phospho-Specific p53 Signaling Phospho-Spe T-Cell Receptor Signaling TGF-Beta Signaling Phosph Thermal Shaker with cooli

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mTORC1-Mediated Inhibition of 4EBP1 Is Essential for Hedgehog Signaling-Driven Translation and Medulloblastoma.

Mechanistic target of rapamycin (MTOR) cooperates with Hedgehog (HH) signaling, but the underlying mechanisms are incompletely understood. Here we provide genetic, biochemical, and pharmacologic evidence that MTOR complex 1 (mTORC1)-dependent translation is a prerequisite for HH signaling. The genetic loss of mTORC1 function inhibited HH signaling-driven growth of the cerebellum and medulloblastoma. Inhibiting translation or mTORC1 blocked HH signaling. Depleting 4EBP1, an mTORC1 target that inhibits translation, alleviated the dependence of HH signaling on mTORC1. Consistent with this, phosphorylated 4EBP1 levels were elevated in HH signaling-driven medulloblastomas in mice and humans. In mice, an mTORC1 inhibitor suppressed medulloblastoma driven by a mutant SMO that is inherently resistant to existing SMO inhibitors, prolonging the survival of the mice. Our study reveals that mTORC1-mediated translation is a key component of HH signaling and an important target for treating medulloblastoma and other cancers driven by HH signaling.

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MOUSE ANTI BOVINE ROTAVIR MOUSE ANTI BORRELIA BURGD Isopeptidase T (short for Isopeptidase T (long form NATIVE HUMAN PROLACTIN, P 4-Amino-5-formylamino-3-i (3R,4S,5R,6S)-1-Aza-4-hyd RABBIT ANTI GSK3 BETA (pS 10x ELISA WASH BUFFER, Pr 10X PHOSPHATE BUFFERED SA PERMANENT AQUEOUS MOUNTIN Mouse Anti-Ca19.9 Sialyl

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A cell based, high throughput assay for quantitative analysis of Hedgehog pathway activation using a Smoothened activation sensor.

The Hedgehog (Hh) signalling cascade plays an important role in development and disease. In the absence of Hh ligand, activity of the key signal transducer Smoothened (Smo) is downregulated by the Hh receptor Patched (Ptc). However, the mechanisms underlying this inhibition, and especially its release upon ligand stimulation, are still poorly understood, in part because tools for following Smo activation at the subcellular level were long lacking. To address this deficit we have developed a high throughput cell culture assay based on a fluorescent sensor for Drosophila Smo activation. We have screened a small molecule inhibitor library, and observed increased Smo sensor fluorescence with compounds aimed at two major target groups, the MAPK signalling cascade and polo and aurora kinases. Biochemical validation for selected inhibitors (dobrafenib, tak-733, volasertib) confirmed the screen results and revealed differences in the mode of Smo activation. Furthermore, monitoring Smo activation at the single cell level indicated that individual cells exhibit different threshold responses to Hh stimulation, which may be mechanistically relevant for the formation of graded Hh responses. Together, these results thus provide proof of principle that our assay may become a valuable tool for dissecting the cell biological basis of Hh pathway activation.

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Establishment of a dog primary prostate cancer organoid using the urine cancer stem cells.

Dog spontaneously develop prostate cancer (PC) like humans. Because most dogs with PC have a poor prognosis, they could be used as a translational model for advanced PC in humans. Stem cell-derived 3-D organoid culture could recapitulate organ structures and physiology. Using patient tissues, a human PC organoid culture system was established. Recent study has shown that urine cells also possess the characteristic of stem cells. However, urine cell-derived PC organoids have never been produced. Therefore, we generated PC organoids using the dog urine samples. Urine organoids were successfully generated from each dog with PC. Each organoid showed cystic structures and resembled the epithelial structures of original tissues. Expression of an epithelial cell marker, E-cadherin, and a myofibloblast marker, α-SMA, was observed in the urine organoids. The organoids also expressed a basal cell marker, CK5, and a luminal cell marker, CK8. CD49f-sorted basal cell organoids rapidly grew compared with CD24-sorted luminal cell organoids. The population of CD44-positive cells was the highest in both organoids and the original urine cells. Tumors were successfully formed with the injection of the organoids into immunodeficient mice. Treatment with a microtubule inhibitor, docetaxel, but not a cyclooxygenase inhibitor, piroxicam, and an mTOR inhibitor, rapamycin, decreased the cell viability of organoids. Treatment with a Hedgehog signal inhibitor, GANT61, increased the radiosensitivity in the organoids. These findings revealed that PC organoids using urine might become a useful tool for investigating the mechanisms of the pathogenesis and treatment of PC in dogs.

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Dog Receptor-binding canc Prostate cancer and hyper Prostate cancer, adjacent Breast cancer tissue arra Multiple organ cancer tis Prostate cancer tissue ar High density prostate can High density (70 cases 20 High density (114 cases 2 High density (208 core) p Prostate cancer test tiss Multiple prostate cancer

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