Relevant bibliographies by topics / Hedgehog Pathway Inhibition

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  4. Conference papers

Academic literature on the topic 'Hedgehog Pathway Inhibition'

Author: Grafiati
Published: 7 June 2025
Last updated: 16 July 2025

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Journal articles on the topic "Hedgehog Pathway Inhibition"

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Sekulic, Aleksandar, and Daniel Von Hoff. "Hedgehog Pathway Inhibition." Cell 164, no. 5 (2016): 831. http://dx.doi.org/10.1016/j.cell.2016.02.021.

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Walsh, Katherine J., Siyao Fan, Amee Patel, et al. "Hedgehog Pathway Inhibition Is a Novel Therapeutic Approach in Lymphomas and Its Efficacy is Inversely Related to PI3 Kinase Inhibition." Blood 116, no. 21 (2010): 1848. http://dx.doi.org/10.1182/blood.v116.21.1848.1848.

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Abstract Abstract 1848 Background: The hedgehog signaling pathway has been shown to be important in the development of malignancies, however, the role of this pathway in lymphomas is uncertain. GDC-0449 is a novel small molecule inhibitor that has been shown to block hedgehog activity by inhibiting SMO. The purpose of this study was to determine a potential role for hedgehog inhibition in the treatment strategies for lymphomas. We further sought to understand the determinants of sensitivity and potential resistance to therapeutic inhibition of this pathway. Methods and Results: We tested the small molecule inhibitor GDC-0449 in cell lines that span the spectrum of lymphoma including Burkitt lymphoma (N=4), ABC DLBCL (N=3), GCB DLBCL (N=7), mantle cell lymphoma (N=2), multiple myeloma (N=2), lymphoid leukemia (N=2), and T cell leukemia (N=2). Using the MTT assay, we identified the IC50 of drug response in these cell lines. We performed gene expression profiling in these cell lines and applied the Cox proportional hazards model using IC50 as the survival variable to identify genes that were associated with either sensitivity or resistance to the drug. We found that the drug was lethal in these cell lines at physiologically achievable concentrations with IC50s ranging from 5 to 22μM. We applied hierarchical clustering to the genes associated with sensitivity and resistance and found that the method distinguished two groups of samples that differed in their average IC50s by over 2-fold (8μM vs 17μM). There was a suggestion of association with lymphoma cell type with Burkitt lymphoma lines being the dominant cell type in the resistant group and DLBCL being the dominant cell type in the sensitive group. Resistance to hedgehog inhibition was found to be highly associated with the phosphatidylinositol 3′-kinase (PI3K) signaling pathway, suggesting that the hedgehog pathway and PI3K pathways act through independent, complementary mechanisms to promote tumor proliferation. In order to test the hypothesis that PI3K signaling is independent of hedgehog signaling we tested the lethality of PI3K inhibition using a dual PI3K/mTOR inhibitor (BEZ235) in the same cell lines. We found an inverse relationship between the hedgehog inhibitor and PI3K inhibitor, i.e. the cell lines that were relatively sensitive to hedgehog inhibition (mean IC50 of 8μm) were resistant to PI3K inhibition(mean IC50 of 0.69μm) and the cell lines that were relatively resistant to hedgehog inhibition (17μm) were relatively sensitive to PI3K inhibition (0.32μm). Conclusion: Hedgehog pathway inhibition is a promising therapeutic approach in a carefully defined subset of patients with lymphoma. Hedgehog and PI3K inhibitors appear to act by distinct mechanisms and may be complementary in the treatment of lymphomas. Disclosures: No relevant conflicts of interest to declare.
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CONNOLLY, E. SANDER. "Medulloblastoma Growth Inhibition by Hedgehog Pathway Inhibition." Neurosurgery 51, no. 6 (2002): NA. http://dx.doi.org/10.1227/01.neu.0000309154.15301.1a.

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Belgacemi, Randa, Soula Danopoulos, Gail Deutsch, et al. "Hedgehog Signaling Pathway Orchestrates Human Lung Branching Morphogenesis." International Journal of Molecular Sciences 23, no. 9 (2022): 5265. http://dx.doi.org/10.3390/ijms23095265.

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The Hedgehog (HH) signaling pathway plays an essential role in mouse lung development. We hypothesize that the HH pathway is necessary for branching during human lung development and is impaired in pulmonary hypoplasia. Single-cell, bulk RNA-sequencing data, and human fetal lung tissues were analyzed to determine the spatiotemporal localization of HH pathway actors. Distal human lung segments were cultured in an air-liquid interface and treated with an SHH inhibitor (5E1) to determine the effect of HH inhibition on human lung branching, epithelial-mesenchymal markers, and associated signaling pathways in vitro. Our results showed an early and regulated expression of HH pathway components during human lung development. Inhibiting HH signaling caused a reduction in branching during development and dysregulated epithelial (SOX2, SOX9) and mesenchymal (ACTA2) progenitor markers. FGF and Wnt pathways were also disrupted upon HH inhibition. Finally, we demonstrated that HH signaling elements were downregulated in lung tissues of patients with a congenital diaphragmatic hernia (CDH). In this study, we show for the first time that HH signaling inhibition alters important genes and proteins required for proper branching of the human developing lung. Understanding the role of the HH pathway on human lung development could lead to the identification of novel therapeutic targets for childhood pulmonary diseases.
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Uśpieński, Tomasz, and Paweł Niewiadomski. "The Proteasome and Cul3-Dependent Protein Ubiquitination Is Required for Gli Protein-Mediated Activation of Gene Expression in the Hedgehog Pathway." Cells 13, no. 17 (2024): 1496. http://dx.doi.org/10.3390/cells13171496.

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Many cellular processes are regulated by proteasome-mediated protein degradation, including regulation of signaling pathways and gene expression. Among the pathways regulated by the ubiquitin–proteasome system is the Hedgehog pathway and its downstream effectors, the Gli transcription factors. Here we provide evidence that proteasomal activity is necessary for maintaining the activation of the Hedgehog pathway, and this crucial event takes place at the level of Gli proteins. We undertook extensive work to demonstrate the specificity of the observed phenomenon by ruling out the involvement of primary cilium, impaired nuclear import, failed dissociation from Sufu, microtubule stabilization, and stabilization of Gli repressor forms. Moreover, we showed that proteasomal-inhibition-mediated Hedgehog pathway downregulation is not restricted to the NIH-3T3 cell line. We demonstrated, using CRISPR/Ca9 mutagenesis, that neither Gli1, Gli2, nor Gli3 are solely responsible for the Hedgehog pathway downregulation upon proteasome inhibitor treatment, and that Cul3 KO renders the same phenotype. Finally, we report two novel E3 ubiquitin ligases, Btbd9 and Kctd3, known Cul3 interactors, as positive Hedgehog pathway regulators. Our data pave the way for a better understanding of the regulation of gene expression and the Hedgehog signaling pathway.
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Atwood, Scott X., Anne Lynn S. Chang, and Anthony E. Oro. "Hedgehog pathway inhibition and the race against tumor evolution." Journal of Cell Biology 199, no. 2 (2012): 193–97. http://dx.doi.org/10.1083/jcb.201207140.

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Dependence of basal cell carcinomas and medulloblastomas on the Hedgehog pathway provides an opportunity for targeted or “personalized” therapy. The recent effectiveness and FDA approval of the first Smoothened inhibitors validates this class of agents, but has revealed drug-resistant tumor variants that bypass Smoothened inhibition. Here, we summarize the effectiveness of Hedgehog pathway inhibitors and highlight promising areas for the development of next generation drug antagonists for Hedgehog-dependent cancers.
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Ko, Yu-Chan, Hack Sun Choi, Ren Liu, and Dong-Sun Lee. "Physalin A, 13,14-Seco-16, 24-Cyclo-Steroid, Inhibits Stemness of Breast Cancer Cells by Regulation of Hedgehog Signaling Pathway and Yes-Associated Protein 1 (YAP1)." International Journal of Molecular Sciences 22, no. 16 (2021): 8718. http://dx.doi.org/10.3390/ijms22168718.

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The Hedgehog (HH) signaling pathway plays an important role in embryonic development and adult organ homeostasis. Aberrant activity of the Hedgehog signaling pathway induces many developmental disorders and cancers. Recent studies have investigated the relationship of this pathway with various cancers. GPCR-like protein Smoothened (SMO) and the glioma-associated oncogene (GLI1) are the main effectors of Hedgehog signaling. Physalin A, a bioactive substance derived from Physalis alkekengi, inhibits proliferation and migration of breast cancer cells and mammospheres formation. Physalin A-induced apoptosis and growth inhibition of mammospheres, and reduced transcripts of cancer stem cell (CSC) marker genes. Physalin A reduced protein expressions of SMO and GLI1/2. Down-regulation of SMO and GLI1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation by reducing GLI1 gene expression. Down-regulation of GLI1 reduced CSC marker genes. Physalin A reduced protein level of YAP1. Down-regulation of YAP1 using siRNA inhibited mammosphere formation. Physalin A reduced mammosphere formation through reduction of YAP1 gene expression. Down-regulation of YAP1 reduced CSC marker genes. We showed that treatment of MDA-MB-231 breast cancer cells with GLI1 siRNA induced inhibition of mammosphere formation and down-regulation of YAP1, a Hippo pathway effector. These results show that Hippo signaling is regulated by the Hedgehog signaling pathway. Physalin A also inhibits the canonical Hedgehog and Hippo signaling pathways, CSC-specific genes, and the formation of mammospheres. These findings suggest that physalin A is a potential therapeutic agent for targeting CSCs.
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Berman, D. M. "Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade." Science 297, no. 5586 (2002): 1559–61. http://dx.doi.org/10.1126/science.1073733.

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Irvine, David A., and Mhairi Copland. "Targeting hedgehog in hematologic malignancy." Blood 119, no. 10 (2012): 2196–204. http://dx.doi.org/10.1182/blood-2011-10-383752.

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Abstract The Hedgehog pathway is a critical mediator of embryonic patterning and organ development, including hematopoiesis. It influences stem cell fate, differentiation, proliferation, and apoptosis in responsive tissues. In adult organisms, hedgehog pathway activity is required for aspects of tissue maintenance and regeneration; however, there is increasing awareness that abnormal hedgehog signaling is associated with malignancy. Hedgehog signaling is critical for early hematopoietic development, but there is controversy over its role in normal hematopoiesis in adult organisms where it may be dispensable. Conversely, hedgehog signaling appears to be an important survival and proliferation signal for a spectrum of hematologic malignancies. Furthermore, hedgehog signaling may be critical for the maintenance and expansion of leukemic stem cells and therefore provides a possible mechanism to selectively target these primitive cell subpopulations, which are resistant to conventional chemotherapy. Indeed, phase 1 clinical trials of hedgehog pathway inhibitors are currently underway to test this hypothesis in myeloid leukemias. This review covers: (1) the hedgehog pathway and its role in normal and malignant hematopoiesis, (2) the recent development of clinical grade small molecule inhibitors of the pathway, and (3) the potential utility of hedgehog pathway inhibition as a therapeutic strategy in hemato-oncology.
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Tukachinsky, Hanna, Kostadin Petrov, Miyako Watanabe, and Adrian Salic. "Mechanism of inhibition of the tumor suppressor Patched by Sonic Hedgehog." Proceedings of the National Academy of Sciences 113, no. 40 (2016): E5866—E5875. http://dx.doi.org/10.1073/pnas.1606719113.

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The Hedgehog cell–cell signaling pathway is crucial for animal development, and its misregulation is implicated in numerous birth defects and cancers. In unstimulated cells, pathway activity is inhibited by the tumor suppressor membrane protein, Patched. Hedgehog signaling is triggered by the secreted Hedgehog ligand, which binds and inhibits Patched, thus setting in motion the downstream events in signal transduction. Despite its critical importance, the mechanism by which Hedgehog antagonizes Patched has remained unknown. Here, we show that vertebrate Patched1 inhibition is caused by direct, palmitate-dependent interaction with the Sonic Hedgehog ligand. We find that a short palmitoylated N-terminal fragment of Sonic Hedgehog binds Patched1 and, strikingly, is sufficient to inhibit it and to activate signaling. The rest of Sonic Hedgehog confers high-affinity Patched1 binding and internalization through a distinct binding site, but, surprisingly, it is not absolutely required for signaling. The palmitate-dependent interaction with Patched1 is specifically impaired in a Sonic Hedgehog mutant causing human holoprosencephaly, the most frequent congenital brain malformation, explaining its drastically reduced potency. The palmitate-dependent interaction is also abolished in constitutively inhibited Patched1 point mutants causing the Gorlin cancer syndrome, suggesting that they might adopt a conformation distinct from the wild type. Our data demonstrate that Sonic Hedgehog signals via the palmitate-dependent arm of a two-pronged contact with Patched1. Furthermore, our results suggest that, during Hedgehog signaling, ligand binding inhibits Patched by trapping it in an inactive conformation, a mechanism that explains the dramatically reduced activity of oncogenic Patched1 mutants.
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Dissertations / Theses on the topic "Hedgehog Pathway Inhibition"

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Han, Shuanglin. "Inhibition of glypican 3 facilitates hepatocellular carcinoma cells to acquire cancer stem cell phenotype by activating epithelial mesenchymal transition pathway." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/26929.

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Hepatocellular carcinoma (HCC) is the most common primary liver cancer. In 2012, 782,000 HCC patients were diagnosed worldwide, and among them 746,000 died. Currently, HCC is the 6th most common and the 3rd most fatal cancer globally. Patients with the advanced HCC have few treatment options. Sorafenib is the first line systemic therapy but it only prolongs patients’ survival time by two months. As a second line therapy, regorafenib could be used to treat the patients with sorafenib resistance, however, this agent also has limited efficacy as it only extends patients survival by <3 months. Despite of advances in the early detection and therapeutic strategies over the recent years, the overall prognosis of HCC patients remains extremely unsatisfactory. Glypican 3 (GPC3) has been thought to be a specific biomarker for HCC because it is almost exclusively and highly expressed by HCC tissues. As such, many therapeutic strategies targeting GPC3 including vaccines, antibodies and chimeric antigen receptor T cells have been developed. However, these treatment options have not been shown to significantly improve the outcomes of HCC patients. Over the past few years, published studies including our own data have indicated that cancer stem cells (CSCs) are the main culprit for cancer initiation, progression, metastasis and relapse. CSCs are also closely linked to drug resistance. Whether the unsatisfactory results of GPC3 targeting therapies are related to their inability to remove CSCs is a practical question remaining to be answered. In this project, we aimed to unveil the possible mechanisms related to the poor efficacy of GPC3 targeted therapies. We started by performing bioinformatic pathway analysis for GPC3 using two large scale public databases including Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). We found that GPC3 was positively correlated with cell cycle related pathways but was negatively correlated with epithelial mesenchymal transition (EMT) pathway, a key mechanism for the generation and maintenance of CSCs. We then performed protein binding predictions and found that GPC3 could bind to SHH, a ligand for sonic hedgehog pathway. As previously published, GPC3 could inhibit the activation of sonic hedgehog pathway by competing with PTCH1, a natural receptor for SHH binding during development. We hypothesized that GPC3 may inhibit the generation of CSCs in HCC by the inhibiting sonic hedgehog pathway and subsequent EMT pathway. Hence, inhibition of GPC3 expression in HCC tumour bulk may facilitate the generation of CSCs. To validate our hypothesis, we demonstrated that GPC3 and CD133 are expressed by different population of cells in the HCC tumour bulk. Based on our studies, we propose that the GPC3 targeted therapies may be able to kill the majority of HCC cells, these therapies are unable to eliminate liver cancer stem cells (LCSCs) such as CD133+ cells. Our further analysis by IHC revealed that GPC3/PTCH1/SHH axis follows a paracrine pattern. We then performed in vitro studies using recombinant human SHH protein to treat HCC cells to mimic the HCC tumour biology in microenvironment. We generated stable GPC3 knockdown cells (Huh7 and Hep3B) using specific short hairpin RNA (shRNA) against GPC3 and found that activation of sonic hedgehog pathway and EMT pathway occurred only when the cells were treated with recombinant human SHH. By using the co-immunoprecipitation (co-IP) experiments in human HEK293T cells, we confirmed that GPC3 could compete with PTCH1 for SHH binding in a dose dependent manner. Functional studies have revealed that the stable GPC3 knockdown cells treated with SHH exhibited stronger metastatic and stemness phenotypes. In order to further demonstrate the possible interaction between GPC3 and stem cell features, we cultured the isolated LCSCs from Huh7 and Hep3B cells and tested the expression level of GPC3 by using Western blotting, qPCR and immunofluorescence. We also extracted the data from two public datasets using other stem cell models and analysed the expression pattern of GPC3 in these models. All the data showed that the expression level of GPC3 in CSCs is significantly lower than it is in the differentiated cells. Based on the published data and our own studies, we proposed that within HCC tumour bulk, high expression level of GPC3 promotes the proliferation of cancer cells but inhibition of GPC3 endows cancer cells with a CSC phenotype via EMT pathway. Our results demonstrate that CSCs targeting strategies should be an integral part of GPC3 targeted therapies in HCC.
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Irvine, David Arthur. "Defining novel therapeutic targets in chronic myeloid leukaemia stem cells : targeting self-renewal through hedgehog pathway inhibition." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4584/.

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Keller, Juliane [Verfasser], and Torsten [Akademischer Betreuer] Kluba. "Inhibition of the Hedgehog pathway in combination with cytostatics as potential therapeutic option in Ewing Sarcoma / Juliane Keller ; Betreuer: Torsten Kluba." Tübingen : Universitätsbibliothek Tübingen, 2020. http://d-nb.info/1204422354/34.

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Guadagnuolo, Viviana <1982&gt. "SMO inhibitor specifically targets the Hedgehog Pathway and reverts the drug-resistance of Leukemic Stem Cells." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5726/1/Guadagnuolo_Viviana_tesi.pdf.

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Abnormal Hedgehog signaling is associated with human malignancies. Smo, a key player of that signaling, is the most suitable target to inhibit this pathway. To this aim several molecules, antagonists of Smo, have been synthesized, and some of them have started the phase I in clinical trials. Our hospital participated to one of these studies which investigated the oral administration of a new selective inhibitor of Smo (SMOi). To evaluate ex vivo SMOi efficacy and to identify new potential clinical biomarkers of responsiveness, we separated bone marrow CD34+ cells from 5 acute myeloid leukemia (AML), 1 myelofibrosis (MF), 2 blastic phases chronic myeloid leukemia (CML) patients treated with SMOi by immunomagnetic separation, and we analysed their gene expression profile using Affimetrix HG-U133 Plus 2.0 platform. This analysis, showed differential expression after 28 days start of therapy (p-value ≤ 0.05) of 1,197 genes in CML patients and 589 genes in AML patients. This differential expression is related to Hedgehog pathway with a p-value = 0.003 in CML patients and with a p-value = 0.0002 in AML patients, suggesting that SMOi targets specifically this pathway. Among the genes differentially expressed we observed strong up-regulation of Gas1 and Kif27 genes, which may work as biomarkers of responsiveness of SMOi treatment in CML CD34+ cells whereas Hedgehog target genes (such as Smo, Gli1, Gli2, Gli3), Bcl2 and Abca2 were down-regulated, in both AML and CML CD34+ cells. It has been reported that Bcl-2 expression could be correlated with cancer therapy resistance and that Hedgehog signaling modulate ATP-binding (ABC) cassette transporters, whose expression has been correlated with chemoresistance. Moreover we confirmed that in vitro SMOi treatment targets Hedgehog pathway, down-regulate ABC transporters, Abcg2 and Abcb1 genes, and in combination with tyrosine kinase inhibitors (TKIs) could revert the chemoresistance mechanism in K562 TKIs-resistant cell line.
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Guadagnuolo, Viviana <1982&gt. "SMO inhibitor specifically targets the Hedgehog Pathway and reverts the drug-resistance of Leukemic Stem Cells." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5726/.

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Abnormal Hedgehog signaling is associated with human malignancies. Smo, a key player of that signaling, is the most suitable target to inhibit this pathway. To this aim several molecules, antagonists of Smo, have been synthesized, and some of them have started the phase I in clinical trials. Our hospital participated to one of these studies which investigated the oral administration of a new selective inhibitor of Smo (SMOi). To evaluate ex vivo SMOi efficacy and to identify new potential clinical biomarkers of responsiveness, we separated bone marrow CD34+ cells from 5 acute myeloid leukemia (AML), 1 myelofibrosis (MF), 2 blastic phases chronic myeloid leukemia (CML) patients treated with SMOi by immunomagnetic separation, and we analysed their gene expression profile using Affimetrix HG-U133 Plus 2.0 platform. This analysis, showed differential expression after 28 days start of therapy (p-value ≤ 0.05) of 1,197 genes in CML patients and 589 genes in AML patients. This differential expression is related to Hedgehog pathway with a p-value = 0.003 in CML patients and with a p-value = 0.0002 in AML patients, suggesting that SMOi targets specifically this pathway. Among the genes differentially expressed we observed strong up-regulation of Gas1 and Kif27 genes, which may work as biomarkers of responsiveness of SMOi treatment in CML CD34+ cells whereas Hedgehog target genes (such as Smo, Gli1, Gli2, Gli3), Bcl2 and Abca2 were down-regulated, in both AML and CML CD34+ cells. It has been reported that Bcl-2 expression could be correlated with cancer therapy resistance and that Hedgehog signaling modulate ATP-binding (ABC) cassette transporters, whose expression has been correlated with chemoresistance. Moreover we confirmed that in vitro SMOi treatment targets Hedgehog pathway, down-regulate ABC transporters, Abcg2 and Abcb1 genes, and in combination with tyrosine kinase inhibitors (TKIs) could revert the chemoresistance mechanism in K562 TKIs-resistant cell line.
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Tian, Fei. "Effect of the Hedgehog Pathway inhibitor GDC-0449 in lung cancer cells and lung cancer stem cells." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-156374.

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The cancer stem cell hypothesis implicates that tumor cell population is heterogeneous with relatively well-differentiated cells and poorly-differentiated cells. Only the small population of tumourigenic poorly-differentiated CSCs can escape the normal limits of self-renewal and has the ability to proliferate and maintain the malignant growth of the tumor. One characteristic of stem cell is that the ability to exclude DNA dyes, such as Hoechst 33342 via the over-expression of ATP-binding cassette transporters (ABC transporters) on the cell membrane. It makes the detecting of the stem cell possible. After the Hoechst 33342 staining, stem cells extrude this dye and show a typical profile of low fluorescence in Hoechst red versus Hoechst blue bivariate dot plots. These low Hoechst 33342 stained cells are named as side population (SP) cells. This characteristic has enabled purification and characterization of CSCs when carried out alone or in combination with stem cell surface markers. The CSC hypothesis could have a fundamental influence on cancer therapy. CSCs have shown significant substantial resistance to conventional chemotherapy in contrast to the differentiated cancer cells. It is essential to design a complete therapy strategy first to reduce or minimize proliferating cell mass and then to differentiate or eliminate CSCs, so that the relapses of metastatic cancers could be prevented. This work aimed at investigating if Hedgehog pathway inhibitor GDC-0449 is effective in the lung cancer cell lines HCC (adeno-carcinoma) and H1339 (small cell lung carcinoma) and also the cisplatin resistant lung cancer cells, and if possible effects of GDC-0449 are mediated via SPs. Furthermore, the effect of GDC-0449 on the calcium homeostasis was also investigated. GDC-0449 showed dose-dependent inhibitory effects on cell growth in both HCC and H1339 cells. The combination of GDC-0449 and cisplatin gave an additional inhibitory effect. GDC- 0449 could also inhibit the cell growth in cisplatin resistant HCC and H1339 cells. SP cells as cancer stem-cell-like cells could be found in HCC and H1339 cells. Only the SP cells showed the repopulation ability but not the non-SP cells. GDC-0449 could inhibit the SP cell fraction in both HCC and H1339 cells. So the inhibitory effect of GDC-0449 on cell growth may be mediated via SP. GDC-0449 affected the expression of the Hh pathway components in both HCC and H1339 cells. In HCC cells, GDC-0449 inhibited the activity of the Hh pathway and the down- regulation of Shh, Patched and Gli-1 could be shown. In H1339 cells, GDC-0449 could also inhibit the pathway activity and decrease the expression of Gli-1 in an autocrine pattern due to the over-expression of Shh. The inhibition of Hh pathway increased the expression of Bmi-1 to compensate the loss of Hh pathway function. The Hh pathway activity could be detected only in SP cells from HCC and H1339 cells. The application of GDC-0449 on HCC and H1339 naïve and cisplatin resistant cells increased [Ca2+]c by decreasing [Ca2+]ER. GDC-0449 induced Ca2+ release from ER into cytoplasm in HCC and H1339 naïve and cisplatin resistant cells. The Ca2+ overload could lead to apoptosis, which was related to the cell growth inhibitory effect of GDC-0449 in lung cancer cells. The expression of SERCA and IP3R was not detectably influenced by GDC-0449. The effect of GDC-0449 on lung cancer cell Ca2+ -regulating machinery was not via the alternation of the expression of ER Ca2+ regulating channels.
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Tian, Fei [Verfasser], and Albrecht [Akademischer Betreuer] Bergner. "Effect of the hedgehog pathway inhibitor GDC-0449 in lung cancer cells and lung cancer stem cells / Fei Tian. Betreuer: Albrecht Bergner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/1034474863/34.

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Eimer, Sandrine. "Etude des réponses induites par l’erlotinib dans des cellules de lignées de glioblastome." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21822/document.

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Le glioblastome (GBM), tumeur de plus haut grade du système nerveux central (OMS grade 4) a un pronostic très sombre, quelque soit le traitement, lié à une résistance à l’apoptose. L’erlotinib (Tarceva®, OSI 774) est un inhibiteur de la tyrosine kinase du récepteur au facteur de croissance épithélial (EGFR). L’hyper-expression et l’amplification du gène de l’EGFR dans 40 à 60% des GBM, fourni un rationnel pour utiliser l’erlotinib. Nous avons montré sur U87-MG et DBTRG-05MG, deux lignées de GBM, l’absence d’apoptose avec l’erlotinib, liée soit à un déficit en pro-caspase 3, soit à une accumulation d’αB-crystalline bloquant l’activation de la caspase-3. L’absence d’apoptose dévie alors la cellule vers l’autophagie. L’inhibition de l’autophagie par ARN interférents ou par la chloroquine permet d’obtenir une synergie avec l’erlotinib en induisant la mort des cellules tumorales à des doses acceptables.Les GBM ont composition cellulaire hétérogène, avec un petit nombre d’éléments appelés cellules souches cancéreuses (CSC). Douées d’auto-renouvellement, elles participent à la propagation tumorale et à la résistance aux traitements. Nous avons testé l’erlotinib sur trois lignées issues de GBM humains, ayant deux modes de croissance distincts selon les conditions de milieu: en neurosphères (NS) et de type adhérent. Erlotinib a un effet inhibiteur minime sur les trois lignées adhérentes, alors que l’effet est significatif sur les lignées NS, traduisant l’importance de la voie d’EGFR pour les NS. Dans les lignées en NS, l’erlotinib est efficace sur les cellules progénitrices, mais n’a pas d’action ni sur les cellules initiatrices de NS, ni sur les cellules différenciées. L’auto-renouvellement des NS n’est pas non plus altéré. L’association cyclopamine, inhibiteur pharmacologique de la voie de Hedgehog, -erlotinib est synergique en bloquant la croissance et l’initiation des NS, laissant présager une efficacité sur les CSC. Les résultats obtenus sur ces différents modèles permettent d’une part de préciser certains mécanismes de résistance des cellules de GBM, et aussi d’orienter les indications et le choix des traitements susceptibles d’être les plus efficaces<br>Glioblastoma (GBM) is the most common primary central nervous system tumor in adults and the prognosis remains dismal, any treatment used. Epidermal Growth Factor Receptor (EGFR) is amplified, overexpressed, and/or mutated in GBM, making it a rational for therapy. Erlotinib, an EGFR kinase inhibitor is strongly associated with clinical response in several cancers. We showed for U87-MG and DBTRG-05MG, two human GBM cell lines, that erlotinib can’t trigger apoptosis, related either to accumulation of αB-crystallin capable to impair caspase 3 cleavage, or to constitutive deficit for procaspase 3 in DBTRG-05MG. Apoptosis deficit switches the cell to autophagic process. Inhibition of autophagy with RNA interference or chloroquine resulted in sensitization of U87 and allowed a synergistic effect with erlotinib at therapeutic doses.Moreover, GBM showed a heterogeneous cell composition with cancer stem cells, progenitors and more differentiated cells. In this study, we test erlotinib in vitro on other GBM models: three cell lines established from surgically resected GBM specimens, grown along two features adherent and neurospheres. On the three differentiated adhering cell lines, erlotinib had only a moderate activity. Conversely, on neurosphere forming cell lines, erlotinib induced a strong inhibition of cell growth related to the EGFR amplification and EGFR expression. A short erlotinib exposure induced cell death primarily in nestin-positive cells; however it was found without effect on neurosphere initiating activity and self renewal. These results suggest that EGFR pathway activation is essential for the proliferation of GBM progenitor cells but dispensable for stem-like cancer cells self–renewal. As Hedgehog pathway is known to be activated in neural stem cells, we assayed the Hedgehog pathway inhibitor cyclopamine in association with erlotinib. While each drug separately was without effect on sphere initiation, their combination led to a 25 fold decrease in the sphere number (p=0.0004).These in vitro models are convenient to investigate resistance mechanisms in GBM. Furthermore, they focus on the necessity to exploit drug combinations for greatest efficiency
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Omar, Aadilah. "Inhibition of sonic hedgehog pathway by small molecule inhibitors: Targeting colon cancer stem cells." Thesis, 2016. http://hdl.handle.net/10539/19630.

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A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the requirements for the degree of Doctor of Philosophy (Internal Medicine). Johannesburg, 2015<br>The existence of Cancer Stem Cells (CSC’s) has been proven extensively in recent years. CSC’s have been positively identified in, and isolated from colon cancer. They have been found to be resilient to therapy and are highly metastatic and it has been suggested that this could be attributed to the presence of CSC’s expressing cell surface CD133. An active Hedgehog-Gli pathway has been detected in human colon carcinoma cells as well as their stem cells. Sonic Hedgehog (Shh) inhibitors such as cyclopamine have been successful in the treatment of other cancer types. CSC’s were isolated from HT29 and DLD1 cells using the CD133 surface protein and these cells were further characterized via their expression of key stem cell markers using fluorescence microscopy. These markers included c-Myc, KLF4 and alkaline phosphatase, all of which showed elevated expression levels in the CSC fraction. The growth pattern of CSC’s in comparison to non-CSC’s was analyzed using cell-impedance (xCELLigence) assays, with clear differences noted in their growth rates. Adhesion assays revealed that although CSC’s have a lower proliferation rate, their adhesive potential proved to be greater, possibly due to them being highly metastatic. The effects of the Shh inhibitors cyclopamine and SANT-2 on cellular adhesion of colon CSC’s were compared to the Shh pathway control molecule tomatidine, and a marked decrease in adhesion potential was noted. With regard to cell invasion, this was significantly decreased when CSC’s were treated with the small molecule inhibitors. In cell migration/scratch assays a similar trend was seen, wherein cell migration was retarded by Hh pathway inhibition. Using confocal microscopy, the cell surface expression of Shh and CD133 was observed following treatment with cyclopamine and while found to significantly reduce Shh expression, CD133 expression remained unaffected. Considering these in vitro results small molecule inhibitors targeting the Shh pathway appear to be promising therapeutic tools for the treatment of metastatic colon CSC’s. Further investigation into the genes involved using PCR arrays would provide more detailed information on the drug action and allow for the development of an enhanced therapeutic.
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Cotugno, Gabriella. "Inhibition of the Sonic Hedgehog pathway as a strategy to treat ocular neovascularization in animal models." Tesi di dottorato, 2009. http://www.fedoa.unina.it/3325/1/Cotugno2009Semm_A.pdf.

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Ocular neovascularization (NV) is a feature of several common retinal and choroidal blinding diseases, including proliferative diabetic retinopathy and age-related macular degeneration. Unbalanced production of pro- vs anti-angiogenic molecules in the eye causes abnormal vessel growth. Although several pro-angiogenic pathways leading to ocular NV have been elucidated, the identification of novel molecules involved in this complex process is desirable to better understand the disease pathogenesis and to develop efficient therapeutic strategies. To this aim, we investigated the role of the morphogen Sonic Hedgehog (Shh) in the development of ocular NV. We observed that the Shh pathway is activated in the retina of the retinopathy of prematurity (ROP) and the laser-induced choroidal NV (CNV) murine models of retinal and choroidal neovascularization, respectively. We show that systemic administration of cyclopamine, a Shh pathway inhibitor, results in reduction of pathological vascularization in both models, suggesting that activation of the Shh pathway plays an important role in the ocular NV process. We then developed two nucleic acid-based systems for specific Shh inhibition in the retina: a Shh-decoy receptor (HIP--22) able to bind and sequester Shh inhibiting its pathway; and short interfering RNAs (siRNA) able to reduce 70% Shh expression levels in vitro. Both HIP--22 and the siRNA inhibited Shh-induced osteogenic differentiation of the mesenchymal cell line C3H10T1/2. In the ROP retina, adeno-associated viral vector-mediated HIP--22 delivery or periocular injections of Shh siRNA resulted in efficient inhibition of the Shh pathway but not of retinal neovascularization, even when the two strategies were combined. Stronger inhibition of the Shh pathway may be required to reduce retinal NV in the ROP model. Alternatively, the inhibition of ocular NV observed following systemic cyclopamine administration may result from secondary, extraocular effects of the Shh pathway blockade. These results suggest Shh as a potential therapeutic target for the treatment of ocular NV. Thorough characterization of Shh role in ocular NV is required for the development of an appropriate therapeutic strategy.
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Book chapters on the topic "Hedgehog Pathway Inhibition"

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Rübe, Claudia E., Bernadine R. Donahue, Jay S. Cooper, et al. "Hedgehog Pathway Inhibition." In Encyclopedia of Radiation Oncology. Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-540-85516-3_746.

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Armstrong, Patrick, Stephanie Martin, and Gary Lask. "Sonic Hedgehog Pathway Inhibition in the Treatment of Advanced Basal Cell Carcinoma." In Biologic and Systemic Agents in Dermatology. Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-66884-0_47.

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Marsters, James C., and Harvey Wong. "Targeting Basal-Cell Carcinoma: Discovery and Development of Vismodegib (GDC-0449), a First-in-Class Inhibitor of the Hedgehog Pathway." In Methods and Principles in Medicinal Chemistry. Wiley-VCH Verlag GmbH & Co. KGaA, 2013. http://dx.doi.org/10.1002/9783527677252.ch05.

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Kumar, M. Santosh, Poornima D. Vijendra, Pratap G. Kenchappa, and A. Gowtami. "Multifactorial Drug - A Revolution in the Treatment of Cancer by Inhibiting Hedgehog Pathway." In Promising Cancer Therapeutic Drug Targets: Recent Advancements. BENTHAM SCIENCE PUBLISHERS, 2025. https://doi.org/10.2174/9789815238570125010011.

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In the human body, Hedgehog (Hh) signaling is an essential pathway and plays a major role in embryo development, tumorigenesis, distant metastasis, poor prognosis, and tissue patterning. The Hh pathway has three ligands in mammals: Sonic Hedgehog (SHh), Desert Hedgehog (DHh), and Indian Hedgehog (IHh). Malfunctions of this pathway are associated with diseases that include cancer. Cancer is one of the leading causes of death worldwide and factors like dietary habits, family history, obesity, environmental conditions, tobacco, and genetic factors affect the likelihood of developing cancer. The Hh signaling pathway through sporadic mutations is explicitly associated with cancer development and progression in various solid malignancies. Abnormal expression of the Hh signaling cascade has been reported in the development of basal cell carcinoma, breast, liver, prostate, colon, pancreas, and stomach cancer. Most researchers target the inhibition of the Hh signaling pathway and therefore it has emerged as a popular and validated therapeutic for the treatment of a wide range of cancers. A novel class of drugs such as sonidegib and vismodegib inhibits the Hedgehog pathway. There has been significant progress regarding the development of multifactorial drugs blocking Hh signaling. The discovery of multifactorial drugs to block the pathway has led to a new treatment that may significantly improve clinical outcomes in cancer patients. Several of these molecules have been included in the clinical testing stage. Yet finding a sustainable multifactorial inhibitor is still a challenge. This book chapter describes the Hh signaling pathway as a vital and multifactorial therapeutic target for cancer.
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Li, Xing-Guo, and Jer-Yen Yang. "Perspective Chapter: Critical Role of Hedgehog in Tumor Microenvironment." In Tumor Microenvironment - New Insights [Working Title]. IntechOpen, 2023. http://dx.doi.org/10.5772/intechopen.108831.

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Hedgehog (Hh) signaling is a highly conserved pathway that plays a pivotal role during embryonic development. Mounting evidence has implicated Hh signaling in various types of cancer. Accordingly, inhibition of aberrant Hh signaling continues to be pursed across multiple cancer types -with some success in certain malignancies. In addition, with the renaissance of antitumor immunotherapy, an in-depth understanding of the molecular mechanisms underlying how the multifaceted functions of Hh signaling shape immunologically suppressive tumor microenvironment might be the key to unlocking a new era of oncological treatments associated with a reduced propensity for the development of drug resistance. Here, we focus on the latest advances regarding the immunological effects of misregulation of Hh signaling on tumor immunity. We also review the current status of clinically approved Hh inhibitors and dissect the mechanisms of drug resistance. Finally, we discuss the potential clinical applications that harness the immunomodulatory effects of Hh signaling not only to circumvent drug resistance, but also to achieve durable efficacy following immunotherapies, thus ultimately resulting in improved patient outcomes.
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JR, Ervin Epstein. "PTCH and the Basal Cell Nevus (Gorlin) Syndrome." In Inborn Errors Of Development. Oxford University PressNew York, NY, 2008. http://dx.doi.org/10.1093/oso/9780195306910.003.0023.

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Abstract The basal cell nevus syndrome (BCNS) is a rare afliction that is inherited as an autosomal dominant trait and is characterized by a wide panoply of clinical manifestations, especially the development of large numbers of cutaneous basal cell carcinomas (BCCs). Causative mutations occur in the PATCHED1 (PTCH1) gene, which encodes an inhibitor of hedgehog signaling. This identification in turn has led to the novel finding that sporadic BCCs, the commonest human cancer, are driven by pivotal mutations in genes encoding proteins that are components of the hedgehog signaling pathway. In addition to postnatal tumors of the skin and, less commonly, of other tissues, BCNS patients also have malformations (e.g., of the ribs and skull) and tissue overgrowths that are explicable on the basis of abnormal PATCHED1 function during embryogenesis.
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Conference papers on the topic "Hedgehog Pathway Inhibition"

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Manzella, Gabriele, Tina Kottarathil, and Beat W. Schaefer. "Abstract 2449: Hedgehog pathway inhibition sensitizes embryonal rhabdomyosarcoma to standard chemotherapy." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-2449.

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Pace, Jennifer, and M. Kyle Hadden. "Abstract 3666: Synthesis and evaluation of itraconazole analogues for hedgehog pathway inhibition." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3666.

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Wang, Yangyang, Francesco Sabbatino, Soldano Ferrone, and Xinhui Wang. "Abstract 4741: Inhibition of TNBC cell growth by CSPG4-specific mAb 225.28 with a Sonic Hedgehog pathway inhibitor." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-4741.

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Brechbiel, Jillian L., Jessica MY Ng, and Tom Curran. "Abstract C110: Abstract B: Hedgehog pathway inhibition in young mice results in severe bone defects." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-c110.

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Omar, Aadilah, Clement Penny, and Paul Ruff. "Abstract A21: Inhibition of Sonic Hedgehog Pathway by small molecule inhibitors: Targeting colon cancer stem cells." In Abstracts: AACR International Conference: New Frontiers in Cancer Research; January 18-22, 2017; Cape Town, South Africa. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.newfront17-a21.

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Wickstrom, Malin, Cecilia Dyberg, Takashi Shimokawa, et al. "Abstract 4725: Inhibition of the Hedgehog signaling pathway - a new target in treatment for children with neuroblastoma." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4725.

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Raven, Peter A., Sebastian Frees, Betty Zhou, Claudia Chavez-Munoz, Michael Cox, and Alan So. "Abstract 4409: Assessment of sonic hedgehog pathway inhibition in a novel orthotopic xenograft bladder cancer murine model." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4409.

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Jackson-Fisher, Amy, Pamela Whalen, Mark Elliott, et al. "Abstract 1958: Interrogating hedgehog pathway and smoothened inhibition by PF-04449913 in patient-derived acute myeloid leukemia models." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-1958.

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Aftab, Blake T., Wei Shi, Benjamin A. Nacev, Sarah Head, Jun O. Liu, and Charles M. Rudin. "Abstract C147: Itraconazole side-chain analogs reveal a distinct structure-activity relationship for inhibition of hedgehog pathway signaling." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-c147.

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Karlou, Maria, Vassiliki Tzelepi, Sankar Maity, et al. "Abstract C253: Effective inhibition of Hedgehog signaling pathway with small molecule Smoothened inhibitor GDC‐0449 in a bone producing prostate cancer xenograft." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-c253.

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