LIVIVO - Suchergebnisse -

Suchergebnis

Treffer 1 - 10 von insgesamt 12

Suchoptionen

Buch ; Online ; Dissertation / Habilitation: Preclinical evaluation of HDAC inhibitors for epigenetic therapy of primary brain tumors

Marquardt, Viktoria [Verfasser] / Kurz, Thomas [Gutachter] / Felsberg, Jörg [Gutachter]

2022

Verfasserangabe	Viktoria Marquardt ; Gutachter: Thomas Kurz, Jörg Felsberg
Schlagwörter	Medizin, Gesundheit ; Medicine, Health
Thema/Rubrik (Code)	sg610
Sprache	Englisch
Verlag	Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf
Erscheinungsort	Düsseldorf
Dokumenttyp	Buch ; Online ; Dissertation / Habilitation
Datenquelle	Digitale Dissertationen im Internet

Volltext online

Volltext online

Zusatzmaterialien

Fernleihe an ZB MED

Sie können sich den gewünschten Titel als lokale Nutzerin oder lokaler Nutzer von ZB MED direkt an den Standort Köln schicken lassen.

Artikel ; Online: N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma.

Tjaden, Britta / Baum, Katharina / Marquardt, Viktoria / Simon, Mareike / Trajkovic-Arsic, Marija / Kouril, Theresa / Siebers, Bettina / Lisec, Jan / Siveke, Jens T / Schulte, Johannes H / Benary, Uwe / Remke, Marc / Wolf, Jana / Schramm, Alexander

Scientific reports

2020 Band 10, Heft 1, Seite(n) 7157

Abstract: N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant ... ...

Abstract	N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.
Mesh-Begriff(e)	Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Glucosamine/metabolism ; Glucose/metabolism ; Humans ; N-Myc Proto-Oncogene Protein/physiology ; Neuroblastoma/genetics ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; Neuroblastoma/therapy
Chemische Substanzen	MYCN protein, human ; N-Myc Proto-Oncogene Protein ; Glucose (IY9XDZ35W2) ; Glucosamine (N08U5BOQ1K)
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2020-04-28
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-64040-1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

Zusatzmaterialien

Über subito bestellen

Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

Details ▾
- Kostenpflichtig bestellen

Artikel ; Online: Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity.

Reßing, Nina / Marquardt, Viktoria / Gertzen, Christoph G W / Schöler, Andrea / Schramm, Alexander / Kurz, Thomas / Gohlke, Holger / Aigner, Achim / Remke, Marc / Hansen, Finn K

MedChemComm

2018 Band 10, Heft 7, Seite(n) 1109–1115

Abstract: Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastoma and glioblastoma. In this work, we have rationally designed a novel class of peptoid-based histone deacetylase inhibitors (HDACi). A ...

Abstract	Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastoma and glioblastoma. In this work, we have rationally designed a novel class of peptoid-based histone deacetylase inhibitors (HDACi). A mini library of β-peptoid-capped HDACi was synthesized using a four-step protocol. All compounds were screened in biochemical assays for their inhibition of HDAC1 and HDAC6 and docking studies were performed to rationalize the observed selectivity profile. The synthesized compounds were further examined for tumor cell-inhibitory activity against a panel of neuroblastoma and glioblastoma cell lines. In particular, non-selective compounds with potent activity against HDAC1 and HDAC6 showed strong antiproliferative effects. The most promising HDACi, compound
Sprache	Englisch
Erscheinungsdatum	2018-10-23
Erscheinungsland	England
Dokumenttyp	Journal Article
ZDB-ID	2545949-1
ISSN	2040-2511 ; 2040-2503
ISSN (online)	2040-2511
ISSN	2040-2503
DOI	10.1039/c8md00454d
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

Zusatzmaterialien

Über subito bestellen

Details ▾
- Kostenpflichtig bestellen

Artikel: N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

Sci Rep

Abstract	N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.
Schlagwörter	covid19
Verlag	WHO
Dokumenttyp	Artikel
Anmerkung	WHO #Covidence: #32346009
Datenquelle	COVID19

Fernleihe an ZB MED

Sie können sich den gewünschten Titel als lokale Nutzerin oder lokaler Nutzer von ZB MED direkt an den Standort Köln schicken lassen.

Details ▾

Artikel ; Online: A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in

Molecular cancer therapeutics

2020 Band 19, Heft 8, Seite(n) 1736–1750

Abstract: Pilocytic astrocytomas as well as other pediatric low-grade gliomas (pLGG) exhibit genetic events leading to aberrant activation of the MAPK pathway. The most common alterations ... ...

Abstract	Pilocytic astrocytomas as well as other pediatric low-grade gliomas (pLGG) exhibit genetic events leading to aberrant activation of the MAPK pathway. The most common alterations are
Sprache	Englisch
Erscheinungsdatum	2020-05-25
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-19-1021
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

Zusatzmaterialien

Verfügbar in ZB MED Köln/Königswinter

Zs.A 5750: Hefte anzeigen

Standort:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

Über subito bestellen

Details ▾
- Im ZB MED-Bestand
- Kostenpflichtig bestellen

Artikel ; Online: Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines.

Stenzel, Katharina / Hamacher, Alexandra / Hansen, Finn K / Gertzen, Christoph G W / Senger, Johanna / Marquardt, Viktoria / Marek, Linda / Marek, Martin / Romier, Christophe / Remke, Marc / Jung, Manfred / Gohlke, Holger / Kassack, Matthias U / Kurz, Thomas

Journal of medicinal chemistry

2017 Band 60, Heft 13, Seite(n) 5334–5348

Abstract: The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of ... ...

Abstract	The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC
Mesh-Begriff(e)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cisplatin/chemistry ; Cisplatin/pharmacology ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Histone Deacetylase Inhibitors/chemical synthesis ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Structure-Activity Relationship ; Urea/analogs & derivatives ; Urea/chemistry ; Urea/pharmacology
Chemische Substanzen	Antineoplastic Agents ; Histone Deacetylase Inhibitors ; Urea (8W8T17847W) ; Histone Deacetylases (EC 3.5.1.98) ; Cisplatin (Q20Q21Q62J)
Sprache	Englisch
Erscheinungsdatum	2017-06-19
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.6b01538
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

Zusatzmaterialien

Verfügbar in ZB MED Köln/Königswinter

Zs.B 151: Hefte anzeigen			Standort: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MB 1: Hefte anzeigen

Über subito bestellen

Details ▾
- Im ZB MED-Bestand
- Kostenpflichtig bestellen

Artikel ; Online: The long non-coding RNA HOTAIRM1 promotes tumor aggressiveness and radiotherapy resistance in glioblastoma.

Ahmadov, Ulvi / Picard, Daniel / Bartl, Jasmin / Silginer, Manuela / Trajkovic-Arsic, Marija / Qin, Nan / Blümel, Lena / Wolter, Marietta / Lim, Jonathan K M / Pauck, David / Winkelkotte, Alina Marie / Melcher, Marlen / Langini, Maike / Marquardt, Viktoria / Sander, Felix / Stefanski, Anja / Steltgens, Sascha / Hassiepen, Christina / Kaufhold, Anna /

Meyer, Frauke-Dorothee / Seibt, Annette / Kleinesudeik, Lara / Hain, Anika / Münk, Carsten / Knobbe-Thomsen, Christiane Brigitte / Schramm, Alexander / Fischer, Ute / Leprivier, Gabriel / Stühler, Kai / Fulda, Simone / Siveke, Jens T / Distelmaier, Felix / Borkhardt, Arndt / Weller, Michael / Roth, Patrick / Reifenberger, Guido / Remke, Marc

Cell death & disease

2021 Band 12, Heft 10, Seite(n) 885

Abstract: Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non- ...

Abstract	Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
Mesh-Begriff(e)	Animals ; Carcinogenesis/genetics ; Carcinogenesis/pathology ; Cell Line, Tumor ; Cell Survival/genetics ; Clone Cells ; Down-Regulation/genetics ; Gene Expression Regulation, Neoplastic ; Glioblastoma/genetics ; Glioblastoma/pathology ; Glioblastoma/radiotherapy ; Humans ; Mice, Nude ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Mitochondria/metabolism ; Neoplasm Invasiveness ; Phenotype ; Prognosis ; Protein Glutamine gamma Glutamyltransferase 2/metabolism ; Proteogenomics ; RNA, Small Interfering/metabolism ; Radiation Tolerance/genetics ; Reactive Oxygen Species/metabolism ; Mice
Chemische Substanzen	MIRN17 microRNA, human ; MicroRNAs ; RNA, Small Interfering ; Reactive Oxygen Species ; long non-coding RNA HOTAIRM1, human ; Protein Glutamine gamma Glutamyltransferase 2 (EC 2.3.2.13)
Sprache	Englisch
Erscheinungsdatum	2021-09-28
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-021-04146-0
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

Zusatzmaterialien

Über subito bestellen

Details ▾
- Kostenpflichtig bestellen

Artikel ; Online: Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation.

Marquardt, Viktoria / Theruvath, Johanna / Pauck, David / Picard, Daniel / Qin, Nan / Blümel, Lena / Maue, Mara / Bartl, Jasmin / Ahmadov, Ulvi / Langini, Maike / Meyer, Frauke-Dorothee / Cole, Allison / Cruz-Cruz, Joselyn / Graef, Claus M / Wölfl, Matthias / Milde, Till / Witt, Olaf / Erdreich-Epstein, Anat / Leprivier, Gabriel /

Kahlert, Ulf / Stefanski, Anja / Stühler, Kai / Keir, Stephen T / Bigner, Darell D / Hauer, Julia / Beez, Thomas / Knobbe-Thomsen, Christiane B / Fischer, Ute / Felsberg, Jörg / Hansen, Finn K / Vibhakar, Rajeev / Venkatraman, Sujatha / Cheshier, Samuel H / Reifenberger, Guido / Borkhardt, Arndt / Kurz, Thomas / Remke, Marc / Mitra, Siddhartha

Journal for immunotherapy of cancer

2022 Band 11, Heft 1

Abstract: Background: While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an ... ...

Abstract	Background: While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway. Methods: We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models. Results: CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment ('eat-me') signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice. Conclusion: Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.
Mesh-Begriff(e)	Humans ; Mice ; Animals ; Medulloblastoma/drug therapy ; NF-kappa B/metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use ; Glioblastoma ; Protein Glutamine gamma Glutamyltransferase 2 ; Quality of Life ; Phagocytosis ; Macrophages ; Inflammation/metabolism ; Cerebellar Neoplasms
Chemische Substanzen	tacedinaline (UMF554N5FG) ; NF-kappa B ; Histone Deacetylase Inhibitors ; Protein Glutamine gamma Glutamyltransferase 2 (EC 2.3.2.13)
Sprache	Englisch
Erscheinungsdatum	2022-12-01
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-005871
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

Zusatzmaterialien

Über subito bestellen

Details ▾
- Kostenpflichtig bestellen

Artikel ; Online: The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors.

Bartl, Jasmin / Zanini, Marco / Bernardi, Flavia / Forget, Antoine / Blümel, Lena / Talbot, Julie / Picard, Daniel / Qin, Nan / Cancila, Gabriele / Gao, Qingsong / Nath, Soumav / Koumba, Idriss Mahoungou / Wolter, Marietta / Kuonen, François / Langini, Maike / Beez, Thomas / Munoz, Christopher / Pauck, David / Marquardt, Viktoria /

Yu, Hua / Souphron, Judith / Korsch, Mascha / Mölders, Christina / Berger, Daniel / Göbbels, Sarah / Meyer, Frauke-Dorothee / Scheffler, Björn / Rotblat, Barak / Diederichs, Sven / Ramaswamy, Vijay / Suzuki, Hiromishi / Oro, Anthony / Stühler, Kai / Stefanski, Anja / Fischer, Ute / Leprivier, Gabriel / Willbold, Dieter / Steger, Gerhard / Buell, Alexander / Kool, Marcel / Lichter, Peter / Pfister, Stefan M / Northcott, Paul A / Taylor, Michael D / Borkhardt, Arndt / Reifenberger, Guido / Ayrault, Olivier / Remke, Marc

Nature communications

2022 Band 13, Heft 1, Seite(n) 4061

Abstract: Most lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) ... ...

Abstract	Most lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) signaling is aberrantly activated in several human cancer entities. We unravel that aberrant expression of the primate-specific lncRNA HedgeHog Interacting Protein-AntiSense 1 (HHIP-AS1) is a hallmark of SHH-driven tumors including medulloblastoma and atypical teratoid/rhabdoid tumors. HHIP-AS1 is actively transcribed from a bidirectional promoter shared with SHH regulator HHIP. Knockdown of HHIP-AS1 induces mitotic spindle deregulation impairing tumorigenicity in vitro and in vivo. Mechanistically, HHIP-AS1 binds directly to the mRNA of cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2) and attenuates its degradation by hsa-miR-425-5p. We uncover that neither HHIP-AS1 nor the corresponding regulatory element in DYNC1I2 are evolutionary conserved in mice. Taken together, we discover an lncRNA-mediated mechanism that enables the pro-mitotic effects of SHH pathway activation in human tumors.
Mesh-Begriff(e)	Animals ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cerebellar Neoplasms/genetics ; Dyneins/metabolism ; Gene Expression Regulation, Neoplastic ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Humans ; Medulloblastoma/genetics ; Membrane Glycoproteins/metabolism ; Mice ; MicroRNAs/genetics ; RNA, Long Noncoding/genetics
Chemische Substanzen	Carrier Proteins ; HHIP protein, human ; Hedgehog Proteins ; Hhip protein, mouse ; Membrane Glycoproteins ; MicroRNAs ; RNA, Long Noncoding ; SHH protein, human ; Shh protein, mouse ; Dyneins (EC 3.6.4.2)
Sprache	Englisch
Erscheinungsdatum	2022-07-13
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-31574-z
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

Zusatzmaterialien

Über subito bestellen

Details ▾
- Kostenpflichtig bestellen

Artikel ; Online: Design, synthesis and 3D-QSAR studies of novel 1,4-dihydropyridines as TGFβ/Smad inhibitors.

Längle, Daniel / Marquardt, Viktoria / Heider, Elena / Vigante, Brigita / Duburs, Gunars / Luntena, Iveta / Flötgen, Dirk / Golz, Christopher / Strohmann, Carsten / Koch, Oliver / Schade, Dennis

European journal of medicinal chemistry

2015 Band 95, Seite(n) 249–266

Abstract: Targeting TGFβ/Smad signaling is an attractive strategy for several therapeutic applications given its role as a key player in many pathologies, including cancer, autoimmune diseases and fibrosis. The class of b-annelated 1,4-dihydropyridines (DHPs) ... ...

Abstract	Targeting TGFβ/Smad signaling is an attractive strategy for several therapeutic applications given its role as a key player in many pathologies, including cancer, autoimmune diseases and fibrosis. The class of b-annelated 1,4-dihydropyridines (DHPs) represents promising novel pharmacological tools as they interfere with this pathway in a novel fashion, i.e. through induction of TGFβ receptor type II degradation. In the present work, >40 rationally designed, novel DHPs were synthesized and evaluated for TGFβ inhibition, substantially expanding the current understanding of the SAR profile. Key findings include that the 2-position tolerates a wide variety of polar functionalities, suggesting that this region could possibly be solvent-exposed within the (thus far) unknown cellular target. A structural explanation for pathway selectivity is provided based on a diverse series of 4″-substituted DHPs, including molecular electrostatic potential (MEP) calculations. Moreover, the absolute configuration for the chiral 4-position was determined by X-ray crystal analysis and revealed that the bioactive (+)-enantiomers are (R)-configured. Another key objective was to establish a 3D-QSAR model which turned out to be robust (r(2) = 0.93) with a good predictive power (r(2)pred = 0.69). This data further reinforces the hypothesis that this type of DHPs exerts its novel TGFβ inhibitory mode of action through binding a distinct target and that unspecific activities that would derive from intrinsic properties of the ligands (e.g., lipophilicity) play a negligible role. Therefore, the present study provides a solid basis for further ligand-based design of additional analogs or DHP scaffold-derived compounds for hit-to-lead optimization, required for more comprehensive pharmacological studies in vivo.
Mesh-Begriff(e)	Chemistry Techniques, Synthetic ; Dihydropyridines/chemical synthesis ; Dihydropyridines/chemistry ; Dihydropyridines/pharmacology ; Drug Design ; HEK293 Cells ; Humans ; Models, Molecular ; Protein Conformation ; Quantitative Structure-Activity Relationship ; Smad Proteins/antagonists & inhibitors ; Transforming Growth Factor beta/antagonists & inhibitors ; Transforming Growth Factor beta/chemistry
Chemische Substanzen	Dihydropyridines ; Smad Proteins ; Transforming Growth Factor beta ; 1,4-dihydropyridine (7M8K3P6I89)
Sprache	Englisch
Erscheinungsdatum	2015-05-05
Erscheinungsland	France
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2015.03.027
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

Volltext online

Zugriff für angemeldete ZB MED Nutzerinnen und Nutzer

Zusatzmaterialien

Verfügbar in ZB MED Köln/Königswinter

Zs.B 784: Hefte anzeigen

Standort:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
ab Jg. 2022: Lesesaal (EG)

Über subito bestellen

Details ▾

Zum Seitenanfang

Ihre letzten Suchen

Volltext online

Zusatzmaterialien

Kategorien

Fernleihe an ZB MED

Zusatzmaterialien

Kategorien

Über subito bestellen

Zusatzmaterialien

Kategorien

Über subito bestellen

Kategorien

Fernleihe an ZB MED

Zusatzmaterialien

Kategorien

Verfügbar in ZB MED Köln/Königswinter

Über subito bestellen

Zusatzmaterialien

Kategorien

Verfügbar in ZB MED Köln/Königswinter

Über subito bestellen

Zusatzmaterialien

Kategorien

Über subito bestellen

Zusatzmaterialien

Kategorien

Über subito bestellen

Zusatzmaterialien

Kategorien

Über subito bestellen

Volltext online

Zusatzmaterialien

Kategorien

Verfügbar in ZB MED Köln/Königswinter

Über subito bestellen