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Artikel ; Online: Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent.

Hackler, László / Gyuris, Márió / Huzián, Orsolya / Alföldi, Róbert / Szebeni, Gábor J / Madácsi, Ramóna / Knapp, Levente / Kanizsai, Iván / Puskás, László G

Molecules (Basel, Switzerland)

2019 Band 24, Heft 23

Abstract: Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer's disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a ... ...

Abstract	Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer's disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization.
Mesh-Begriff(e)	Cell Line, Tumor ; Flow Cytometry ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Humans ; Hydroxyquinolines/chemical synthesis ; Hydroxyquinolines/chemistry ; Hydroxyquinolines/pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit/chemistry ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Oxyquinoline/analogs & derivatives ; Protein Stability/drug effects ; Quinidine/chemistry ; Quinine/chemistry ; Stereoisomerism
Chemische Substanzen	HIF1A protein, human ; Hydroxyquinolines ; Hypoxia-Inducible Factor 1, alpha Subunit ; Oxyquinoline (5UTX5635HP) ; Quinine (A7V27PHC7A) ; Quinidine (ITX08688JL)
Sprache	Englisch
Erscheinungsdatum	2019-11-23
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules24234269
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Synthesis and Cytoprotective Characterization of 8-Hydroxyquinoline Betti Products.

Kanizsai, Iván / Madácsi, Ramóna / Hackler, László / Gyuris, Márió / Szebeni, Gábor J / Huzián, Orsolya / Puskás, László G

Molecules (Basel, Switzerland)

2018 Band 23, Heft 8

Abstract: The 8-hydroxyquinoline pharmacophore scaffold has been shown to possess a range of activities as metal chelation, enzyme inhibition, cytotoxicity, and cytoprotection. Based on our previous findings we set out to optimize the scaffold for cytoprotective ... ...

Abstract	The 8-hydroxyquinoline pharmacophore scaffold has been shown to possess a range of activities as metal chelation, enzyme inhibition, cytotoxicity, and cytoprotection. Based on our previous findings we set out to optimize the scaffold for cytoprotective activity for its potential application in central nervous system related diseases. A 48-membered Betti-library was constructed by the utilization of formic acid mediated industrial-compatible coupling with sets of aromatic primary amines such as anilines, oxazoles, pyridines, and pyrimidines, with (hetero)aromatic aldehydes and 8-hydroxiquinoline derivatives. After column chromatography and re-crystallization, the corresponding analogues were obtained in yields of 13⁻90%. The synthesized analogs were optimized with the utilization of a cytoprotection assay with chemically induced oxidative stress, and the most active compounds were further tested in orthogonal assays, a real time cell viability method, a fluorescence-activated cell sorting (FACS)-based assay measuring mitochondrial membrane potential changes, and gene expression analysis. The best candidates showed potent, nanomolar activity in all test systems and support the need for future studies in animal models of central nervous system (CNS) disorders.
Mesh-Begriff(e)	Aldehydes/chemistry ; Aniline Compounds/chemistry ; Cell Death/drug effects ; Cell Line ; Cell Survival/drug effects ; Cytoprotection/drug effects ; Gene Expression Regulation/drug effects ; Humans ; Hypoxia/genetics ; Inhibitory Concentration 50 ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Oxyquinoline/chemical synthesis ; Oxyquinoline/chemistry ; Oxyquinoline/pharmacology ; Structure-Activity Relationship
Chemische Substanzen	Aldehydes ; Aniline Compounds ; Oxyquinoline (5UTX5635HP) ; aniline (SIR7XX2F1K)
Sprache	Englisch
Erscheinungsdatum	2018-08-02
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules23081934
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: A vas(III) es a kitozán közötti kölcsönhatás természete es a vas(III)-kitozán "komplex" szerkezete.

Sipos, Pál / Berkesi, Ottó / Tombácz, Etelka / Katona, Hajnalka / Madácsi, Ramóna

Acta pharmaceutica Hungarica

2007 Band 77, Heft 3, Seite(n) 165–175

Abstract: The interactions between the cationic polymer chitosan (a copolymer, consisting mainly of 2-amino-2-deoxy-D-glucopyranose and, to a lesser extent, of 2-acetamido-2-deoxy-D-glucopyranose, Chit) and iron(III) were investigated. The solution properties were ...

Titelübersetzung	The nature of interactions between iron(III) and the structure of the Fe(III)-chitosan "complex".
Abstract	The interactions between the cationic polymer chitosan (a copolymer, consisting mainly of 2-amino-2-deoxy-D-glucopyranose and, to a lesser extent, of 2-acetamido-2-deoxy-D-glucopyranose, Chit) and iron(III) were investigated. The solution properties were studied by pH-metry, UV-Vis spectrophotometry and viscometry. Solid state iron(III)-Chit samples were also prepared and characterized by IR-spectroscopy and electronmicroscopy. In aqueous solutions, the precipitation pH of the FeO(OH) is significantly shifted towards the higher pH-s in presence of Chit. However, the additivity of the pH-metric titration curves, the lack of variation both in tin presence and absence of iron(III), indicate that there is no specific coordination chemical interaction between the Chit and ferric ions. It is well established that spherical FeO(OH) particles with afew nm diameter, morphologically similar to the core of the iron(III)-storage protein ferritin, are formed during the hydrolysis of iron(III) even in the absence of complexing agents. Such isolated FeO(OH) spheres were observed in samples obtained from solutions containing iron(III) and Chit. The fact, that visible precipitation of FeO(OH) can only be observed, when the Chit itself precipitates from aqueous solutions (i.e., pH approximately 7), indicates that the role of Chit in these systems is to inhibit the aggregation of the subcolloidal FeO(OH) particles. These observations are in strong contrast with those obtained for interactions between iron(III) and various anionic biopolymers, such as heparin, hyaluronate, dextran sulfate and chondroitin sulphate A and C, and suggest that coordination chemical interactions play very important role in determining the nanostructure of composite materials containing iron(III) and polysaccharides.
Mesh-Begriff(e)	Binding Sites ; Biocompatible Materials ; Chitosan/chemistry ; Ferric Compounds/chemistry ; Hydrogen-Ion Concentration ; Kinetics ; Solutions ; Spectrophotometry, Infrared
Chemische Substanzen	Biocompatible Materials ; Ferric Compounds ; Solutions ; Chitosan (9012-76-4)
Sprache	Ungarisch
Erscheinungsdatum	2007
Erscheinungsland	Hungary
Dokumenttyp	English Abstract ; Journal Article
ZDB-ID	392228-5
ISSN	0001-6659
ISSN	0001-6659
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Aromatic sulfonamides containing a condensed piperidine moiety as potential oxidative stress-inducing anticancer agents.

Madácsi, Ramóna / Kanizsai, Iván / Fehér, Liliána Z / Gyuris, Márió / Ozsvári, Béla / Erdélyi, András / Wölfling, János / Puskás, László G

Medicinal chemistry (Shariqah (United Arab Emirates))

2012 Band 9, Heft 7, Seite(n) 911–919

Abstract: A 30-membered piperidine ring-fused aromatic sulfonamide library was synthetized, including N-arylsulfonyl 1,2,3,4-tetrahydroquinolines, 1,2,3,4-tetrahydroisoquinolines and 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles. The compounds induced oxidative ... ...

Abstract	A 30-membered piperidine ring-fused aromatic sulfonamide library was synthetized, including N-arylsulfonyl 1,2,3,4-tetrahydroquinolines, 1,2,3,4-tetrahydroisoquinolines and 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles. The compounds induced oxidative stress and glutathione depletion in HT168 melanoma and K562 leukemia cells and in micromolar concentrations exerted cytotoxic effects. Among the tested sulfonamides, compounds 21, 22, 23, 35 and 41 exhibited 100% cytotoxic effects with low (< 10 µM) EC50 values on K562 cells. The cytotoxicity of lead compound 22 was investigated in 24 different cancer cell lines, and it was found to be active against leukemia, melanoma, glioblastoma, and liver, breast and lung cancer cells, as confirmed by classical biochemical and holographic microscopic analyses.
Mesh-Begriff(e)	Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Inhibitory Concentration 50 ; K562 Cells ; Molecular Structure ; Oxidative Stress/drug effects ; Piperidines/chemistry ; Structure-Activity Relationship ; Sulfonamides/chemical synthesis ; Sulfonamides/chemistry ; Sulfonamides/pharmacology
Chemische Substanzen	Antineoplastic Agents ; Piperidines ; Sulfonamides ; piperidine (67I85E138Y)
Sprache	Englisch
Erscheinungsdatum	2012-09-01
Erscheinungsland	Netherlands
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1875-6638
ISSN (online)	1875-6638
DOI	10.2174/1573406411309070004
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: A cell-microelectronic sensing technique for the screening of cytoprotective compounds.

Ozsvári, Béla / Puskás, László G / Nagy, Lajos I / Kanizsai, Iván / Gyuris, Márió / Madácsi, Ramóna / Fehér, Liliána Z / Gerö, Domokos / Szabó, Csaba

International journal of molecular medicine

2010 Band 25, Heft 4, Seite(n) 525–530

Abstract: In recent years, a new cell-based high throughput paradigm has emerged, which seeks to identify novel, pharmacologically active cytoprotective compounds. The essence of this approach is to create experimental models of cell injury relevant for a ... ...

Abstract	In recent years, a new cell-based high throughput paradigm has emerged, which seeks to identify novel, pharmacologically active cytoprotective compounds. The essence of this approach is to create experimental models of cell injury relevant for a particular disease by establishing in vitro cell-based models, followed by high-throughput testing of compounds that affect the cellular response in a desired manner. Prior approaches typically used simple end-point analyses. To assess the cytoprotective effects of novel drug candidates in real-time, we have applied a cell-microelectronic sensing technique (RT-CES), which measures changes in the impedance of individual microelectronic wells that correlates linearly with cell index (reflecting cell number, adherence and cell growth), thereby allowing the continuous determination of cell viability during oxidative stress. In vitro cytotoxicity was elicited by hydrogen peroxide in myocytes (H9c2) and hepatocytes (Hep3B). Cells were post-treated at 30 min with various reference molecules and novel cytoprotective compounds. Cytoprotection detected in the RT-CES system correlated well with the results of two classical end-point-based methods (improvement in MTT and reduction of LDH release). The RT-CES method, when used as described in the current report, is suitable for the screening of molecular libraries to identify molecules or molecule combinations that attenuate oxidative stress-induced cell damage.
Mesh-Begriff(e)	Animals ; Biosensing Techniques/methods ; Cell Line ; Cell Survival/drug effects ; Cytoprotection/drug effects ; Drug Evaluation, Preclinical/methods ; Electronics/methods ; Microscopy, Fluorescence ; Oxidative Stress/drug effects ; Rats ; Small Molecule Libraries/analysis ; Small Molecule Libraries/pharmacology
Chemische Substanzen	Small Molecule Libraries
Sprache	Englisch
Erscheinungsdatum	2010-03-01
Erscheinungsland	Greece
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1444428-8
ISSN	1791-244X ; 1107-3756
ISSN (online)	1791-244X
ISSN	1107-3756
DOI	10.3892/ijmm_00000373
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Lipid droplet binding thalidomide analogs activate endoplasmic reticulum stress and suppress hepatocellular carcinoma in a chemically induced transgenic mouse model.

Nagy, Lajos I / Molnár, Eszter / Kanizsai, Iván / Madácsi, Ramóna / Ózsvári, Béla / Fehér, Liliána Z / Fábián, Gabriella / Marton, Annamária / Vizler, Csaba / Ayaydin, Ferhan / Kitajka, Klára / Hackler, László / Mátés, Lajos / Deák, Ferenc / Kiss, Ibolya / Puskás, László G

Lipids in health and disease

2013 Band 12, Seite(n) 175

Abstract: Background: Hepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and it has limited treatment options.: Results: In this study, we report the in vitro and in vivo effects of two novel amino-trifluoro- ... ...

Abstract	Background: Hepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and it has limited treatment options. Results: In this study, we report the in vitro and in vivo effects of two novel amino-trifluoro-phtalimide analogs, Ac-915 and Ac-2010. Both compounds bind lipid droplets and endoplasmic reticulum membrane, and interact with several proteins with chaperone functions (HSP60, HSP70, HSP90, and protein disulfide isomerase) as determined by affinity chromatography and resonant waveguide optical biosensor technology. Both compounds inhibited protein disulfide isomerase activity and induced cell death of different HCC cells at sub or low micromolar ranges detected by classical biochemical end-point assay as well as with real-time label-free measurements. Besides cell proliferation inhibiton, analogs also inhibited cell migration even at 250 nM. Relative biodistribution of the analogs was analysed in native tissue sections of different organs after administration of drugs, and by using fluorescent confocal microscopy based on the inherent blue fluorescence of the compounds. The analogs mainly accumulated in the liver. The effects of Ac-915 and Ac-2010 were also demonstrated on the advanced stages of hepatocarcinogenesis in a transgenic mouse model of N-nitrosodiethylamine (DEN)-induced HCC. Significantly less tumor development was found in the livers of the Ac-915- or Ac-2010-treated groups compared with control mice, characterized by less liver tumor incidence, fewer tumors and smaller tumor size. Conclusion: These results imply that these amino-trifluoro-phthalimide analogs could serve potent clinical candidates against HCC alone or in combination with dietary polyunsaturated fatty acids.
Mesh-Begriff(e)	Animals ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Carcinoma, Hepatocellular/chemically induced ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Chaperonin 60/genetics ; Chaperonin 60/metabolism ; Diethylnitrosamine ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Endoplasmic Reticulum Stress/genetics ; Female ; Gene Expression ; HSP70 Heat-Shock Proteins/genetics ; HSP70 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/genetics ; HSP90 Heat-Shock Proteins/metabolism ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Humans ; Lipids/chemistry ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Liver Neoplasms/chemically induced ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Mice ; Mice, Transgenic ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Thalidomide/analogs & derivatives ; Thalidomide/pharmacokinetics ; Thalidomide/pharmacology ; Tumor Burden/drug effects
Chemische Substanzen	Antineoplastic Agents ; Chaperonin 60 ; HSP70 Heat-Shock Proteins ; HSP90 Heat-Shock Proteins ; Hspd1 protein, mouse ; Lipids ; Mitochondrial Proteins ; Diethylnitrosamine (3IQ78TTX1A) ; Thalidomide (4Z8R6ORS6L)
Sprache	Englisch
Erscheinungsdatum	2013-11-22
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1476-511X
ISSN (online)	1476-511X
DOI	10.1186/1476-511X-12-175
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells

Madácsi Ramóna / Kanizsai Iván / Gyuris Márió / Magyary István / Molnár Eszter / Rásó Erzsébet / Ayaydin Ferhan / Vizler Csaba / Fehér Liliána Z / Puskás László G / Fábián Gabriella / Farkas Klaudia / Hegyi Péter / Baska Ferenc / Ózsvári Béla / Kitajka Klára

Lipids in Health and Disease, Vol 9, Iss 1, p

2010 Band 56

Abstract: Abstract Background Cytoplasmic lipid-droplets are common inclusions of eukaryotic cells. Lipid-droplet binding thalidomide analogs (2,6-dialkylphenyl-4/5-amino-substituted-5,6,7-trifluorophthalimides) with potent anticancer activities were synthesized. ... ...

Abstract	Abstract Background Cytoplasmic lipid-droplets are common inclusions of eukaryotic cells. Lipid-droplet binding thalidomide analogs (2,6-dialkylphenyl-4/5-amino-substituted-5,6,7-trifluorophthalimides) with potent anticancer activities were synthesized. Results Cytotoxicity was detected in different cell lines including melanoma, leukemia, hepatocellular carcinoma, glioblastoma at micromolar concentrations. The synthesized analogs are non-toxic to adult animals up to 1 g/kg but are teratogenic to zebrafish embryos at micromolar concentrations with defects in the developing muscle. Treatment of tumor cells resulted in calcium release from the endoplasmic reticulum (ER), induction of reactive oxygen species (ROS), ER stress and cell death. Antioxidants could partially, while an intracellular calcium chelator almost completely diminish ROS production. Exogenous docosahexaenoic acid or eicosapentaenoic acid induced calcium release and ROS generation, and synergized with the analogs in vitro , while oleic acid had no such an effect. Gene expression analysis confirmed the induction of ER stress-mediated apoptosis pathway components, such as GADD153, ATF3, Luman/CREB3 and the ER-associated degradation-related HERPUD1 genes. Tumor suppressors, P53, LATS2 and ING3 were also up-regulated in various cell lines after drug treatment. Amino-phthalimides down-regulated the expression of CCL2, which is implicated in tumor metastasis and angiogenesis. Conclusions Because of the anticancer, anti-angiogenic action and the wide range of applicability of the immunomodulatory drugs, including thalidomide analogs, lipid droplet-binding members of this family could represent a new class of agents by affecting ER-membrane integrity and perturbations of ER homeostasis.
Schlagwörter	Physiology ; QP1-981 ; Science ; Q ; DOAJ:Physiology ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
Thema/Rubrik (Code)	572
Sprache	Englisch
Erscheinungsdatum	2010-06-01T00:00:00Z
Verlag	BioMed Central
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Quantification of punctate iron sources using magnetic resonance phase.

McAuley, Grant / Schrag, Matthew / Sipos, Pál / Sun, Shu-Wei / Obenaus, Andre / Neelavalli, Jaladhar / Haacke, E Mark / Holshouser, Barbara / Madácsi, Ramóna / Kirsch, Wolff

Magnetic resonance in medicine

2010 Band 63, Heft 1, Seite(n) 106–115

Abstract: Iron-mediated tissue damage is present in cerebrovascular and neurodegenerative diseases and neurotrauma. Brain microbleeds are often present in these maladies and are assuming increasing clinical importance. Because brain microbleeds present a source of ...

Abstract	Iron-mediated tissue damage is present in cerebrovascular and neurodegenerative diseases and neurotrauma. Brain microbleeds are often present in these maladies and are assuming increasing clinical importance. Because brain microbleeds present a source of pathologic iron to the brain, the noninvasive quantification of this iron pool is potentially valuable. Past efforts to quantify brain iron have focused on content estimation within distributed brain regions. In addition, conventional approaches using "magnitude" images have met significant limitations. In this study, a technique is presented to quantify the iron content of punctate samples using phase images. Samples are modeled as magnetic dipoles and phase shifts due to local dipole field perturbations are mathematically related to sample iron content and radius using easily recognized geometric features in phase images. Phantoms containing samples of a chitosan-ferric oxyhydroxide composite (which serves as a mimic for hemosiderin) were scanned with a susceptibility-weighted imaging sequence at 11.7 T. Plots relating sample iron content and radius to phase image features were compared to theoretical predictions. The primary result is the validation of the technique by the excellent agreement between theory and the iron content plot. This research is a potential first step toward quantification of punctate brain iron sources such as brain microbleeds.
Mesh-Begriff(e)	Algorithms ; Cerebral Hemorrhage/diagnosis ; Cerebral Hemorrhage/metabolism ; Humans ; Image Enhancement/methods ; Image Interpretation, Computer-Assisted/methods ; Iron/analysis ; Magnetic Resonance Imaging/instrumentation ; Magnetic Resonance Imaging/methods ; Magnetic Resonance Spectroscopy/instrumentation ; Magnetic Resonance Spectroscopy/methods ; Phantoms, Imaging ; Reproducibility of Results ; Sensitivity and Specificity
Chemische Substanzen	Iron (E1UOL152H7)
Sprache	Englisch
Erscheinungsdatum	2010-01
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	605774-3
ISSN	1522-2594 ; 0740-3194
ISSN (online)	1522-2594
ISSN	0740-3194
DOI	10.1002/mrm.22185
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells.

Puskás, László G / Fehér, Liliána Z / Vizler, Csaba / Ayaydin, Ferhan / Rásó, Erzsébet / Molnár, Eszter / Magyary, István / Kanizsai, Iván / Gyuris, Márió / Madácsi, Ramóna / Fábián, Gabriella / Farkas, Klaudia / Hegyi, Péter / Baska, Ferenc / Ozsvári, Béla / Kitajka, Klára

Lipids in health and disease

2010 Band 9, Seite(n) 56

Abstract: Background: Cytoplasmic lipid-droplets are common inclusions of eukaryotic cells. Lipid-droplet binding thalidomide analogs (2,6-dialkylphenyl-4/5-amino-substituted-5,6,7-trifluorophthalimides) with potent anticancer activities were synthesized.: ... ...

Abstract	Background: Cytoplasmic lipid-droplets are common inclusions of eukaryotic cells. Lipid-droplet binding thalidomide analogs (2,6-dialkylphenyl-4/5-amino-substituted-5,6,7-trifluorophthalimides) with potent anticancer activities were synthesized. Results: Cytotoxicity was detected in different cell lines including melanoma, leukemia, hepatocellular carcinoma, glioblastoma at micromolar concentrations. The synthesized analogs are non-toxic to adult animals up to 1 g/kg but are teratogenic to zebrafish embryos at micromolar concentrations with defects in the developing muscle. Treatment of tumor cells resulted in calcium release from the endoplasmic reticulum (ER), induction of reactive oxygen species (ROS), ER stress and cell death. Antioxidants could partially, while an intracellular calcium chelator almost completely diminish ROS production. Exogenous docosahexaenoic acid or eicosapentaenoic acid induced calcium release and ROS generation, and synergized with the analogs in vitro, while oleic acid had no such an effect. Gene expression analysis confirmed the induction of ER stress-mediated apoptosis pathway components, such as GADD153, ATF3, Luman/CREB3 and the ER-associated degradation-related HERPUD1 genes. Tumor suppressors, P53, LATS2 and ING3 were also up-regulated in various cell lines after drug treatment. Amino-phthalimides down-regulated the expression of CCL2, which is implicated in tumor metastasis and angiogenesis. Conclusions: Because of the anticancer, anti-angiogenic action and the wide range of applicability of the immunomodulatory drugs, including thalidomide analogs, lipid droplet-binding members of this family could represent a new class of agents by affecting ER-membrane integrity and perturbations of ER homeostasis.
Mesh-Begriff(e)	Animals ; Cell Line, Tumor ; Drug Synergism ; Embryo, Nonmammalian ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum/ultrastructure ; Fatty Acids, Unsaturated/pharmacology ; Homeostasis ; Humans ; Neoplasms/metabolism ; Neoplasms/pathology ; Oxidative Stress/drug effects ; Thalidomide/analogs & derivatives ; Thalidomide/pharmacology ; Zebrafish
Chemische Substanzen	Fatty Acids, Unsaturated ; Thalidomide (4Z8R6ORS6L)
Sprache	Englisch
Erscheinungsdatum	2010-06-02
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1476-511X
ISSN (online)	1476-511X
DOI	10.1186/1476-511X-9-56
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Verfügbar in ZB MED Köln/Königswinter

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Verfügbar in ZB MED Köln/Königswinter

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Verfügbar in ZB MED Köln/Königswinter

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