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  1. Article ; Online: Targeting YB-1 via entinostat enhances cisplatin sensitivity of pleural mesothelioma in vitro and in vivo.

    Schelch, Karin / Emminger, Dominik / Zitta, Benjamin / Johnson, Thomas G / Kopatz, Verena / Eder, Sebastian / Ries, Alexander / Stefanelli, Alessia / Heffeter, Petra / Hoda, Mir A / Hoetzenecker, Konrad / Dome, Balazs / Berger, Walter / Reid, Glen / Grusch, Michael

    Cancer letters

    2023  Volume 574, Page(s) 216395

    Abstract: Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB- ...

    Abstract Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.
    Language English
    Publishing date 2023-09-18
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2023.216395
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1177: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  2. Article ; Online: Carboplatin-induced upregulation of pan β-tubulin and class III β-tubulin is implicated in acquired resistance and cross-resistance of ovarian cancer.

    Pernar Kovač, Margareta / Tadić, Vanja / Kralj, Juran / Duran, George E / Stefanelli, Alessia / Stupin Polančec, Darija / Dabelić, Sanja / Bačić, Niko / Tomicic, Maja T / Heffeter, Petra / Sikic, Branimir I / Brozovic, Anamaria

    Cellular and molecular life sciences : CMLS

    2023  Volume 80, Issue 10, Page(s) 294

    Abstract: Resistance to platinum- and taxane-based chemotherapy represents a major obstacle to long-term survival in ovarian cancer (OC) patients. Here, we studied the interplay between acquired carboplatin (CBP) resistance using two OC cell models, MES-OV CBP and ...

    Abstract Resistance to platinum- and taxane-based chemotherapy represents a major obstacle to long-term survival in ovarian cancer (OC) patients. Here, we studied the interplay between acquired carboplatin (CBP) resistance using two OC cell models, MES-OV CBP and SK-OV-3 CBP, and non-P-glycoprotein-mediated cross-resistance to paclitaxel (TAX) observed only in MES-OV CBP cells. Decreased platination, mesenchymal-like phenotype, and increased expression of α- and γ-tubulin were observed in both drug-resistant variants compared with parental cells. Both variants revealed increased protein expression of class III β-tubulin (TUBB3) but differences in TUBB3 branching and nuclear morphology. Transient silencing of TUBB3 sensitized MES-OV CBP cells to TAX, and surprisingly also to CBP. This phenomenon was not observed in the SK-OV-3 CBP variant, probably due to the compensation by other β-tubulin isotypes. Reduced TUBB3 levels in MES-OV CBP cells affected DNA repair protein trafficking and increased whole-cell platination level. Furthermore, TUBB3 depletion augmented therapeutic efficiency in additional OC cells, showing vice versa drug-resistant pattern, lacking β-tubulin isotype compensation visible at the level of total β-tubulin (TUBB) in vitro and ex vivo. In summary, the level of TUBB in OC should be considered together with TUBB3 in therapy response prediction.
    MeSH term(s) Humans ; Female ; Carboplatin/pharmacology ; Carboplatin/therapeutic use ; Up-Regulation ; Tubulin/genetics ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Transcriptional Activation
    Chemical Substances Carboplatin (BG3F62OND5) ; Tubulin
    Language English
    Publishing date 2023-09-17
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-023-04943-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 195: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands.

    Teixeira, Ricardo G / Stefanelli, Alessia / Pilon, Adhan / Warmers, Rebecca / Fontrodona, Xavier / Romero, Isabel / Costa, Paulo J / Villa de Brito, Maria J / Hudec, Xenia / Pirker, Christine / Türck, Sebastian / Antunes, Alexandra M M / Kowol, Christian R / Ott, Ingo / Brozovic, Anamaria / Sombke, Andy / Eckhard, Margret / Tomaz, Ana Isabel / Heffeter, Petra /
    Valente, Andreia

    Journal of medicinal chemistry

    2024  Volume 67, Issue 8, Page(s) 6081–6098

    Abstract: In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane ( ... ...

    Abstract In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh
    MeSH term(s) Humans ; Phosphines/chemistry ; Phosphines/pharmacology ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/chemical synthesis ; Silver/chemistry ; Silver/pharmacology ; 2,2'-Dipyridyl/chemistry ; 2,2'-Dipyridyl/pharmacology ; Cell Line, Tumor ; Coordination Complexes/pharmacology ; Coordination Complexes/chemistry ; Coordination Complexes/chemical synthesis ; Apoptosis/drug effects ; Crystallography, X-Ray ; Ligands ; Cell Death/drug effects ; Drug Screening Assays, Antitumor ; Structure-Activity Relationship ; Drug Resistance, Neoplasm/drug effects
    Chemical Substances Phosphines ; Antineoplastic Agents ; Silver (3M4G523W1G) ; 2,2'-Dipyridyl (551W113ZEP) ; Coordination Complexes ; phosphine (FW6947296I) ; Ligands
    Language English
    Publishing date 2024-02-24
    Publishing country United States
    Document type 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.3c01036
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
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  4. Article: Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance.

    Pósa, Vivien / Stefanelli, Alessia / Nunes, Julia H Bormio / Hager, Sonja / Mathuber, Marlene / May, Nóra V / Berger, Walter / Keppler, Bernhard K / Kowol, Christian R / Enyedy, Éva A / Heffeter, Petra

    Cancers

    2022  Volume 14, Issue 18

    Abstract: COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. ...

    Abstract COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe
    Language English
    Publishing date 2022-09-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers14184455
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Cancer Cell Resistance Against the Clinically Investigated Thiosemicarbazone COTI-2 Is Based on Formation of Intracellular Copper Complex Glutathione Adducts and ABCC1-Mediated Efflux.

    Bormio Nunes, Julia H / Hager, Sonja / Mathuber, Marlene / Pósa, Vivien / Roller, Alexander / Enyedy, Éva A / Stefanelli, Alessia / Berger, Walter / Keppler, Bernhard K / Heffeter, Petra / Kowol, Christian R

    Journal of medicinal chemistry

    2020  Volume 63, Issue 22, Page(s) 13719–13732

    Abstract: COTI-2 is a novel anticancer thiosemicarbazone in phase I clinical trial. However, the effects of metal complexation (a main characteristic of thiosemicarbazones) and acquired resistance mechanisms are widely unknown. Therefore, in this study, the copper ...

    Abstract COTI-2 is a novel anticancer thiosemicarbazone in phase I clinical trial. However, the effects of metal complexation (a main characteristic of thiosemicarbazones) and acquired resistance mechanisms are widely unknown. Therefore, in this study, the copper and iron complexes of COTI-2 were synthesized and evaluated for their anticancer activity and impact on drug resistance in comparison to metal-free thiosemicarbazones. Investigations using Triapine-resistant SW480/Tria and newly established COTI-2-resistant SW480/Coti cells revealed distinct structure-activity relationships. SW480/Coti cells were found to overexpress ABCC1, and COTI-2 being a substrate for this efflux pump. This was unexpected, as ABCC1 has strong selectivity for glutathione adducts. The recognition by ABCC1 could be explained by the reduction kinetics of a ternary Cu-COTI-2 complex with glutathione. Thus, only thiosemicarbazones forming stable, nonreducible copper(II)-glutathione adducts are recognized and, in turn, effluxed by ABCC1. This reveals a crucial connection between copper complex chemistry, glutathione interaction, and the resistance profile of clinically relevant thiosemicarbazones.
    MeSH term(s) Aminoquinolines/chemistry ; Aminoquinolines/metabolism ; Aminoquinolines/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Copper/chemistry ; Copper/metabolism ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/physiology ; Glutathione/chemistry ; Glutathione/metabolism ; Humans ; Intracellular Fluid/drug effects ; Intracellular Fluid/metabolism ; Multidrug Resistance-Associated Proteins/metabolism ; Thiosemicarbazones/chemistry ; Thiosemicarbazones/metabolism ; Thiosemicarbazones/pharmacology ; X-Ray Diffraction
    Chemical Substances Aminoquinolines ; Antineoplastic Agents ; COTI-2 compound ; Multidrug Resistance-Associated Proteins ; Thiosemicarbazones ; Copper (789U1901C5) ; Glutathione (GAN16C9B8O) ; multidrug resistance-associated protein 1 (Y49M64GZ4Q)
    Language English
    Publishing date 2020-11-15
    Publishing country United States
    Document type 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.0c01277
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
    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: Show issues

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  6. Article ; Online: Carnosic acid induces proteasomal degradation of Cyclin B1, RB and SOX2 along with cell growth arrest and apoptosis in GBM cells.

    Cortese, Katia / Daga, Antonio / Monticone, Massimiliano / Tavella, Sara / Stefanelli, Alessia / Aiello, Cinzia / Bisio, Angela / Bellese, Grazia / Castagnola, Patrizio

    Phytomedicine : international journal of phytotherapy and phytopharmacology

    2016  Volume 23, Issue 7, Page(s) 679–685

    Abstract: Background: Carnosic acid (CA) is a diterpenoid found in Rosmarinus officinalis L. and Salvia officinalis L. as well as in many other Lamiaceae. This compound is reported to have antioxidant and antimicrobial properties. In addition, a number of reports ...

    Abstract Background: Carnosic acid (CA) is a diterpenoid found in Rosmarinus officinalis L. and Salvia officinalis L. as well as in many other Lamiaceae. This compound is reported to have antioxidant and antimicrobial properties. In addition, a number of reports showed that CA has a cytotoxic activity toward several cancer cell lines.
    Purpose: The aim of this study was to establish whether CA has any specific antiproliferative effect toward human glioblastoma (GBM) cells and to analyze the molecular mechanisms involved.
    Methods: We evaluated cell survival by MTT assay, apoptosis and DNA content by flow cytometry, protein expression and phosphorylation by immunoblot analyses.
    Results: Our results showed that CA inhibited cell survival on both normal astrocytes and GBM cells. In GBM cells, in particular, CA caused an early G2 block, a reduction in the percentage of cells expressing Ki67, an enhanced expression of p21(WAF) and induced apoptosis. Furthermore, we showed that CA promoted proteasomal degradation of several substrate proteins, including Cyclin B1, retinoblastoma (RB), SOX2, and glial fibrillary acid protein (GFAP), whereas MYC levels were not modified. In addition, CA dramatically reduced the activity of CDKs.
    Conclusion: In conclusion, our findings strongly suggest that CA promotes a profound deregulation of cell cycle control and reduces the survival of GBM cells via proteasome-mediated degradation of Cyclin B1, RB and SOX2.
    MeSH term(s) Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Astrocytes/drug effects ; Brain Neoplasms/pathology ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation ; Cyclin B1/drug effects ; Cyclin B1/genetics ; DNA, Neoplasm/biosynthesis ; DNA, Neoplasm/genetics ; Diterpenes, Abietane/pharmacology ; Dose-Response Relationship, Drug ; G2 Phase/drug effects ; Glioblastoma/pathology ; Humans ; Proteasome Endopeptidase Complex/drug effects ; Proteasome Endopeptidase Complex/genetics ; Retinoblastoma Protein/drug effects ; Retinoblastoma Protein/genetics ; SOXB1 Transcription Factors/drug effects ; SOXB1 Transcription Factors/genetics
    Chemical Substances Antineoplastic Agents, Phytogenic ; CCNB1 protein, human ; Cyclin B1 ; DNA, Neoplasm ; Diterpenes, Abietane ; Retinoblastoma Protein ; SOX2 protein, human ; SOXB1 Transcription Factors ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; salvin (LI791SXT24)
    Language English
    Publishing date 2016-06-15
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1205240-1
    ISSN 1618-095X ; 0944-7113
    ISSN (online) 1618-095X
    ISSN 0944-7113
    DOI 10.1016/j.phymed.2016.03.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4115: Show issues Location:
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