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  1. Article ; Online: Reactive Oxygen Species (ROS)-Sensitive Prodrugs of the Tyrosine Kinase Inhibitor Crizotinib.

    Bielec, Bjoern / Poetsch, Isabella / Ahmed, Esra / Heffeter, Petra / Keppler, Bernhard K / Kowol, Christian R

    Molecules (Basel, Switzerland)

    2020  Volume 25, Issue 5

    Abstract: Tyrosine kinase inhibitors revolutionized cancer therapy but still evoke strong adverse effects that can dramatically reduce patients' quality of life. One possibility to enhance drug safety is the exploitation of prodrug strategies to selectively ... ...

    Abstract Tyrosine kinase inhibitors revolutionized cancer therapy but still evoke strong adverse effects that can dramatically reduce patients' quality of life. One possibility to enhance drug safety is the exploitation of prodrug strategies to selectively activate a drug inside the tumor tissue. In this study, we designed a prodrug strategy for the approved c-MET, ALK, and ROS1 tyrosine kinase inhibitor crizotinib. Therefore, a boronic-acid trigger moiety was attached to the 2-aminopyridine group of crizotinib, which is a crucial position for target kinase binding. The influence of the modifications on the c-MET- and ALK-binding ability was investigated by docking studies, and the strongly reduced interactions could be confirmed by cell-free kinase inhibition assay. Furthermore, the newly synthesized compounds were tested for their activation behavior with H
    MeSH term(s) Boronic Acids/chemistry ; Cell Line, Tumor ; Cell Survival/drug effects ; Crizotinib/chemistry ; Flow Cytometry ; Humans ; Prodrugs/chemistry ; Prodrugs/metabolism ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Stability ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/metabolism ; Reactive Oxygen Species/chemistry ; Reactive Oxygen Species/metabolism
    Chemical Substances Boronic Acids ; Prodrugs ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins ; Reactive Oxygen Species ; Crizotinib (53AH36668S)
    Language English
    Publishing date 2020-03-04
    Publishing country Switzerland
    Document type 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/molecules25051149
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.MO 81: Show issues

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  2. Article: Influence of the Fatty Acid Metabolism on the Mode of Action of a Cisplatin(IV) Complex with Phenylbutyrate as Axial Ligands.

    Mendrina, Theresa / Poetsch, Isabella / Schueffl, Hemma / Baier, Dina / Pirker, Christine / Ries, Alexander / Keppler, Bernhard K / Kowol, Christian R / Gibson, Dan / Grusch, Michael / Berger, Walter / Heffeter, Petra

    Pharmaceutics

    2023  Volume 15, Issue 2

    Abstract: For a variety of cancer types, platinum compounds are still among the best treatment options. However, their application is limited by side effects and drug resistance. Consequently, multi-targeted platinum(IV) prodrugs that target specific traits of the ...

    Abstract For a variety of cancer types, platinum compounds are still among the best treatment options. However, their application is limited by side effects and drug resistance. Consequently, multi-targeted platinum(IV) prodrugs that target specific traits of the malignant tissue are interesting new candidates. Recently, cisPt(PhB)
    Language English
    Publishing date 2023-02-16
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics15020677
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Stepwise optimization of tumor-targeted dual-action platinum(iv)-gemcitabine prodrugs.

    Kastner, Alexander / Mendrina, Theresa / Babu, Tomer / Karmakar, Subhendu / Poetsch, Isabella / Berger, Walter / Keppler, Bernhard K / Gibson, Dan / Heffeter, Petra / Kowol, Christian R

    Inorganic chemistry frontiers

    2023  Volume 11, Issue 2, Page(s) 534–548

    Abstract: While platinum-based chemotherapeutic agents have established themselves as indispensable components of anticancer therapy, they are accompanied by a variety of side effects and the rapid occurrence of drug resistance. A promising strategy to address ... ...

    Abstract While platinum-based chemotherapeutic agents have established themselves as indispensable components of anticancer therapy, they are accompanied by a variety of side effects and the rapid occurrence of drug resistance. A promising strategy to address these challenges is the use of platinum(iv) prodrugs, which remain inert until they reach the tumor tissue, thereby mitigating detrimental effects on healthy cells. Typically, platinum drugs are part of combination therapy settings. Consequently, a very elegant strategy is the development of platinum(iv) prodrugs bearing a second, clinically relevant therapeutic in axial position. In the present study, we focused on gemcitabine as an approved antimetabolite, which is highly synergistic with platinum drugs. In addition, to increase plasma half-life and facilitate tumor-specific accumulation, an albumin-binding maleimide moiety was attached. Our investigations revealed that maleimide-cisplatin(iv)-gemcitabine complexes cannot carry sufficient amounts of gemcitabine to induce a significant effect
    Language English
    Publishing date 2023-12-06
    Publishing country England
    Document type Journal Article
    ISSN 2052-1553
    ISSN 2052-1553
    DOI 10.1039/d3qi02032k
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Metal- and metalloid-based compounds to target and reverse cancer multidrug resistance.

    Valente, Andreia / Podolski-Renić, Ana / Poetsch, Isabella / Filipović, Nenad / López, Óscar / Turel, Iztok / Heffeter, Petra

    Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy

    2021  Volume 58, Page(s) 100778

    Abstract: Drug resistance remains the major cause of cancer treatment failure especially at the late stage of the disease. However, based on their versatile chemistry, metal and metalloid compounds offer the possibility to design fine-tuned drugs to circumvent and ...

    Abstract Drug resistance remains the major cause of cancer treatment failure especially at the late stage of the disease. However, based on their versatile chemistry, metal and metalloid compounds offer the possibility to design fine-tuned drugs to circumvent and even specifically target drug-resistant cancer cells. Based on the paramount importance of platinum drugs in the clinics, two main areas of drug resistance reversal strategies exist: overcoming resistance to platinum drugs as well as multidrug resistance based on ABC efflux pumps. The current review provides an overview of both aspects of drug design and discusses the open questions in the field. The areas of drug resistance covered in this article involve: 1) Altered expression of proteins involved in metal uptake, efflux or intracellular distribution, 2) Enhanced drug efflux via ABC transporters, 3) Altered metabolism in drug-resistant cancer cells, 4) Altered thiol or redox homeostasis, 5) Altered DNA damage recognition and enhanced DNA damage repair, 6) Impaired induction of apoptosis and 7) Altered interaction with the immune system. This review represents the first collection of metal (including platinum, ruthenium, iridium, gold, and copper) and metalloid drugs (e.g. arsenic and selenium) which demonstrated drug resistance reversal activity. A special focus is on compounds characterized by collateral sensitivity of ABC transporter-overexpressing cancer cells. Through this approach, we wish to draw the attention to open research questions in the field. Future investigations are warranted to obtain more insights into the mechanisms of action of the most potent compounds which target specific modalities of drug resistance.
    MeSH term(s) Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug Resistance, Multiple/genetics ; Drug Resistance, Neoplasm/genetics ; Humans ; Metalloids/pharmacology ; Neoplasms/drug therapy ; Neoplasms/genetics
    Chemical Substances Antineoplastic Agents ; Metalloids
    Language English
    Publishing date 2021-08-06
    Publishing country Scotland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1474513-6
    ISSN 1532-2084 ; 1368-7646
    ISSN (online) 1532-2084
    ISSN 1368-7646
    DOI 10.1016/j.drup.2021.100778
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5099: Show issues Location:
    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)

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  5. Article ; Online: Synthesis and Cytotoxicity of Water-Soluble Dual- and Triple-Action Satraplatin Derivatives: Replacement of Equatorial Chlorides of Satraplatin by Acetates.

    Karmakar, Subhendu / Poetsch, Isabella / Kowol, Christian R / Heffeter, Petra / Gibson, Dan

    Inorganic chemistry

    2019  Volume 58, Issue 24, Page(s) 16676–16688

    Abstract: Pt(II) complexes, such as cisplatin and oxaliplatin, are in widespread use as anticancer drugs. Their use is limited by the toxic side effects and the ability of tumors to develop resistance to the drugs. A popular approach to overcome these drawbacks is ...

    Abstract Pt(II) complexes, such as cisplatin and oxaliplatin, are in widespread use as anticancer drugs. Their use is limited by the toxic side effects and the ability of tumors to develop resistance to the drugs. A popular approach to overcome these drawbacks is to use their kinetically inert octahedral Pt(IV) derivatives that act as prodrugs. The most successful Pt(IV) complex in clinical trials to date is satraplatin,
    Language English
    Publishing date 2019-12-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1484438-2
    ISSN 1520-510X ; 0020-1669
    ISSN (online) 1520-510X
    ISSN 0020-1669
    DOI 10.1021/acs.inorgchem.9b02796
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  6. Article ; Online: Detection of oxaliplatin- and cisplatin-DNA lesions requires different global genome repair mechanisms that affect their clinical efficacy.

    Slyskova, Jana / Muniesa-Vargas, Alba / da Silva, Israel Tojal / Drummond, Rodrigo / Park, Jiyeong / Häckes, David / Poetsch, Isabella / Ribeiro-Silva, Cristina / Moretton, Amandine / Heffeter, Petra / Schärer, Orlando D / Vermeulen, Wim / Lans, Hannes / Loizou, Joanna I

    NAR cancer

    2023  Volume 5, Issue 4, Page(s) zcad057

    Abstract: The therapeutic efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the ... ...

    Abstract The therapeutic efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the underlying molecular causes for this tumor specificity are not clear. Hence, stratification of patients based on DNA repair profiling is not sufficiently utilized for treatment selection. Using a combination of genetic, transcriptomics and imaging approaches, we identified factors that promote global genome nucleotide excision repair (GG-NER) of DNA-platinum adducts induced by oxaliplatin, but not by cisplatin. We show that oxaliplatin-DNA lesions are a poor substrate for GG-NER initiating factor XPC and that DDB2 and HMGA2 are required for efficient binding of XPC to oxaliplatin lesions and subsequent GG-NER initiation. Loss of DDB2 and HMGA2 therefore leads to hypersensitivity to oxaliplatin but not to cisplatin. As a result, low DDB2 levels in different colon cancer cells are associated with GG-NER deficiency and oxaliplatin hypersensitivity. Finally, we show that colon cancer patients with low DDB2 levels have a better prognosis after oxaliplatin treatment than patients with high DDB2 expression. We therefore propose that DDB2 is a promising predictive marker of oxaliplatin treatment efficiency in colon cancer.
    Language English
    Publishing date 2023-12-05
    Publishing country England
    Document type Journal Article
    ISSN 2632-8674
    ISSN (online) 2632-8674
    DOI 10.1093/narcan/zcad057
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  7. Article ; Online: The IAP family member BRUCE regulates autophagosome-lysosome fusion.

    Ebner, Petra / Poetsch, Isabella / Deszcz, Luiza / Hoffmann, Thomas / Zuber, Johannes / Ikeda, Fumiyo

    Nature communications

    2018  Volume 9, Issue 1, Page(s) 599

    Abstract: Autophagy has an important role in cellular homeostasis by degrading and recycling cytotoxic components. Ubiquitination is known to target cargoes for autophagy; however, key components of this pathway remain elusive. Here we performed an RNAi screen to ... ...

    Abstract Autophagy has an important role in cellular homeostasis by degrading and recycling cytotoxic components. Ubiquitination is known to target cargoes for autophagy; however, key components of this pathway remain elusive. Here we performed an RNAi screen to uncover ubiquitin modifiers that are required for starvation-induced macroautophagy in mammalian cells. Our screen uncovered BRUCE/Apollon/Birc6, an IAP protein, as a new autophagy regulator. Depletion of BRUCE leads to defective fusion of autophagosomes and lysosomes. Mechanistically, BRUCE selectively interacts with two ATG8 members GABARAP and GABARAPL1, as well as with Syntaxin 17, which are all critical regulators of autophagosome-lysosome fusion. In addition, BRUCE colocalizes with LAMP2. Interestingly, a non-catalytic N-terminal BRUCE fragment that is sufficient to bind GABARAP/GABARAPL1 and Syntaxin 17, and to colocalize with LAMP2, rescues autolysosome formation in Bruce
    MeSH term(s) Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Apoptosis/genetics ; Apoptosis Regulatory Proteins ; Autophagosomes/metabolism ; Autophagy/genetics ; CRISPR-Cas Systems ; Cell Line ; Cells, Cultured ; HEK293 Cells ; Humans ; Inhibitor of Apoptosis Proteins/genetics ; Inhibitor of Apoptosis Proteins/metabolism ; Lysosomes/genetics ; Lysosomes/metabolism ; Membrane Fusion ; Mice, Knockout ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Protein Binding ; RNA Interference
    Chemical Substances Adaptor Proteins, Signal Transducing ; Apoptosis Regulatory Proteins ; GABARAP protein, human ; GABARAPL1 protein, human ; Inhibitor of Apoptosis Proteins ; Microtubule-Associated Proteins
    Language English
    Publishing date 2018-02-09
    Publishing country England
    Document type 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/s41467-018-02823-x
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  8. Article ; Online: A Dogma in Doubt: Hydrolysis of Equatorial Ligands of Pt

    Kastner, Alexander / Poetsch, Isabella / Mayr, Josef / Burda, Jaroslav V / Roller, Alexander / Heffeter, Petra / Keppler, Bernhard K / Kowol, Christian R

    Angewandte Chemie (International ed. in English)

    2019  Volume 58, Issue 22, Page(s) 7464–7469

    Abstract: Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, ... ...

    Abstract Due to their high kinetic inertness and consequently reduced side reactions with biomolecules, Pt
    Language English
    Publishing date 2019-04-25
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.201900682
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  9. Article ; Online: Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands.

    Fronik, Philipp / Poetsch, Isabella / Kastner, Alexander / Mendrina, Theresa / Hager, Sonja / Hohenwallner, Katharina / Schueffl, Hemma / Herndler-Brandstetter, Dietmar / Koellensperger, Gunda / Rampler, Evelyn / Kopecka, Joanna / Riganti, Chiara / Berger, Walter / Keppler, Bernhard K / Heffeter, Petra / Kowol, Christian R

    Journal of medicinal chemistry

    2021  Volume 64, Issue 16, Page(s) 12132–12151

    Abstract: Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition ...

    Abstract Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting
    MeSH term(s) Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Coordination Complexes/chemical synthesis ; Coordination Complexes/pharmacology ; Coordination Complexes/therapeutic use ; Drug Screening Assays, Antitumor ; Female ; Humans ; Immunologic Factors/chemical synthesis ; Immunologic Factors/pharmacology ; Immunologic Factors/therapeutic use ; Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors ; Male ; Maleimides/chemical synthesis ; Maleimides/pharmacology ; Maleimides/therapeutic use ; Mice, Inbred BALB C ; Mice, SCID ; Molecular Structure ; Neoplasms/drug therapy ; Platinum/chemistry ; Prodrugs/chemical synthesis ; Prodrugs/pharmacology ; Prodrugs/therapeutic use ; Structure-Activity Relationship ; Succinimides/chemical synthesis ; Succinimides/pharmacology ; Succinimides/therapeutic use ; Mice
    Chemical Substances Antineoplastic Agents ; Coordination Complexes ; Immunologic Factors ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; Maleimides ; Prodrugs ; Succinimides ; Platinum (49DFR088MY)
    Language English
    Publishing date 2021-08-17
    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.1c00770
    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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