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  1. Article ; Online: Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells.

    Rysanek, David / Vasicova, Pavla / Kolla, Jayaprakash Narayana / Sedlak, David / Andera, Ladislav / Bartek, Jiri / Hodny, Zdenek

    Aging

    2022  Volume 14, Issue 16, Page(s) 6381–6414

    Abstract: Accumulation of senescent cells in tissues with advancing age participates in the pathogenesis of several human age-associated diseases. Specific senescent secretome, the resistance of senescent cells to apoptotic stimuli, and lack of immune system ... ...

    Abstract Accumulation of senescent cells in tissues with advancing age participates in the pathogenesis of several human age-associated diseases. Specific senescent secretome, the resistance of senescent cells to apoptotic stimuli, and lack of immune system response contribute to the accumulation of senescent cells and their adverse effects in tissues. Inhibition of antiapoptotic machinery, augmented in senescent cells, by BCL-2 protein family inhibitors represents a promising approach to eliminate senescent cells from tissues. This study aimed to explore synergistic and selective senolytic effects of anti-apoptotic BCL-2 family targeting compounds, particularly BH3 mimetics. Using human non-transformed cells RPE-1, BJ, and MRC-5 brought to ionizing radiation-, oncogene-, drug-induced and replicative senescence, we found synergy in combining MCL-1 selective inhibitors with other BH3 mimetics. In an attempt to uncover the mechanism of such synergy, we revealed that the surviving subpopulation of cells resistant to individually applied ABT-737/ABT-263, MIK665, ABT-199, and S63845 BCL-2 family inhibitors showed elevated MCL-1 compared to untreated control cells indicating the presence of a subset of cells expressing high MCL-1 levels and, therefore, resistant to BCL-2 inhibitors within the original population of senescent cells. Overall, we found that combining BCL-2 inhibitors can be beneficial for eliminating senescent cells, thereby enabling use of lower, potentially less toxic, doses of drugs compared to monotherapy, thereby overcoming the resistance of the subpopulation of senescent cells to monotherapy.
    MeSH term(s) Apoptosis ; Cellular Senescence ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
    Chemical Substances Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2
    Language English
    Publishing date 2022-08-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1945-4589
    ISSN (online) 1945-4589
    DOI 10.18632/aging.204207
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Structure-Activity Relationship of

    Sedlák, David / Wilson, Tyler A / Tjarks, Werner / Radomska, Hanna S / Wang, Hongyan / Kolla, Jayaprakash Narayana / Leśnikowski, Zbigniew J / Špičáková, Alena / Ali, Tehane / Ishita, Keisuke / Rakotondraibe, Liva Harinantenaina / Vibhute, Sandip / Wang, Dasheng / Anzenbacher, Pavel / Bennett, Chad / Bartunek, Petr / Coss, Christopher C

    Journal of medicinal chemistry

    2021  Volume 64, Issue 13, Page(s) 9330–9353

    Abstract: Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic ... ...

    Abstract Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of
    MeSH term(s) Boron Compounds/chemical synthesis ; Boron Compounds/chemistry ; Boron Compounds/pharmacology ; Dose-Response Relationship, Drug ; Estrogen Receptor beta/agonists ; Estrogens/chemical synthesis ; Estrogens/chemistry ; Estrogens/pharmacology ; HEK293 Cells ; Humans ; Molecular Structure ; Structure-Activity Relationship
    Chemical Substances Boron Compounds ; Estrogen Receptor beta ; Estrogens
    Language English
    Publishing date 2021-06-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; 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.1c00555
    Database MEDical Literature Analysis and Retrieval System OnLINE

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