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Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells

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 senescen...

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Autores principales: Rysanek, David, Vasicova, Pavla, Kolla, Jayaprakash Narayana, Sedlak, David, Andera, Ladislav, Bartek, Jiri, Hodny, Zdenek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9467395/
https://www.ncbi.nlm.nih.gov/pubmed/35951353
http://dx.doi.org/10.18632/aging.204207
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author Rysanek, David
Vasicova, Pavla
Kolla, Jayaprakash Narayana
Sedlak, David
Andera, Ladislav
Bartek, Jiri
Hodny, Zdenek
author_facet Rysanek, David
Vasicova, Pavla
Kolla, Jayaprakash Narayana
Sedlak, David
Andera, Ladislav
Bartek, Jiri
Hodny, Zdenek
author_sort Rysanek, David
collection PubMed
description 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.
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spelling pubmed-94673952022-09-14 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 (Albany NY) Research Paper 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. Impact Journals 2022-08-08 /pmc/articles/PMC9467395/ /pubmed/35951353 http://dx.doi.org/10.18632/aging.204207 Text en Copyright: © 2022 Rysanek et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Rysanek, David
Vasicova, Pavla
Kolla, Jayaprakash Narayana
Sedlak, David
Andera, Ladislav
Bartek, Jiri
Hodny, Zdenek
Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells
title Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells
title_full Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells
title_fullStr Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells
title_full_unstemmed Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells
title_short Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells
title_sort synergism of bcl-2 family inhibitors facilitates selective elimination of senescent cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9467395/
https://www.ncbi.nlm.nih.gov/pubmed/35951353
http://dx.doi.org/10.18632/aging.204207
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