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Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups
SIMPLE SUMMARY: Cellular senescence may contribute to aging and age-related diseases, and the elimination of senescent cells is considered a promising anti-aging strategy. Drug-induced senescence in cancer cells during chemotherapy may also promote a number of adverse effects. Thus, in the present s...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833762/ https://www.ncbi.nlm.nih.gov/pubmed/35158873 http://dx.doi.org/10.3390/cancers14030605 |
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author | Lewińska, Anna Przybylski, Paweł Adamczyk-Grochala, Jagoda Błoniarz, Dominika Litwinienko, Grzegorz Wnuk, Maciej |
author_facet | Lewińska, Anna Przybylski, Paweł Adamczyk-Grochala, Jagoda Błoniarz, Dominika Litwinienko, Grzegorz Wnuk, Maciej |
author_sort | Lewińska, Anna |
collection | PubMed |
description | SIMPLE SUMMARY: Cellular senescence may contribute to aging and age-related diseases, and the elimination of senescent cells is considered a promising anti-aging strategy. Drug-induced senescence in cancer cells during chemotherapy may also promote a number of adverse effects. Thus, in the present study, the usefulness of three quercetin derivatives as senolytic agents was studied upon stimulation of senescence program in breast cancer cells. We have shown that quercetin derivative with blocked hydroxy groups (QD3) sensitized etoposide-induced senescent breast cancer cells to apoptotic cell death that was accompanied by a decrease in proinflammatory and HSP70-based responses. We suggest that these prosenescent and senolytic activities can be combined to design a novel anti-cancer strategy, at least, against breast cancer cells. ABSTRACT: Drug-induced senescence program may be activated both in normal and cancer cells as a consequence of chemotherapeutic treatment, leading to some adverse side effects such as senescence-associated secretory phenotype (SASP), secondary senescence, and cancer promotion. Targeted elimination of senescent cells can be achieved by drugs with senolytic activity (senolytics), for example, the plant-derived natural compound quercetin, especially when co-treated with kinase inhibitor dasatinib. In the present study, three quercetin derivatives were synthesized and tested for improved senolytic action against etoposide-induced senescent human normal mammary epithelial cells and triple-negative breast cancer cells in vitro. Transformation of catechol moiety into diphenylmethylene ketal and addition of three acetyl groups to the quercetin molecule (QD3 derivative) promoted the clearance of senescent cancer cells as judged by increased apoptosis compared to etoposide-treated cells. A QD3-mediated senolytic effect was accompanied by decreased SA-beta galactosidase activity and the levels of p27, IL-1β, IL-8, and HSP70 in cancer cells. Similar effects were not observed in senescent normal cells. In conclusion, a novel senolytic agent QD3 was described as acting against etoposide-induced senescent breast cancer cells in vitro. Thus, a new one-two punch anti-cancer strategy based on combined action of a pro-senescence anti-cancer drug and a senolytic agent is proposed. |
format | Online Article Text |
id | pubmed-8833762 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88337622022-02-12 Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups Lewińska, Anna Przybylski, Paweł Adamczyk-Grochala, Jagoda Błoniarz, Dominika Litwinienko, Grzegorz Wnuk, Maciej Cancers (Basel) Communication SIMPLE SUMMARY: Cellular senescence may contribute to aging and age-related diseases, and the elimination of senescent cells is considered a promising anti-aging strategy. Drug-induced senescence in cancer cells during chemotherapy may also promote a number of adverse effects. Thus, in the present study, the usefulness of three quercetin derivatives as senolytic agents was studied upon stimulation of senescence program in breast cancer cells. We have shown that quercetin derivative with blocked hydroxy groups (QD3) sensitized etoposide-induced senescent breast cancer cells to apoptotic cell death that was accompanied by a decrease in proinflammatory and HSP70-based responses. We suggest that these prosenescent and senolytic activities can be combined to design a novel anti-cancer strategy, at least, against breast cancer cells. ABSTRACT: Drug-induced senescence program may be activated both in normal and cancer cells as a consequence of chemotherapeutic treatment, leading to some adverse side effects such as senescence-associated secretory phenotype (SASP), secondary senescence, and cancer promotion. Targeted elimination of senescent cells can be achieved by drugs with senolytic activity (senolytics), for example, the plant-derived natural compound quercetin, especially when co-treated with kinase inhibitor dasatinib. In the present study, three quercetin derivatives were synthesized and tested for improved senolytic action against etoposide-induced senescent human normal mammary epithelial cells and triple-negative breast cancer cells in vitro. Transformation of catechol moiety into diphenylmethylene ketal and addition of three acetyl groups to the quercetin molecule (QD3 derivative) promoted the clearance of senescent cancer cells as judged by increased apoptosis compared to etoposide-treated cells. A QD3-mediated senolytic effect was accompanied by decreased SA-beta galactosidase activity and the levels of p27, IL-1β, IL-8, and HSP70 in cancer cells. Similar effects were not observed in senescent normal cells. In conclusion, a novel senolytic agent QD3 was described as acting against etoposide-induced senescent breast cancer cells in vitro. Thus, a new one-two punch anti-cancer strategy based on combined action of a pro-senescence anti-cancer drug and a senolytic agent is proposed. MDPI 2022-01-25 /pmc/articles/PMC8833762/ /pubmed/35158873 http://dx.doi.org/10.3390/cancers14030605 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Communication Lewińska, Anna Przybylski, Paweł Adamczyk-Grochala, Jagoda Błoniarz, Dominika Litwinienko, Grzegorz Wnuk, Maciej Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups |
title | Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups |
title_full | Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups |
title_fullStr | Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups |
title_full_unstemmed | Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups |
title_short | Senolysis-Based Elimination of Chemotherapy-Induced Senescent Breast Cancer Cells by Quercetin Derivative with Blocked Hydroxy Groups |
title_sort | senolysis-based elimination of chemotherapy-induced senescent breast cancer cells by quercetin derivative with blocked hydroxy groups |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833762/ https://www.ncbi.nlm.nih.gov/pubmed/35158873 http://dx.doi.org/10.3390/cancers14030605 |
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