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Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics
Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and overall health of the cancer survivors seriously. However, there is still a lack of effective protection strategies against such in...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400526/ https://www.ncbi.nlm.nih.gov/pubmed/36648735 http://dx.doi.org/10.1007/s11357-023-00728-2 |
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author | Gao, Yueyue Wu, Tong Tang, Xianan Wen, Jingyi Zhang, Yan Zhang, Jinjin Wang, Shixuan |
author_facet | Gao, Yueyue Wu, Tong Tang, Xianan Wen, Jingyi Zhang, Yan Zhang, Jinjin Wang, Shixuan |
author_sort | Gao, Yueyue |
collection | PubMed |
description | Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and overall health of the cancer survivors seriously. However, there is still a lack of effective protection strategies against such injury. Cellular senescence can be induced by chemotherapeutic agents in multiple organs and may corrode the structure and function of normal tissues. We hypothesized that the widely used first-line chemotherapy drug, doxorubicin, could increase senescent cell burden in normal ovarian tissue during the therapeutic process and that elimination of senescent cells with senolytics would ameliorate doxorubicin-induced ovarian injury. Here, we demonstrated an accumulation of cellular senescence in doxorubicin-treated ovaries through detecting p16 and p21 expression levels and senescence-associated β-galactosidase (SA-β-gal) activity as well as senescence-associated secretory phenotype (SASP) factors. Short-term intervention with the classic senolytic combination dasatinib and quercetin (DQ) or fisetin significantly reduced the load of senescent cells in ovaries after doxorubicin treatment. However, neither DQ nor fisetin alleviated doxorubicin-related ovarian dysfunction. Further experiments showed that ovarian apoptosis and fibrosis following doxorubicin exposure could not be improved by senolytics. Collectively, our study shows that senolytic treatment can eliminate accumulated senescent cells, but cannot reverse the massive follicle loss and ovarian stromal fibrosis caused by doxorubicin, suggesting that cellular senescence may not be one of the key mechanisms in doxorubicin-induced ovarian injury. |
format | Online Article Text |
id | pubmed-10400526 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-104005262023-08-05 Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics Gao, Yueyue Wu, Tong Tang, Xianan Wen, Jingyi Zhang, Yan Zhang, Jinjin Wang, Shixuan GeroScience Original Article Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and overall health of the cancer survivors seriously. However, there is still a lack of effective protection strategies against such injury. Cellular senescence can be induced by chemotherapeutic agents in multiple organs and may corrode the structure and function of normal tissues. We hypothesized that the widely used first-line chemotherapy drug, doxorubicin, could increase senescent cell burden in normal ovarian tissue during the therapeutic process and that elimination of senescent cells with senolytics would ameliorate doxorubicin-induced ovarian injury. Here, we demonstrated an accumulation of cellular senescence in doxorubicin-treated ovaries through detecting p16 and p21 expression levels and senescence-associated β-galactosidase (SA-β-gal) activity as well as senescence-associated secretory phenotype (SASP) factors. Short-term intervention with the classic senolytic combination dasatinib and quercetin (DQ) or fisetin significantly reduced the load of senescent cells in ovaries after doxorubicin treatment. However, neither DQ nor fisetin alleviated doxorubicin-related ovarian dysfunction. Further experiments showed that ovarian apoptosis and fibrosis following doxorubicin exposure could not be improved by senolytics. Collectively, our study shows that senolytic treatment can eliminate accumulated senescent cells, but cannot reverse the massive follicle loss and ovarian stromal fibrosis caused by doxorubicin, suggesting that cellular senescence may not be one of the key mechanisms in doxorubicin-induced ovarian injury. Springer International Publishing 2023-01-17 /pmc/articles/PMC10400526/ /pubmed/36648735 http://dx.doi.org/10.1007/s11357-023-00728-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Gao, Yueyue Wu, Tong Tang, Xianan Wen, Jingyi Zhang, Yan Zhang, Jinjin Wang, Shixuan Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics |
title | Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics |
title_full | Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics |
title_fullStr | Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics |
title_full_unstemmed | Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics |
title_short | Increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics |
title_sort | increased cellular senescence in doxorubicin-induced murine ovarian injury: effect of senolytics |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400526/ https://www.ncbi.nlm.nih.gov/pubmed/36648735 http://dx.doi.org/10.1007/s11357-023-00728-2 |
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