The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency
Young female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is charac...
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/24/17193 |
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| author | Zixin Xu Nozomi Takahashi Miyuki Harada Chisato Kunitomi Akari Kusamoto Hiroshi Koike Tsurugi Tanaka Nanoka Sakaguchi Yoko Urata Osamu Wada-Hiraike Yasushi Hirota Yutaka Osuga |
| author_facet | Zixin Xu Nozomi Takahashi Miyuki Harada Chisato Kunitomi Akari Kusamoto Hiroshi Koike Tsurugi Tanaka Nanoka Sakaguchi Yoko Urata Osamu Wada-Hiraike Yasushi Hirota Yutaka Osuga |
| author_sort | Zixin Xu |
| collection | DOAJ |
| description | Young female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is characterized by permanent cell growth arrest, in the pathologies of various diseases. Moreover, several promising senolytics, including dasatinib and quercetin (DQ), which remove senescent cells, are being developed. In the present study, we investigated whether cellular senescence is involved in Cy-induced POI and whether DQ treatment rescues Cy-induced ovarian damage. Expression of the cellular senescence markers p16, p21, p53, and γH2AX was upregulated in granulosa cells of POI mice and in human granulosa cells treated with Cy, which was abrogated by DQ treatment. The administration of Cy decreased the numbers of primordial and primary follicles, with a concomitant increase in the ratio of growing to dormant follicles, which was partially rescued by DQ. Moreover, DQ treatment significantly improved the response to ovulation induction and fertility in POI mice by extending reproductive life. Thus, cellular senescence plays critical roles in Cy-induced POI, and targeting senescent cells with senolytics, such as DQ, might be a promising strategy to protect against Cy-induced ovarian damage. |
| first_indexed | 2024-03-08T20:41:47Z |
| format | Article |
| id | doaj.art-5b81eeecfffb4dfe90dfd6c5fc5ef536 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:41:47Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5b81eeecfffb4dfe90dfd6c5fc5ef5362023-12-22T14:13:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241719310.3390/ijms242417193The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian InsufficiencyZixin Xu0Nozomi Takahashi1Miyuki Harada2Chisato Kunitomi3Akari Kusamoto4Hiroshi Koike5Tsurugi Tanaka6Nanoka Sakaguchi7Yoko Urata8Osamu Wada-Hiraike9Yasushi Hirota10Yutaka Osuga11Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanDepartment of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, JapanYoung female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is characterized by permanent cell growth arrest, in the pathologies of various diseases. Moreover, several promising senolytics, including dasatinib and quercetin (DQ), which remove senescent cells, are being developed. In the present study, we investigated whether cellular senescence is involved in Cy-induced POI and whether DQ treatment rescues Cy-induced ovarian damage. Expression of the cellular senescence markers p16, p21, p53, and γH2AX was upregulated in granulosa cells of POI mice and in human granulosa cells treated with Cy, which was abrogated by DQ treatment. The administration of Cy decreased the numbers of primordial and primary follicles, with a concomitant increase in the ratio of growing to dormant follicles, which was partially rescued by DQ. Moreover, DQ treatment significantly improved the response to ovulation induction and fertility in POI mice by extending reproductive life. Thus, cellular senescence plays critical roles in Cy-induced POI, and targeting senescent cells with senolytics, such as DQ, might be a promising strategy to protect against Cy-induced ovarian damage.https://www.mdpi.com/1422-0067/24/24/17193cellular senescencecyclophosphamideprimary ovarian insufficiencysenolyticssenotherapeutics |
| spellingShingle | Zixin Xu Nozomi Takahashi Miyuki Harada Chisato Kunitomi Akari Kusamoto Hiroshi Koike Tsurugi Tanaka Nanoka Sakaguchi Yoko Urata Osamu Wada-Hiraike Yasushi Hirota Yutaka Osuga The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency International Journal of Molecular Sciences cellular senescence cyclophosphamide primary ovarian insufficiency senolytics senotherapeutics |
| title | The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency |
| title_full | The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency |
| title_fullStr | The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency |
| title_full_unstemmed | The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency |
| title_short | The Role of Cellular Senescence in Cyclophosphamide-Induced Primary Ovarian Insufficiency |
| title_sort | role of cellular senescence in cyclophosphamide induced primary ovarian insufficiency |
| topic | cellular senescence cyclophosphamide primary ovarian insufficiency senolytics senotherapeutics |
| url | https://www.mdpi.com/1422-0067/24/24/17193 |
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