Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510000, China.
Oxid Med Cell Longev. 2022 Jun 3;2022:9144644. doi: 10.1155/2022/9144644. eCollection 2022.
Ovarian damage induced by platinum-based chemotherapy seriously affects young women with cancer, manifesting as infertility, early menopause, and premature ovarian insufficiency. However, effective prevention strategies for such damage are lacking. Senescent cells may be induced by chemotherapeutic agents. We hypothesized that cisplatin can lead to senescence in ovarian cells during the therapeutic process, and senolytic drugs can protect animals against cisplatin-induced ovarian injury. Here, we demonstrated the existence of senescent cells in cisplatin-treated ovaries, identified the senescence-associated secretory phenotype, and observed significant improvement of ovarian function by treatment with metformin or dasatinib and quercetin (DQ) independently or in combination. These senotherapies improved both oocyte quality and fertility, increased the ovarian reserve, and enhanced hormone secretion in cisplatin-exposed mice. Additionally, attenuated fibrosis, reorganized subcellular structure, and mitigated DNA damage were observed in the ovaries of senotherapeutic mice. Moreover, RNA sequencing analysis revealed upregulation of the proliferation-related genes , , , and ; and the antioxidative gene after metformin plus DQ treatment. Gene ontology analysis further revealed that combining senotherapies enhanced ovarian cell differentiation, development, and communication. In this study, we demonstrated that metformin plus DQ recovered ovarian function to a greater extent compared to metformin or DQ independently, with more follicular reserve, increased pups per litter, and reduced DNA damage. Collectively, our work indicates that senotherapies might prevent cisplatin-induced ovarian injury by removing senescent cells and reducing DNA damage, which represent a promising therapeutic avenue to prevent chemotherapy-induced ovarian damage.
铂类化疗引起的卵巢损伤严重影响年轻癌症患者的生育能力，导致不孕、早绝经和卵巢早衰。然而，目前缺乏有效的预防策略。化疗药物可能会诱导衰老细胞的产生。我们假设顺铂在治疗过程中会导致卵巢细胞衰老，而衰老细胞清除药物可以保护动物免受顺铂引起的卵巢损伤。在这里，我们证明了衰老细胞在顺铂处理的卵巢中存在，鉴定了衰老相关分泌表型，并观察到二甲双胍或达沙替尼和槲皮素（DQ）单独或联合治疗可显著改善卵巢功能。这些衰老疗法改善了卵母细胞质量和生育能力，增加了卵巢储备，并增强了顺铂暴露小鼠的激素分泌。此外，衰老疗法小鼠的卵巢中观察到纤维化减轻、亚细胞结构重排和 DNA 损伤减轻。此外，RNA 测序分析显示，二甲双胍加 DQ 治疗后，与增殖相关的基因 、 、 、 和 以及抗氧化基因 上调。基因本体分析进一步表明，联合衰老疗法增强了卵巢细胞的分化、发育和通讯。在这项研究中，我们证明了与二甲双胍或 DQ 单独治疗相比，二甲双胍加 DQ 更能恢复卵巢功能，具有更多的卵泡储备，每窝幼崽增加，并且 DNA 损伤减少。总之，我们的工作表明，衰老细胞疗法通过清除衰老细胞和减少 DNA 损伤可能预防顺铂引起的卵巢损伤，这代表了预防化疗引起的卵巢损伤的一种有前途的治疗途径。
