Department of Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, 00133, Rome, Italy.
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
Cell Death Dis. 2019 Sep 27;10(10):726. doi: 10.1038/s41419-019-1961-y.
Premature ovarian failure and infertility are adverse effects of cancer therapies. The mechanism underlying chemotherapy-mediated depletion of the ovarian reserve remains unclear. Here, we aim to identify the signaling pathways involved in the loss of the ovarian reserve to prevent the damaging effects of chemotherapy. We evaluated the effects of cyclophosphamide, one of the most damaging chemotherapeutic drugs, against follicle reserve. In vivo studies showed that the cyclophosphamide-induced loss of ovarian reserve occurred through a sequential mechanism. Cyclophosphamide exposure induced the activation of both DNAPK-γH2AX-checkpoint kinase 2 (CHK2)-p53/TAp63α isoform and protein kinase B (AKT)-forkhead box O3 (FOXO3a) signaling axes in the nucleus of oocytes. Concomitant administration of an allosteric ABL inhibitor and cyclophosphamide modulated both pathways while protecting the ovarian reserve from chemotherapy assaults. As a consequence, the fertility of the treated mice was prolonged. On the contrary, the administration of an allosteric ABL activator enhanced the lethal effects of cyclophosphamide while shortening mouse fertility. Therefore, kinase-independent inhibition may serve as an effective ovarian-protective strategy in women under chemotherapy.
卵巢早衰和不孕是癌症治疗的不良反应。化疗介导的卵巢储备耗竭的机制尚不清楚。在这里，我们旨在确定参与卵巢储备丧失的信号通路，以防止化疗的破坏性影响。我们评估了环磷酰胺（一种最具破坏性的化疗药物之一）对卵泡储备的影响。体内研究表明，环磷酰胺诱导的卵巢储备丧失是通过一个连续的机制发生的。环磷酰胺暴露诱导卵母细胞核中 DNA 依赖性蛋白激酶-γH2AX-检查点激酶 2（CHK2）-p53/TAp63α 异构体和蛋白激酶 B（AKT）-叉头框 O3（FOXO3a）信号轴的激活。同时给予变构 ABL 抑制剂和环磷酰胺可调节这两条通路，同时保护卵巢储备免受化疗的侵袭。因此，治疗小鼠的生育能力延长。相反，给予变构 ABL 激活剂增强了环磷酰胺的致死作用，同时缩短了小鼠的生育能力。因此，激酶非依赖性抑制可能是化疗女性的一种有效的卵巢保护策略。
