Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death

作者：F. Li, Volkan Turan, Sylvie Lierman, Claude Cuvelier, Petra De Sutter, Kutluk Oktay · 发表于：Human Reproduction · 年份：2013 · DOI：10.1093/humrep/det391 · 被引用次数：177 · 研究领域：Reproductive Biology and Fertility、Ovarian cancer diagnosis and treatment、Sphingolipid Metabolism and Signaling

STUDY QUESTION: Can Sphingosine-1-phosphate (S1P), a ceramide-induced death pathway inhibitor, prevent cyclophosphamide (Cy) or doxorubicin (Doxo) induced apoptotic follicle death in human ovarian xenografts? SUMMARY ANSWER: S1P can block human apoptotic follicle death induced by both drugs, which have differing mechanisms of cytotoxicity. WHAT IS KNOWN ALREADY: S1P has been shown to decrease the impact of chemotherapy and radiation on germinal vesicle oocytes in animal studies but no human translational data exist. STUDY DESIGN, SIZE, DURATION: Experimental human ovarian xenografting to test the in vivo protective effect of S1P on primordial follicle survival in the chemotherapy setting. The data were validated by assessing the same protective effect in the ovaries of xenografted mice in parallel. PARTICIPANTS/MATERIALS, SETTING, METHODS: Xenografted mice were treated with Cy (75 mg/kg), Cy+S1P (200 μM), Doxo (10 mg/kg), Doxo+S1P or vehicle only (Control). S1P was administered via continuous infusion using a mini-osmotic pump beginning 24 h prior to and ending 72 h post-chemotherapy. Grafts were then recovered and stained with anti-caspase 3 antibody for the detection of apoptosis in primordial follicles. The percentage of apoptotic to total primordial follicles was calculated in each group. MAIN RESULTS AND THE ROLE OF CHANCE: Both Cy and Doxo resulted in a significant increase in apoptotic follicle death in human ovarian xenografts compared with controls (62.0 ± 3.9% versu...