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

(2014) HUMAN REPRODUCTION. 29(1). p.107-113
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Abstract
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? S1P can block human apoptotic follicle death induced by both drugs, which have differing mechanisms of cytotoxicity. 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. 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. Xenografted mice were treated with Cy (75 mg/kg), CyS1P (200 M), Doxo (10 mg/kg), DoxoS1P 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. Both Cy and Doxo resulted in a significant increase in apoptotic follicle death in human ovarian xenografts compared with controls (62.0 3.9 versus 25.7 7.4, P 0.01 and 76.7 7.4 versus 25.7 7.4, P 0.01, respectively). This chemotherapy-induced apoptotic death was reduced both in the CyS1P (32.7 4.4, P 0.01) and the DoxoS1P group (27.1 7.6, P 0.01) compared with Cy and Doxo groups, respectively. In the DoxoS1P and CyS1P groups, the percentages of apoptotic follicles were similar to those of vehicle-treated controls (P 0.05). The findings from the ovaries of the severe combined immunodeficient mice mirrored the findings with human tissue. The functionality of the rescued human ovarian follicles needs to be evaluated in future studies though the studies in rodents showed that rescued oocytes can result in healthy offspring. In addition, the impact of S1P on cancer cells should be further studied. S1P and its future analogs hold promise for preserving fertility by pharmacological means for patients undergoing chemotherapy.
Keywords
AUTOTRANSPLANTATION, METAANALYSIS, TRANSPLANTATION, DAMAGE, HORMONE, APOPTOSIS, FEMALE FERTILITY, BREAST-CANCER, SIGNALING PATHWAY, CRYOPRESERVED OVARIAN TISSUE, Sphingosine-1-phosphate, cyclophosphamide, doxorubicin, apoptosis, human ovarian xenograft

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Please use this url to cite or link to this publication:

Chicago
Li, Fang, Volkan Turan, Sylvie Lierman, Claude Cuvelier, Petra De Sutter, and Kutluk Oktay. 2014. “Sphingosine-1-phosphate Prevents Chemotherapy-induced Human Primordial Follicle Death.” Human Reproduction 29 (1): 107–113.
APA
Li, Fang, Turan, V., Lierman, S., Cuvelier, C., De Sutter, P., & Oktay, K. (2014). Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death. HUMAN REPRODUCTION, 29(1), 107–113.
Vancouver
1.
Li F, Turan V, Lierman S, Cuvelier C, De Sutter P, Oktay K. Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death. HUMAN REPRODUCTION. 2014;29(1):107–13.
MLA
Li, Fang, Volkan Turan, Sylvie Lierman, et al. “Sphingosine-1-phosphate Prevents Chemotherapy-induced Human Primordial Follicle Death.” HUMAN REPRODUCTION 29.1 (2014): 107–113. Print.
@article{4246655,
  abstract     = {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?
S1P can block human apoptotic follicle death induced by both drugs, which have differing mechanisms of cytotoxicity.
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.
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.
Xenografted mice were treated with Cy (75 mg/kg), CyS1P (200 M), Doxo (10 mg/kg), DoxoS1P 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.
Both Cy and Doxo resulted in a significant increase in apoptotic follicle death in human ovarian xenografts compared with controls (62.0 3.9 versus 25.7 7.4, P 0.01 and 76.7 7.4 versus 25.7 7.4, P 0.01, respectively). This chemotherapy-induced apoptotic death was reduced both in the CyS1P (32.7 4.4, P 0.01) and the DoxoS1P group (27.1 7.6, P 0.01) compared with Cy and Doxo groups, respectively. In the DoxoS1P and CyS1P groups, the percentages of apoptotic follicles were similar to those of vehicle-treated controls (P 0.05). The findings from the ovaries of the severe combined immunodeficient mice mirrored the findings with human tissue.
The functionality of the rescued human ovarian follicles needs to be evaluated in future studies though the studies in rodents showed that rescued oocytes can result in healthy offspring. In addition, the impact of S1P on cancer cells should be further studied.
S1P and its future analogs hold promise for preserving fertility by pharmacological means for patients undergoing chemotherapy.},
  author       = {Li, Fang and Turan, Volkan and Lierman, Sylvie and Cuvelier, Claude and De Sutter, Petra and Oktay, Kutluk},
  issn         = {0268-1161},
  journal      = {HUMAN REPRODUCTION},
  keywords     = {AUTOTRANSPLANTATION,METAANALYSIS,TRANSPLANTATION,DAMAGE,HORMONE,APOPTOSIS,FEMALE FERTILITY,BREAST-CANCER,SIGNALING PATHWAY,CRYOPRESERVED OVARIAN TISSUE,Sphingosine-1-phosphate,cyclophosphamide,doxorubicin,apoptosis,human ovarian xenograft},
  language     = {eng},
  number       = {1},
  pages        = {107--113},
  title        = {Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death},
  url          = {http://dx.doi.org/10.1093/humrep/det391},
  volume       = {29},
  year         = {2014},
}

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