Mahaut Leconte1, Pietro Santulli2, Sandrine Chouzenoux3, Louis Marcellin4, Olivier Cerles3, Charles Chapron4, Bertrand Dousset1, Frédéric Batteux5. 1. Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Digestive and Endocrine Surgery, Hôpital Cochin, AP-HP, Paris cedex, France. 2. Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Gynecology Obstetrics II and Reproductive Medicine, Faculty of Medicine, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin, University Paris Descartes, Sorbonne Paris Cité, Paris, France Institut Cochin, University Paris Descartes, Sorbonne Paris Cité CNRS (UMR 8104), Paris, France pietro.santulli@cch.aphp.fr. 3. Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France. 4. Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Gynecology Obstetrics II and Reproductive Medicine, Faculty of Medicine, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin, University Paris Descartes, Sorbonne Paris Cité, Paris, France Institut Cochin, University Paris Descartes, Sorbonne Paris Cité CNRS (UMR 8104), Paris, France. 5. Department of "Development, Reproduction and Cancer", Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France Department of Immunology, Hôpital Cochin, AP-HP, Paris cedex, France.
Abstract
INTRODUCTION: Sorafenib is a strong multikinase inhibitor targeting 2 different pathways of endometriosis pathogenesis: RAF kinase and vascular endothelial growth factor receptor (VEGFR). We investigate whether Sorafenib could control the growth of endometriotic lesions both in vitro and in vivo. METHODS: Stromal primary cells were extracted from endometrial and endometriotic biopsies from patients with (n = 10) and without (n = 10) endometriosis. Proliferation, apoptosis, mitogen-activated protein kinases, and VEGFR-2 autophosphorylation were explored with and without Sorafenib treatment. Human endometriotic lesions were implanted in 30 nude mice randomized according to Sorafenib or placebo treatment. RESULTS: Treating endometriotic cells with Sorafenib abrogated the phosphorylation of extracellular signal-regulated kinase in stromal cells of women with endometriosis compared to controls. In addition, this study highlights the antiangiogenic role of Sorafenib which translates as a decreased phosphorylated VEGFR-2-VEGFR-2 ratio in endometriosis. Using a xenogenic mouse model of endometriosis, we confirmed that Sorafenib regulates the endometriosis activity in vivo by targeting endometriosis-related proliferation and inflammation. CONCLUSION: Our data suggest that Sorafenib controls the growth of endometriotic lesions in vitro and in vivo.
INTRODUCTION:Sorafenib is a strong multikinase inhibitor targeting 2 different pathways of endometriosis pathogenesis: RAF kinase and vascular endothelial growth factor receptor (VEGFR). We investigate whether Sorafenib could control the growth of endometriotic lesions both in vitro and in vivo. METHODS: Stromal primary cells were extracted from endometrial and endometriotic biopsies from patients with (n = 10) and without (n = 10) endometriosis. Proliferation, apoptosis, mitogen-activated protein kinases, and VEGFR-2 autophosphorylation were explored with and without Sorafenib treatment. Humanendometriotic lesions were implanted in 30 nude mice randomized according to Sorafenib or placebo treatment. RESULTS: Treating endometriotic cells with Sorafenib abrogated the phosphorylation of extracellular signal-regulated kinase in stromal cells of women with endometriosis compared to controls. In addition, this study highlights the antiangiogenic role of Sorafenib which translates as a decreased phosphorylated VEGFR-2-VEGFR-2 ratio in endometriosis. Using a xenogenic mouse model of endometriosis, we confirmed that Sorafenib regulates the endometriosis activity in vivo by targeting endometriosis-related proliferation and inflammation. CONCLUSION: Our data suggest that Sorafenib controls the growth of endometriotic lesions in vitro and in vivo.