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Inhibition of MAPK and VEGFR by Sorafenib Controls the Progression of Endometriosis

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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.

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Authors and Affiliations

  1. Department of “Development, Reproduction and Cancer”, Institut Cochin, INSERM U1016, University Paris Descartes, Sorbonne Paris Cité, Paris, France

    Mahaut Leconte MD, PhD, Pietro Santulli MD, PhD, Sandrine Chouzenoux, Louis Marcellin MD, Olivier Cerles MSCI, Charles Chapron MD, Bertrand Dousset MD & Frédéric Batteux MD, PhD

  2. Department of Digestive and Endocrine Surgery, Hôpital Cochin, AP-HP, Paris cedex, France

    Mahaut Leconte MD, PhD & Bertrand Dousset MD

  3. 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

    Pietro Santulli MD, PhD, Louis Marcellin MD & Charles Chapron MD

  4. Institut Cochin, University Paris Descartes, Sorbonne Paris Cité CNRS (UMR 8104), Paris, France

    Pietro Santulli MD, PhD, Louis Marcellin MD & Charles Chapron MD

  5. Department of Immunology, Hôpital Cochin, AP-HP, Paris cedex, France

    Frédéric Batteux MD, PhD

  6. Department of Gynecology Obstetrics II and Reproductive Medicine, Port Royal—Hôpitaux Universitaires Paris Centre, 53, avenue de l’Observatoire, 75679, Paris 14, France

    Pietro Santulli MD, PhD

Authors
  1. Mahaut Leconte MD, PhD
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  2. Pietro Santulli MD, PhD
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  3. Sandrine Chouzenoux
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  4. Louis Marcellin MD
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  5. Olivier Cerles MSCI
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  6. Charles Chapron MD
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  8. Frédéric Batteux MD, PhD
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Corresponding author

Correspondence to Pietro Santulli MD, PhD.

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Leconte, M., Santulli, P., Chouzenoux, S. et al. Inhibition of MAPK and VEGFR by Sorafenib Controls the Progression of Endometriosis. Reprod. Sci. 22, 1171–1180 (2015). https://doi.org/10.1177/1933719115592708

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