title: Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo.
abstract: Endometriosis affects 6-10% of women in their reproductive years, causing chronic pelvic pain and infertility. Its pathogenesis remains poorly understood and current treatments, based on hormonal therapy or surgery, are often insufficient. The purpose of our study was to investigate the role of the ERK pathway in the development of endometriosis and to test the effects of protein kinase inhibitors on the proliferation of endometriotic cells in vitro and in vivo. We studied ex vivo human endometrial and endometriotic cells in culture. Stromal and epithelial cells were extracted from endometrial and endometriotic biopsies from patients with endometriosis and from patients without endometriosis. The ERK pathway was explored by western blot on cell lysates and by ELISA on total crushed specimens of endometrium. Cells in culture were treated with A771726, PD98059, and U0126. Human endometriotic lesions were implanted in nude mice. Mice were treated with A771726, leflunomide, PD98059, U0126 or PBS during 2 weeks before sacrifice and extraction of the endometriotic implants for histological examination. We found that the ERK pathway was significantly activated in endometriotic cells and in endometrial cells from patients with endometriosis compared to endometrial cells of control patients, both by ELISA and by western blot. This phenomenon was associated with an increased proliferation of endometriotic cells compared to endometrial cells. Treating endometriotic cells with A771726, PD98059 or U0126 abrogated the phosphorylation of ERK and significantly decreased the cellular proliferation in vitro. In vivo, A771726, leflunomide, PD98059, and U0126 controlled the growth of endometriotic implants in the mouse model of endometriosis. Our study shows that protein kinase inhibitors could be new candidates to treat endometriosis. However, further studies are needed to evaluate their effects and tolerability in humans.
authors.affiliation: Université Paris Descartes, Faculté de Médecine, EA 1833 AP-HP Hôpital Cochin, 75679 Paris Cedex 14, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ngô
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Mahaut
authors.initials: M
authors.lastname: Leconte
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Sylviane
authors.initials: S
authors.lastname: Arkwright
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Vacher-Lavenu
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.forename: Charles
authors.initials: C
authors.lastname: Chapron
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004715:Endometriosis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004717:Endometrium / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000637:transplantation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004847:Epithelial Cells / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017154:Stromal Cells / Q000473:pathology
chemical_list: D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases