The mTOR/AKT Inhibitor Temsirolimus Prevents Deep Infiltrating Endometriosis in Mice

Laboratory of Immunology, Paris Descartes University, Hospital Cochin, Paris, France.
American Journal Of Pathology (Impact Factor: 4.59). 06/2011; 179(2):880-9. DOI: 10.1016/j.ajpath.2011.04.020
Source: PubMed

ABSTRACT Deep infiltrating endometriosis (DIE) is a particular clinical and histological entity of endometriosis responsible for chronic pelvic pain and infertility. Here we characterize the proliferative phenotype of DIE cells, to explore the cellular and molecular mechanisms that could explain their aggressive potential. In addition, the inhibition of mTOR/AKT pathway was tested, as a potential treatment of DIE. Included were 22 patients with DIE and 12 control patients without endometriosis. Epithelial and stromal cells were extracted from biopsies of eutopic endometrium and deep infiltrating endometriotic nodules from patients with DIE. Cell proliferation was determined by thymidine incorporation. Oxidative stress was assayed by spectrofluorometry. The ERK and mTOR/AKT pathways were analyzed in vitro by Western blot and for AKT in vivo in a mouse model of DIE. The proliferation rate of eutopic endometrial cells and of deep infiltrating endometriotic cells from DIE patients was higher than that of endometrial cells from controls. The hyperproliferative phenotype of endometriotic cells was associated with an increase in endogenous oxidative stress, and with activation of the ERK and mTOR/AKT pathways. mTOR/AKT inhibition by temsirolimus decreased endometriotic cell proliferation both in vitro and in vivo in a mouse model of DIE. Blocking the mTOR/AKT pathway offers new prospects for the treatment of DIE.

Download full-text


Available from: Mahaut Leconte, Sep 29, 2015
40 Reads
  • Source
    • "Oestrogen-induced ROS play important roles in cell proliferation, migration, invasion and cell transformation, by increasing genomic instability and by transducing signal through redox sensitive transcription factors (Okoh et al., 2011). Various sources of evidence support the role of oxidants in the development of endometriosis, a metastatic benign pathology (Borghese et al., 2010), as endometriotic cells show higher endogenous oxidative stress with increased ROS production and alterations in ROS detoxification pathways (Ngo et al., 2009; Leconte et al., 2011). However, despite evidence that oxidative stress may play a role in endometriosis (Agarwal et al., 2005), to date no study has explored the peritoneal fluid protein oxidative status. "
    [Show abstract] [Hide abstract]
    ABSTRACT: STUDY QUESTION Are protein oxidative stress markers [thiols, advanced oxidation protein products (AOPP), protein carbonyls and nitrates/nitrites] in perioperative peritoneal fluid higher in women with histologically proven endometriosis when compared with endometriosis-free controls?
    Human Reproduction 11/2014; 30(1). DOI:10.1093/humrep/deu290 · 4.57 Impact Factor
  • Source
    • "Only patients with complete surgical exploration of the abdominopelvic cavity have been included in our series; (ii) all patients underwent a preoperative protocol work-up including TVUS during the month preceding the surgery. All scans were performed by a single experienced radiologist (AEM); (iii) only women with histologically proven uterine leiomyomas were allocated in the leiomyoma group; (iv) for the homogeneity of the study, the control group only included women with benign ovarian cysts, paratubal cysts or tubal defects without any evidence of uterine leiomyoma; (v) because endometriotic cells display a high endogenous oxidative stress with an increase in ROS production and alterations in ROS detoxification pathways [15,16], women with endometriosis were not included in the study; (vi) although some studies have suggested the relationship between oxidative stress and uterine leiomyoma [22–25], none of these studies have focused on the oxidative status in sera from women with leiomyoma. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Uterine leiomyomas (fibroids) are the most common gynaecological benign tumors in premenopausal women. Evidences support the role of oxidative stress in the development of uterine leiomyoma. We have analysed oxidative stress markers (thiols, advanced oxidized protein products (AOPP), protein carbonyls and nitrates/nitrites) in preoperative sera from women with histologically proven uterine leiomyoma. We conducted a laboratory study in a tertiary-care university hospital. Fifty-nine women with histologically proven uterine leiomyoma and ninety-two leiomyoma-free control women have been enrolled in this study. Complete surgical exploration of the abdominopelvic cavity was performed in each patient. Preoperative serum samples were obtained from all study participants to assay serum thiols, AOPP, protein carbonyls and nitrates/nitrites. Concentrations of serum protein carbonyl groups and AOPP were higher in leiomyoma patients than in the control group (p=0.005 and p<0.001, respectively). By contrast, serum thiol levels were lower in leiomyoma patients (p<0.001). We found positive correlations between serum AOPP concentrations and total fibroids weight (r=0.339; p=0.028), serum AOPP and serum protein carbonyls with duration of infertility (r=0.762; p=0.006 and r=0.683; p=0.021, respectively). This study, for the first time, reveals a significant increase of protein oxidative stress status and reduced antioxidant capacity in sera from women with uterine leiomyoma.
    PLoS ONE 08/2013; 8(8):e72069. DOI:10.1371/journal.pone.0072069 · 3.23 Impact Factor
  • Source
    • "Elle doit tenir compte du désir de grossesse, de la présence de facteurs d'infertilité associés, du caractère multifocal des lésions et de l'hétérogénéité de la maladie. Il n'existe à ce jour aucun traitement agissant sur les mécanismes à l'origine de la maladie, même si de nouveaux traitements comme les anti-aromatases [63] [64], les anti-oxydants [64], les antimétabolites comme le 5-FU [65], les inhibiteurs de protéine kinase [66], les inhibiteurs de la voie ERK et de la voie Akt [67] ou encore les agonistes des cannabinoïdes [68] expérimentés chez l'animal semblent prometteur. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Endometriosis affects 6 to 10 % of all women of childbearing age. Intestinal involvement is defined by muscularis infiltration and has been estimated to occur in 8 % to 12 % of women with endometriosis. The most common sites are rectum, sigmoid and ileocaecal junction. In most cases, intestinal endometriosis is associated with deep infiltrating endometriosis, multifocal and aggressive form of endometriosis, responsible for refractory pelvic pain and infertility. The symptoms are nonspecific but are characterized by cyclic exacerbation of pain. The preoperative work-up includes a rectal endoscopic ultrasonography, a transvaginal ultrasonography, a pelvic magnetic resonance imaging and a multidetector CT scan. There is currently no cure other than surgical removal of lesions. Medical treatments are based on a hormone used to block ovarian function.
    La Presse Médicale 10/2011; 41(4):358-66. · 1.08 Impact Factor
Show more