Pharmacologic therapies in endometriosis: a systematic review
2012; Elsevier BV; Volume: 98; Issue: 3 Linguagem: Inglês
10.1016/j.fertnstert.2012.07.1120
ISSN1556-5653
AutoresSérgio Reis Soares, Alicia Martínez‐Varea, Juan José Hidalgo‐Mora, António Pellicer,
Tópico(s)Endometrial and Cervical Cancer Treatments
ResumoTo assess the literature on preclinical and clinical efficacy and safety data of pharmacologic groups proposed in the treatment of endometriosis, we performed a systematic review of publications from March 2002 to January 2012 via PubMed search. Additional relevant articles were identified from citations within these publications. A high number of medications were tested in preclinical models of endometriosis due to their theoretic capacity of disrupting important pathophysiologic pathways of the disease, such as inflammatory response, angiogenesis and cell survival, proliferation, migration, adhesion, and invasion. Tumor necrosis factor α-blockers, nuclear factor κB inhibitors, antiangiogenic agents, statins, antioxidants, immunomodulators, flavonoids, histone deacetylase inhibitors, matrix metalloproteinase inhibitors, metformin, novel modulators of sex steroids expression, and apoptotic agents were all effective in in vitro/animal models. Most of these agents have not been tried in the clinical setting, mainly because of the high risk of adverse effects. However, some of them can be used in humans. Dopamine agonists and valproic acid have already been tested in pilot studies with good results. Etanercept, metformin, and statins are used in humans for other indications, and endostatin is now being tested in phase 2 oncologic trials. These drugs may constitute alternatives to conventional therapy with estrogen inhibitors and anti-inflammatory agents. To assess the literature on preclinical and clinical efficacy and safety data of pharmacologic groups proposed in the treatment of endometriosis, we performed a systematic review of publications from March 2002 to January 2012 via PubMed search. Additional relevant articles were identified from citations within these publications. A high number of medications were tested in preclinical models of endometriosis due to their theoretic capacity of disrupting important pathophysiologic pathways of the disease, such as inflammatory response, angiogenesis and cell survival, proliferation, migration, adhesion, and invasion. Tumor necrosis factor α-blockers, nuclear factor κB inhibitors, antiangiogenic agents, statins, antioxidants, immunomodulators, flavonoids, histone deacetylase inhibitors, matrix metalloproteinase inhibitors, metformin, novel modulators of sex steroids expression, and apoptotic agents were all effective in in vitro/animal models. Most of these agents have not been tried in the clinical setting, mainly because of the high risk of adverse effects. However, some of them can be used in humans. Dopamine agonists and valproic acid have already been tested in pilot studies with good results. Etanercept, metformin, and statins are used in humans for other indications, and endostatin is now being tested in phase 2 oncologic trials. These drugs may constitute alternatives to conventional therapy with estrogen inhibitors and anti-inflammatory agents. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/soaressr-pharmacological-therapies-endometriosis-review/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/soaressr-pharmacological-therapies-endometriosis-review/ Pharmacologic therapy is based on targeting molecular steps that are relevant for the pathophysiologic process of a disease. The pathophysiology of endometriosis comprises the inflammatory response, cell survival, proliferation, migration, adhesion and invasion, and neoangiogenesis. The molecular pathways involved in these processes are all integrated (Fig. 1). Medications capable of affecting the activity of one molecule very often interfere with several processes simultaneously. Moreover, in a number of cases, one agent may actually have a direct impact on more than one pathophysiologic target. The "major proinflammatory cytokines/transcription factors axis" is the crossroads of the molecular pathways involved in the fundamental aspects of the pathophysiology of endometriosis. It is the core of the rich and intricate interconnection that exists among them. Cytokines such as tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), released by peritoneal macrophages and ectopic endometrial cells, activate transcription factors such as nuclear factor-κB (NF-κB) and activator protein 1 (AP-1). Active transcription factors bind to the DNA of ectopic endometrial/endometriotic cells and induce the transcriptional activity of genes that encode for the following products:1.Other cytokines, such as IL-6, IL-8, macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein (MCP-1), granulocyte macrophage colony-stimulating factor (GM-CSF), and TNF-α and IL-1β themselves (1González-Ramos R. Van Langendonckt A. Defrère S. Lousse J.-C. Colette S. Devoto L. et al.Involvement of the nuclear factor-қB pathway in the pathogenesis of endometriosis.Fertil Steril. 2010; 94: 1985-1994Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 2Yagyu T. Kobayashi H. Matsuzaki H. Wakahara K. Kondo T. Kurita N. et al.Thalidomide inhibits tumor necrosis factor-α-induced interleukin-8 expression in endometriotic stromal cells, possibly through suppression of nuclear factor-κB activation.J Clin Endocrinol Metab. 2005; 90: 3017-3021Crossref PubMed Scopus (41) Google Scholar, 3Huber A.V. Saleh L. Prast J. Haslinger P. Knöfler M. Human chorionic gonadotropin attenuates NF-κB activation and cytokine expression of endometriotic stromal cells.Mol Hum Reprod. 2007; 13: 595-604Crossref PubMed Scopus (20) Google Scholar, 4Grund E.M. Kagan D. Tran C.A. Zeitvogel A. Starzinski-Powitz A. Nataraja S. et al.Tumor necrosis factor-α regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase, p38, and nuclear factor-κB in human endometriotic epithelial cells.Mol Pharm. 2008; 73: 1394-1404Crossref Scopus (53) Google Scholar).2.Nitric oxide (NO) and vascular endothelial growth factor (VEGF), the most prominent proangiogenic factor in endometriosis (5Zhang J.J. Xu Z.M. Dai H.Y. Ji X.Q. Duan Y.Y. Zhang C.M. et al.Application of the nuclear factor-κB inhibitor pyrrolidine dithiocarbamate for the treatment of endometriosis: an in vitro study.Fertil Steril. 2010; 94: 2942-2944Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar).3.Matrix metalloproteinases (MMPs)—MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9—involved in the degradation and remodeling of the extracellular matrix of the peritoneal surface (4Grund E.M. Kagan D. Tran C.A. Zeitvogel A. Starzinski-Powitz A. Nataraja S. et al.Tumor necrosis factor-α regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase, p38, and nuclear factor-κB in human endometriotic epithelial cells.Mol Pharm. 2008; 73: 1394-1404Crossref Scopus (53) Google Scholar, 5Zhang J.J. Xu Z.M. Dai H.Y. Ji X.Q. Duan Y.Y. Zhang C.M. et al.Application of the nuclear factor-κB inhibitor pyrrolidine dithiocarbamate for the treatment of endometriosis: an in vitro study.Fertil Steril. 2010; 94: 2942-2944Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 6Zhang J.J. Xu Z.M. Zhang C.M. Dai H.Y. Ji X.Q. Wang X.F. et al.Pyrrolidine dithiocarbamate inhibits nuclear factor-κB pathway activation and regulates adhesion, migration, invasion and apoptosis of endometriotic stromal cells.Mol Hum Reprod. 2011; 17: 175-181Crossref PubMed Scopus (21) Google Scholar, 7Zhang H.I. Li M. Wang F. Liu S. Li J. Wen Z. et al.Endometriotic epithelial cells induce MMPs expression in endometrial stromal cells via an NFқB-dependent pathway.Gynecol Endocrinol. 2010; 26: 456-467Crossref PubMed Scopus (4) Google Scholar).4.Increased antiapoptotic gene profile (6Zhang J.J. Xu Z.M. Zhang C.M. Dai H.Y. Ji X.Q. Wang X.F. et al.Pyrrolidine dithiocarbamate inhibits nuclear factor-κB pathway activation and regulates adhesion, migration, invasion and apoptosis of endometriotic stromal cells.Mol Hum Reprod. 2011; 17: 175-181Crossref PubMed Scopus (21) Google Scholar, 8Nasu K. Nishida M. Ueda T. Yuge A. Takai N. Narahara H. Application of the nuclear factor-κB inhibitor BAY 11–7085 for the treatment of endometriosis: an in vitro study.Am J Phisiol Endocrinol Metab. 2007; 293: E16-E23Crossref PubMed Scopus (32) Google Scholar, 9Kim J.H. Yang Y.I. Lee K.T. Park H.J. Choi J.H. Costunolide induces apoptosis in human endometriotic cells through inhibition of the prosurvival Akt and nuclear factor kappa B signaling pathway.Biol Pharm Bull. 2011; 34: 580-585Crossref PubMed Scopus (14) Google Scholar).5.Adhesion molecules, such as CD-44s (a cell surface glycoprotein involved in the adhesion of endometrial cells to peritoneal mesothelial cells), intercellular adhesion molecule 1 (ICAM-1, also a cytokine), and vascular cell adhesion molecule 1 (VCAM-1) (4Grund E.M. Kagan D. Tran C.A. Zeitvogel A. Starzinski-Powitz A. Nataraja S. et al.Tumor necrosis factor-α regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase, p38, and nuclear factor-κB in human endometriotic epithelial cells.Mol Pharm. 2008; 73: 1394-1404Crossref Scopus (53) Google Scholar, 5Zhang J.J. Xu Z.M. Dai H.Y. Ji X.Q. Duan Y.Y. Zhang C.M. et al.Application of the nuclear factor-κB inhibitor pyrrolidine dithiocarbamate for the treatment of endometriosis: an in vitro study.Fertil Steril. 2010; 94: 2942-2944Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 6Zhang J.J. Xu Z.M. Zhang C.M. Dai H.Y. Ji X.Q. Wang X.F. et al.Pyrrolidine dithiocarbamate inhibits nuclear factor-κB pathway activation and regulates adhesion, migration, invasion and apoptosis of endometriotic stromal cells.Mol Hum Reprod. 2011; 17: 175-181Crossref PubMed Scopus (21) Google Scholar). Therefore, the definition of therapeutic agents as "anti-inflammatory," "immunomodulators," or "inducers of apoptosis" is, to a non-negligible extent, too reductionist, especially if they relate to the major proinflammatory cytokines/transcription factors axis. Still, for the sake of organization, some classification cannot be avoided. Whenever possible, we have tried to classify a pharmacologic agent according to its most immediate and direct molecular effect. For instance, any molecule that inhibits estrogen production may ultimately lead to, among other things, reduced angiogenesis, but this agent is classified as a sex steroid expression modulator rather than an antiangiogenic agent. Pharmacologic groups were divided in two: those only tested in experimental in vitro and animal models, and those with at least one agent already tested in the treatment of endometriosis in humans. We provide a systematic review of the literature available in the PubMed database on clinical and experimental in vitro and animal studies on pharmacologic therapy in endometriosis, published in English or in Spanish, from March 2002 to January 2012. Classic therapies for which the most relevant studies were published more than 10 years ago have already been extensively reviewed—such as gonadotropin-releasing hormone (GnRH) agonists, danazol, and oral contraceptive pills (OCPs)—and are not included in this systematic review. Table 1 shows the list of medications searched for. Terms were searched in combination with the word "endometriosis," as in this example: "endometriosis AND TNF-α blockers." Additional relevant articles were identified from citations within these publications. References with abstracts that demonstrated them to be unrelated to the pharmacologic treatment of endometriosis were excluded without a full text assessment, as were reviews and case reports. All original articles with abstracts that indicated them to be within the scope of this study were fully assessed; when this assessment was confirmed, they were included in the review (10Liberati A. Altman D.G. Tetzlaff J. Mulrow C. Gøtzsche P.C. Ioannidis J.P. et al.The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.Ann Intern Med. 2009; 151: W-65-W-94Crossref Google Scholar). Figure 2 summarizes the steps involved in literature selection based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Institutional review board approval did not apply.Table 1Terms searched at Pubmed: medications in combination with "endometriosis."AnginexAngiostatinAnti-oxidantsApoptotic agent(s)Aromatase inhibitorsClomiphene citrateContraceptive AND patchesContraceptive AND vaginal ringCOX-2 inhibitorsDopamine agonistsEndostatinEtanerceptFlavonoidsGnRH-antagonistsHistone deacetylase inhibitorHyaluronic acidImiquimodInterleukin-12IsoflavonesLeflunomideLevamisoleMatrix metalloproteinase inhibitorMelatoninMetforminMitogen activated protein kinase inhibitorNuclear factor kappa B inhibitorsPatchesPeroxisome proliferator activated receptorProgesteroneProgesterone receptor bindingProgesterone receptor modulatorRapamycinSelective estrogen receptor beta agonistSelective estrogen receptor modulatorsSoluble flt-1StatinsThalidomideTNF-α blockersTNP-470VEGF blockersVEGF inhibitors Open table in a new tab The inflammatory cytokine TNF-α is a potent inducer of the activation of transcription factors that determine the production of proteins that coordinate the pathophysiology of endometriosis. Specific TNF-α blockers or general anti-inflammatory agents may interfere with this process (11Falconer H. Mwenda J.M. Chai D.C. Song X.Y. Cornillie F.J. Bergqvist A. et al.Effects of anti-TNF-mAb treatment on pregnancy in baboons with induced endometriosis.Fertil Steril. 2008; 89: 1537-1545Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). In this section, we focus on specific TNF-α blockers (anti-inflammatory agents are described later). Soluble TNF-α receptor 1 (also known as TNF-binding protein, or TBP) has been demonstrated to block the transcription of inflammatory cytokines involved in endometriosis in the immortalized 12Z epithelial endometriotic cell line (4Grund E.M. Kagan D. Tran C.A. Zeitvogel A. Starzinski-Powitz A. Nataraja S. et al.Tumor necrosis factor-α regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase, p38, and nuclear factor-κB in human endometriotic epithelial cells.Mol Pharm. 2008; 73: 1394-1404Crossref Scopus (53) Google Scholar). In human endometriotic stromal cell (hESCs) cultures, small interfering RNA (si-RNA) that silences the TNF-α gene was shown to determine the down-regulation of the expression of IL-8 and genes that inhibit apoptosis, which are major markers of the TNF-α activated NF-κB pathway (12Miyamoto A. Taniguchi F. Tagashira Y. Watanabe A. Harada T. Terakawa N. TNFα gene silencing reduced lypopolisaccharide-promoted proliferation of endometriotic stromal cells.Am J Reprod Immunol. 2009; 61: 277-285Crossref PubMed Scopus (4) Google Scholar). Etanercept is a fusion protein consisting of human recombinant soluble TNF receptor 2 (p75) conjugated to a human Fc antibody subunit, which neutralizes TNF activity. It is used for rheumatoid arthritis, juvenile rheumatoid arthritis, and psoriatic arthritis, with no known serious adverse effects with long-term usage. In vitro, enhanced proliferation observed in epithelial and hESCs cultured with peritoneal fluid from patients has been shown to be significantly inhibited by this agent (13Braun D.P. Ding J. Dmowski W.P. Peritoneal fluid-mediated enhancement of eutopic and ectopic endometrial cell proliferation is dependent on tumor necrosis factor-alpha in women with endometriosis.Fertil Steril. 2002; 78: 727-732Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). The effects of etanercept on endometriotic implants in a rat model were evaluated in randomized controlled studies (14Yildirim G. Attar R. Ficicioglu C. Karateke A. Ozkan F. Yesildaglar N. Etanercept causes regression of endometriotic implants in a rat model.Arch Gynecol Obstet. 2011; 283: 1297-1302Crossref PubMed Scopus (6) Google Scholar, 15Islimye M. Kilic S. Zulfikaroglu E. Topcu O. Zergeroglu S. Batioglu S. Regression of endometrial autografts in a rat model of endometriosis treated with etanercept.Eur J Obstet Gynecol Reprod Biol. 2011; 159: 184-189Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 16Zulfikaroglu E. Kilic S. Islimye M. Aydin M. Zergeroglu S. Batioglu S. Efficacy of anti-tumor necrosis factor therapy on endometriosis in an experimental rat model.Arch Gynecol Obstet. 2011; 283: 799-804Crossref PubMed Scopus (7) Google Scholar, 17Cayci T. Akgul E.O. Kurt Y.G. Ceyhan T.S. Aydin I. Onguru O. et al.The levels of nitric oxide and asymmetric dimethylarginine in the rat endometriosis model.J Obstet Gynaecol Res. 2011; 37: 1041-1047Crossref PubMed Scopus (5) Google Scholar). Treated animals showed significant changes in the volume of lesions, histopathologic scores, and molecular parameters such as serum levels of VEGF, IL-6, and TNF-α. The same effect was observed with the use of infliximab (a monoclonal antibody against TNF-α) (17Cayci T. Akgul E.O. Kurt Y.G. Ceyhan T.S. Aydin I. Onguru O. et al.The levels of nitric oxide and asymmetric dimethylarginine in the rat endometriosis model.J Obstet Gynaecol Res. 2011; 37: 1041-1047Crossref PubMed Scopus (5) Google Scholar). Both etanercept and infliximab reduced endometriotic implants and plasma NO levels, while the levels of asymmetric dimethyl arginine (ADMA), an endogenous nitric oxide synthase (NOS) antagonist, were increased. The use of etanercept in spontaneous peritoneal endometriosis in baboons was tested in a randomized, controlled, blinded study that included 12 animals that received either etanercept or placebo (18Barrier B.F. Bates G.W. Leland M.M. Leach D.A. Robinson R.D. Propst A.M. Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons.Fertil Steril. 2004; 81: 775-779Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). In spite of the small sample size, a statistically significant decrease in red lesion surface area was noted in the treatment group. The efficacy of c5N, a specific anti-TNF-α monoclonal antibody (mAb), in the reduction of established lesions in experimental endometriosis induced in baboons was also tested in a randomized controlled study (19Falconer H. Mwenda J.M. Chai D.C. Wagner C. Song X.Y. Mihalyi A. et al.Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon.Hum Reprod. 2006; 21: 1856-1862Crossref PubMed Scopus (50) Google Scholar). Laparoscopic controls were made the moment medication was administered and 25 days after treatment. The antibody significantly decreased the total number, surface area, and volume of endometriosis-like lesions, mainly through a reduction in the most active red lesions. No impact on the menstrual cycle was found. Later, the same animals included in this study were resubmitted to intravenous (IV) doses of c5N, and two of them died of unspecified causes (11Falconer H. Mwenda J.M. Chai D.C. Song X.Y. Cornillie F.J. Bergqvist A. et al.Effects of anti-TNF-mAb treatment on pregnancy in baboons with induced endometriosis.Fertil Steril. 2008; 89: 1537-1545Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Adverse events associated with TNF-α inhibitors such as malignancies and activation of latent infections were reported (20Colombel J.F. Loftus Jr., E.V. Tremaine W.J. Egan L.J. Harmsen W.S. Schleck C.D. et al.The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients.Gastroenterology. 2004; 126: 19-31Abstract Full Text Full Text PDF PubMed Scopus (651) Google Scholar). However, studies with animals and humans have yet to definitively tie etanercept, the TNF-α inhibitor currently used for the treatment of various inflammatory diseases, to such side effects (11Falconer H. Mwenda J.M. Chai D.C. Song X.Y. Cornillie F.J. Bergqvist A. et al.Effects of anti-TNF-mAb treatment on pregnancy in baboons with induced endometriosis.Fertil Steril. 2008; 89: 1537-1545Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). The use of other agents from this pharmacologic group in the treatment of endometriosis demands caution and should not be considered at present. The NF-κB peptide family comprises the most important group of transcription factors involved in the inflammatory and immune responses seen in endometriosis. Nuclear factor κB is activated by cytokines such as TNF-α and IL-1β and binds to DNA to determine key transcriptional activity (1González-Ramos R. Van Langendonckt A. Defrère S. Lousse J.-C. Colette S. Devoto L. et al.Involvement of the nuclear factor-қB pathway in the pathogenesis of endometriosis.Fertil Steril. 2010; 94: 1985-1994Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 21Sakamoto Y. Harada T. Horie S. Iba Y. Taniguchi F. Yoshida S. et al.Tumor necrosis factor-α-induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-κB activation: gonadotropin releasing hormone agonist treatment reduced IL-8 expression.J Clin Endocrinol Metab. 2003; 88: 730-735Crossref PubMed Scopus (79) Google Scholar). A number of substances have been presented in the literature on endometriosis as NF-κB inhibitors: molecules that act directly at NF-κB blocking, such as IκB protease inhibitor (TPCK), thalidomide, BAY 11-7085, the urinary preparation human chorionic gonadotropin A (hCG-A), pyrrolidinedithiocarbamate (PDTC), and costunolide; or others, such as GnRH agonists, known to treat endometriosis by inducing hypoestrogenemia (2Yagyu T. Kobayashi H. Matsuzaki H. Wakahara K. Kondo T. Kurita N. et al.Thalidomide inhibits tumor necrosis factor-α-induced interleukin-8 expression in endometriotic stromal cells, possibly through suppression of nuclear factor-κB activation.J Clin Endocrinol Metab. 2005; 90: 3017-3021Crossref PubMed Scopus (41) Google Scholar, 3Huber A.V. Saleh L. Prast J. Haslinger P. Knöfler M. Human chorionic gonadotropin attenuates NF-κB activation and cytokine expression of endometriotic stromal cells.Mol Hum Reprod. 2007; 13: 595-604Crossref PubMed Scopus (20) Google Scholar, 5Zhang J.J. Xu Z.M. Dai H.Y. Ji X.Q. Duan Y.Y. Zhang C.M. et al.Application of the nuclear factor-κB inhibitor pyrrolidine dithiocarbamate for the treatment of endometriosis: an in vitro study.Fertil Steril. 2010; 94: 2942-2944Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 6Zhang J.J. Xu Z.M. Zhang C.M. Dai H.Y. Ji X.Q. Wang X.F. et al.Pyrrolidine dithiocarbamate inhibits nuclear factor-κB pathway activation and regulates adhesion, migration, invasion and apoptosis of endometriotic stromal cells.Mol Hum Reprod. 2011; 17: 175-181Crossref PubMed Scopus (21) Google Scholar, 7Zhang H.I. Li M. Wang F. Liu S. Li J. Wen Z. et al.Endometriotic epithelial cells induce MMPs expression in endometrial stromal cells via an NFқB-dependent pathway.Gynecol Endocrinol. 2010; 26: 456-467Crossref PubMed Scopus (4) Google Scholar, 8Nasu K. Nishida M. Ueda T. Yuge A. Takai N. Narahara H. Application of the nuclear factor-κB inhibitor BAY 11–7085 for the treatment of endometriosis: an in vitro study.Am J Phisiol Endocrinol Metab. 2007; 293: E16-E23Crossref PubMed Scopus (32) Google Scholar, 9Kim J.H. Yang Y.I. Lee K.T. Park H.J. Choi J.H. Costunolide induces apoptosis in human endometriotic cells through inhibition of the prosurvival Akt and nuclear factor kappa B signaling pathway.Biol Pharm Bull. 2011; 34: 580-585Crossref PubMed Scopus (14) Google Scholar, 21Sakamoto Y. Harada T. Horie S. Iba Y. Taniguchi F. Yoshida S. et al.Tumor necrosis factor-α-induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-κB activation: gonadotropin releasing hormone agonist treatment reduced IL-8 expression.J Clin Endocrinol Metab. 2003; 88: 730-735Crossref PubMed Scopus (79) Google Scholar). Most of the studies of NF-κB activation inhibitors as potential therapeutic agents in endometriosis use the model of in vitro culture of hESCs or, less frequently, the 11Z and 12Z immortalized epithelial endometriotic cell lines (2Yagyu T. Kobayashi H. Matsuzaki H. Wakahara K. Kondo T. Kurita N. et al.Thalidomide inhibits tumor necrosis factor-α-induced interleukin-8 expression in endometriotic stromal cells, possibly through suppression of nuclear factor-κB activation.J Clin Endocrinol Metab. 2005; 90: 3017-3021Crossref PubMed Scopus (41) Google Scholar, 3Huber A.V. Saleh L. Prast J. Haslinger P. Knöfler M. Human chorionic gonadotropin attenuates NF-κB activation and cytokine expression of endometriotic stromal cells.Mol Hum Reprod. 2007; 13: 595-604Crossref PubMed Scopus (20) Google Scholar, 5Zhang J.J. Xu Z.M. Dai H.Y. Ji X.Q. Duan Y.Y. Zhang C.M. et al.Application of the nuclear factor-κB inhibitor pyrrolidine dithiocarbamate for the treatment of endometriosis: an in vitro study.Fertil Steril. 2010; 94: 2942-2944Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 6Zhang J.J. Xu Z.M. Zhang C.M. Dai H.Y. Ji X.Q. Wang X.F. et al.Pyrrolidine dithiocarbamate inhibits nuclear factor-κB pathway activation and regulates adhesion, migration, invasion and apoptosis of endometriotic stromal cells.Mol Hum Reprod. 2011; 17: 175-181Crossref PubMed Scopus (21) Google Scholar, 7Zhang H.I. Li M. Wang F. Liu S. Li J. Wen Z. et al.Endometriotic epithelial cells induce MMPs expression in endometrial stromal cells via an NFқB-dependent pathway.Gynecol Endocrinol. 2010; 26: 456-467Crossref PubMed Scopus (4) Google Scholar, 8Nasu K. Nishida M. Ueda T. Yuge A. Takai N. Narahara H. Application of the nuclear factor-κB inhibitor BAY 11–7085 for the treatment of endometriosis: an in vitro study.Am J Phisiol Endocrinol Metab. 2007; 293: E16-E23Crossref PubMed Scopus (32) Google Scholar, 9Kim J.H. Yang Y.I. Lee K.T. Park H.J. Choi J.H. Costunolide induces apoptosis in human endometriotic cells through inhibition of the prosurvival Akt and nuclear factor kappa B signaling pathway.Biol Pharm Bull. 2011; 34: 580-585Crossref PubMed Scopus (14) Google Scholar). The effects of cell culture exposure to NF-κB inhibitors have been studied at the molecular and the cellular level. In the former, a reduction in NF-κB activation and corresponding inhibition of the expression of genes that encode for inflammatory cytokines (IL-6, IL-8, MCP-1, GM-CSF), extracellular matrix remodeling mediators (MMP-2, MMP-3, MMP-7, MMP-9), apoptosis inhibitors, CD-44 and VEGF and their protein products were consistently documented (2Yagyu T. Kobayashi H. Matsuzaki H. Wakahara K. Kondo T. Kurita N. et al.Thalidomide inhibits tumor necrosis factor-α-induced interleukin-8 expression in endometriotic stromal cells, possibly through suppression of nuclear factor-κB activation.J Clin Endocrinol Metab. 2005; 90: 3017-3021Crossref PubMed Scopus (41) Google Scholar, 3Huber A.V. Saleh L. Prast J. Haslinger P. Knöfler M. Human chorionic gonadotropin attenuates NF-κB activation and cytokine expression of endometriotic stromal cells.Mol Hum Reprod. 2007; 13: 595-604Crossref PubMed Scopus (20) Google Scholar, 5Zhang J.J. Xu Z.M. Dai H.Y. Ji X.Q. Duan Y.Y. Zhang C.M. et al.Application of the nuclear factor-κB inhibitor pyrrolidine dithiocarbamate for the treatment of endometriosis: an in vitro study.Fertil Steril. 2010; 94: 2942-2944Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 6Zhang J.J. Xu Z.M. Zhang C.M. Dai H.Y. Ji X.Q. Wang X.F. et al.Pyrrolidine dithiocarbamate inhibits nuclear factor-κB pathway activation and regulates adhesion, migration, invasion and apoptosis of endometriotic stromal cells.Mol Hum Reprod. 2011; 17: 175-181Crossref PubMed Scopus (21) Google Scholar, 7Zhang H.I. Li M. Wang F. Liu S. Li J. Wen Z. et al.Endometriotic epithelial cells induce MMPs expression in endometrial stromal cells via an NFқB-dependent pathway.Gynecol Endocrinol. 2010; 26: 456-467Crossref PubMed Scopus (4) Google Scholar, 8Nasu K. Nishida M. Ueda T. Yuge A. Takai N. Narahara H. Application of the nuclear factor-κB inhibitor BAY 11–7085 for the treatment of endometriosis: an in vitro study.Am J Phisiol Endocrinol Metab. 2007; 293: E16-E23Crossref PubMed Scopus (32) Google Scholar, 9Kim J.H. Yang Y.I. Lee K.T. Park H.J. Choi J.H. Costunolide induces apoptosis in human endometriotic cells through inhibition of the prosurvival Akt and nuclear factor kappa B signaling pathway.Biol Pharm Bull. 2011; 34: 580-585Crossref PubMed Scopus (14) Google Scholar, 21Sakamoto Y. Harada T. Horie S. Iba Y. Taniguchi F. Yoshida S. et al.Tumor necrosis factor-α-induced interleukin-8 (IL-8) expression in endometriotic stromal cells, probably through nuclear factor-κB activation: gonadotropin releasing hormone agonist treatment reduced IL-8 expression.J Clin Endocrinol Metab. 2003; 88: 730-735Crossref PubMed Scopus (79) Google Scholar). At the cellular level, cell proliferation, motility, adhesion, and invasion ability tested in vitro were significantly reduced, and apoptosis was increased (6Zhang J.J. Xu Z.M. Zhang C.M. Dai H.Y. Ji X.Q. Wang X.F. et al.Pyrrolidine dithiocarbamate inhibits nuclear factor-κB pathway activation and regulates adhesion, migration, invasion and apoptosis of endometriotic stromal cells.Mol Hum Reprod. 2011; 17: 175-181Crossref PubMed Scopus (21) Google Scholar, 8Nasu K. Nishida M. Ueda T. Yuge A. Takai N. Narahara H. Application of the nuclear factor-κB inhibitor BAY 11–7085 for the treatment of endometriosis: an in vitro study.Am J Phisiol Endocrinol Metab. 2007; 293: E16-E23Crossref PubMed Scopus (32) Google Scholar, 9Kim J.H. Yang Y.I. Lee K.T. Park H.J. Choi J.H. Costunolide induces apoptosis in human endometriotic cells through inhibition of the prosurvival Akt and nuclear factor
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