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

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.

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.

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.

Our data suggest that Sorafenib controls the growth of endometriotic lesions in vitro and in vivo. Similar content being viewed by others

de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376(9742):730–738. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science. 2005;308(5728):1587–1589. Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:442–469. Chapron C, Chopin N, Borghese B, et al. Deeply infiltrating endo-metriosis: pathogenetic implications of the anatomical distribution. Hum Reprod. 2006;21(7):1839–1845. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279. Hsu CY, Hsieh TH, Tsai CF, et al. miRNA-199a-5p regulates VEGFA in endometrial mesenchymal stem cells and contributes to the pathogenesis of endometriosis. J Pathol. 2014;232(3):330–343. Laschke MW, Giebels C, Menger MD. Vasculogenesis: a new piece of the endometriosis puzzle. Hum Reprod Update. 2011;17(5):628–636. Laschke MW, Menger MD. In vitro and in vivo approaches to study angiogenesis in the pathophysiology and therapy of endo-metriosis. Hum Reprod Upd. 2007;13(4):331–342. Laschke MW, Menger MD. Anti-angiogenic treatment strategies for the therapy of endometriosis. Hum Reprod Update. 2012;18(6):682–702. Anaf V, Simon P, El Nakadi I, et al. Relationship between endo-metriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod. 2000;15(8):1744–1750. Yuge A, Nasu K, Matsumoto H, Nishida M, Narahara H. Collagen gel contractility is enhanced in human endometriotic stromal cells: a possible mechanism underlying the pathogenesis of endometriosis-associated fibrosis. Hum Reprod. 2007;22(4):938–944. Itoga T, Matsumoto T, Takeuchi H, et al. Fibrosis and smooth muscle metaplasia in rectovaginal endometriosis. Pathol Int. 2003;53(6):371–375. Santulli P, Marcellin L, Noel JC, et al. Sphingosine pathway deregulation in endometriotic tissues. Fertil Steril. 2012;97(4):904–911. Santulli P, Borghese B, Noel JC, et al. Hormonal Therapy Deregulates Prostaglandin-Endoperoxidase Synthase 2 (PTGS2) expression in endometriotic tissues. J Clin Endocrinol Metab. 2014;99(3):881–890. Leconte M, Chapron C, Dousset B. Surgical treatment of rectal endometriosis. J Chir (Paris). 2007;144(1):5–10. Rogers PA, D’Hooghe TM, Fazleabas A, et al. Priorities for endo-metriosis research: recommendations from an international consensus workshop. Reprod Sci. 2009;16(4):335–346. Ngo C, Chereau C, Nicco C, Weill B, Chapron C, Batteux F. Reactive oxygen species controls endometriosis progression. Am J Pathol. 2009;175(1):225–234. Ngo C, Nicco C, Leconte M, et al. Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo. J Pathol. 2010;222(2):148–157. Li MQ, Shao J, Meng YH, et al. NME1 suppression promotes growth, adhesion and implantation of endometrial stromal cells via Akt and MAPK/Erk1/2 signal pathways in the endometriotic milieu. Hum Reprod. 2013;28(10):2822–2831. Leconte M, Nicco C, Ngo C, et al. The mTOR/AKT inhibitor tem-sirolimus prevents deep infiltrating endometriosis in mice. Am J Pathol. 2011;179(2):880–889. Kim TH, Yu Y, Luo L, Lydon JP, Jeong JW, Kim JJ. Activated AKT pathway promotes establishment of endometriosis. Endocrinology. 2014;155(5):1921–1930. Santulli P, Chouzenoux S, Fiorese M, et al. Protein oxidative stress markers in peritoneal fluids of women with deep infiltrating endometriosis are increased. Hum Reprod. 2015;30(1):49–60. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4(12):937–947. Streuli I, de Ziegler D, Santulli P, et al. An update on the pharmacological management of endometriosis. Expert Opin Pharmac-other. 2013;14(3):291–305. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/ MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–7109. Coriat R, Nicco C, Chereau C, et al. Sorafenib-induced hepatocel-lular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo. Mol Cancer Ther. 2012;11(10):2284–2293. Chapron C, Lafay-Pillet MC, Monceau E, et al. Questioning patients about their adolescent history can identify markers associated with deep infiltrating endometriosis. Fertil Steril. 2011;95(3):877–881. Chapron C, Souza C, de Ziegler D, et al. Smoking habits of 411 women with histologically proven endometriosis and 567 unaffected women. Fertil Steril. 2010;94(6):2353–2355. Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril. 1985;43(3):351–352. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–263. Chapron C, Bourret A, Chopin N, et al. Surgery for bladder endo-metriosis: long-term results and concomitant management of associated posterior deep lesions. Hum Reprod. 2010;25(4):884–889. Thubert T, Santulli P, Marcellin L, et al. Measurement of hs-CRP is irrelevant to diagnose and stage endometriosis: prospective study of 834 patients. Am J Obstet Gynecol. 2014;210(6):533. e531–533. e510. Kavian N, Servettaz A, Marut W, et al. Sunitinib inhibits the phos-phorylation of platelet-derived growth factor receptor beta in the skin of mice with scleroderma-like features and prevents the development of the disease. Arthritis Rheum. 2012;64(6):1990–2000. AFS. Revised American Fertility Society classification of endo-metriosis: 1985. Fertil Steril. 1985;43(3):351–352. Moggio A, Pittatore G, Cassoni P, Marchino GL, Revelli A, Bussolati B. Sorafenib inhibits growth, migration, and angio-genic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis. Fertil Steril. 2012;98(6):1521–1530. e1522. Ozer H, Boztosun A, Acmaz G, Atilgan R, Akkar OB, Kosar MI. The efficacy of bevacizumab, sorafenib, and retinoic acid on rat endometriosis model. Reprod Sci. 2013;20(1):26–32. Igney FH, Asadullah K, Zollner TM. Techniques: species’ finest blend–humanized mouse models in inflammatory skin disease research. Trends Pharmacol Sci. 2004;25(10):543–549. Carter CA, Chen C, Brink C, et al. Sorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma. Cancer Chemother Pharmacol. 2007;59(2):183–195. Tang TC, Man S, Lee CR, Xu P, Kerbel RS. Impact of metronomic UFT/cyclophosphamide chemotherapy and antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopic hepatocellular carcinoma. Neoplasia. 2010;12(3):264–274. Krajewska J, Handkiewicz-Junak D, Jarzab B. Sorafenib for the treatment of thyroid cancer: an updated review. Expert Opin Pharmacother. 2015;16(4):573–583. Kim S, Yazici YD, Calzada G, et al. Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther. 2007;6(6):1785–1792. McLaren J. Vascular endothelial growth factor and endometriotic angiogenesis. Hum Reprod Update. 2000;6(1):45–55. McLaren J, Prentice A, Charnock-Jones DS, et al. Vascular endothelial growth factor is produced by peritoneal fluid macro-phages in endometriosis and is regulated by ovarian steroids. J Clin Invest. 1996;98(2):482–489. McLaren J, Prentice A, Charnock-Jones DS, Smith SK. Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis. Hum Reprod. 1996;11(1):220–223. Nap AW, Griffioen AW, Dunselman GA, et al. Antiangiogenesis therapy for endometriosis. J Clin Endocrinol Metab. 2004;89(3):1089–1095. Vodolazkaia A, El-Aalamat Y, Popovic D, et al. Evaluation of a panel of 28 biomarkers for the non-invasive diagnosis of endome-triosis. Hum Reprod. 2012;27(9):2698–2711. Santulli P, Chouzenoux S, Fiorese M, et al. Protein oxidative stress markers in peritoneal fluids of women with deep infiltrating endometriosis are increased. Hum Reprod. 2015;30(1):49–60. Becker CM, Rohwer N, Funakoshi T, et al. 2-methoxyestradiol inhibits hypoxia-inducible factor-1{alpha} and suppresses growth of lesions in a mouse model of endometriosis. Am J Pathol. 2008;172(2):534–544. Xu M, Zheng YL, Xie XY, et al. Sorafenib blocks the HIF-1alpha/ VEGFA pathway, inhibits tumor invasion, and induces apoptosis in hepatoma cells. DNA Cell Biol. 2014;33(5):275–281. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article 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 Published: Issue date: DOI: https://doi.org/10.1177/1933719115592708