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.
BerkleyKJRapkinAJPapkaRE. The pains of endometriosis. Science. 2005;308(5728):1587–1589.
4.
SampsonJA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:442–469.
5.
ChapronCChopinNBorgheseB. Deeply infiltrating endometriosis: pathogenetic implications of the anatomical distribution. Hum Reprod. 2006;21(7):1839–1845.
6.
BulunSE. Endometriosis. N Engl J Med. 2009;360(3):268–279.
7.
HsuCYHsiehTHTsaiCF, 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.
8.
LaschkeMWGiebelsCMengerMD. Vasculogenesis: a new piece of the endometriosis puzzle. Hum Reprod Update. 2011;17(5):628–636.
9.
LaschkeMWMengerMD. In vitro and in vivo approaches to study angiogenesis in the pathophysiology and therapy of endometriosis. Hum Reprod Upd. 2007;13(4):331–342.
10.
LaschkeMWMengerMD. Anti-angiogenic treatment strategies for the therapy of endometriosis. Hum Reprod Update. 2012;18(6):682–702.
11.
AnafVSimonPEl NakadiI. Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod. 2000;15(8):1744–1750.
12.
YugeANasuKMatsumotoHNishidaMNaraharaH. 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.
13.
ItogaTMatsumotoTTakeuchiH. Fibrosis and smooth muscle metaplasia in rectovaginal endometriosis. Pathol Int. 2003;53(6):371–375.
14.
SantulliPMarcellinLNoelJC. Sphingosine pathway deregulation in endometriotic tissues. Fertil Steril. 2012;97(4):904–911.
LeconteMChapronCDoussetB. Surgical treatment of rectal endometriosis. J Chir (Paris). 2007;144(1):5–10.
17.
RogersPAD’HoogheTMFazleabasA. Priorities for endometriosis research: recommendations from an international consensus workshop. Reprod Sci. 2009;16(4):335–346.
18.
NgoCChereauCNiccoCWeillBChapronCBatteuxF. Reactive oxygen species controls endometriosis progression. Am J Pathol. 2009;175(1):225–234.
19.
NgoCNiccoCLeconteM. Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo. J Pathol. 2010;222(2):148–157.
20.
LiMQShaoJMengYH. 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.
21.
LeconteMNiccoCNgoC. The mTOR/AKT inhibitor temsirolimus prevents deep infiltrating endometriosis in mice. Am J Pathol. 2011;179(2):880–889.
22.
KimTHYuYLuoLLydonJPJeongJWKimJJ. Activated AKT pathway promotes establishment of endometriosis. Endocrinology. 2014;155(5):1921–1930.
23.
SantulliPChouzenouxSFioreseM. Protein oxidative stress markers in peritoneal fluids of women with deep infiltrating endometriosis are increased. Hum Reprod. 2015;30(1):49–60.
24.
Sebolt-LeopoldJSHerreraR. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4(12):937–947.
25.
StreuliIde ZieglerDSantulliP. An update on the pharmacological management of endometriosis. Expert Opin Pharmacother. 2013;14(3):291–305.
26.
WilhelmSMCarterCTangL. 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.
27.
CoriatRNiccoCChereauC. Sorafenib-induced hepatocellular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo. Mol Cancer Ther. 2012;11(10):2284–2293.
28.
ChapronCLafay-PilletMCMonceauE. Questioning patients about their adolescent history can identify markers associated with deep infiltrating endometriosis. Fertil Steril. 2011;95(3):877–881.
29.
ChapronCSouzaCde ZieglerD. Smoking habits of 411 women with histologically proven endometriosis and 567 unaffected women. Fertil Steril. 2010;94(6):2353–2355.
30.
Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril. 1985;43(3):351–352.
31.
NoyesRWHertigATRockJ. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–263.
32.
ChapronCBourretAChopinN. Surgery for bladder endometriosis: long-term results and concomitant management of associated posterior deep lesions. Hum Reprod. 2010;25(4):884–889.
33.
ThubertTSantulliPMarcellinL. 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.
34.
KavianNServettazAMarutW. Sunitinib inhibits the phosphorylation 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.
35.
AFS. Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril. 1985;43(3):351–352.
36.
MoggioAPittatoreGCassoniPMarchinoGLRevelliABussolatiB. Sorafenib inhibits growth, migration, and angiogenic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis. Fertil Steril. 2012;98(6):1521–1530. e1522.
37.
OzerHBoztosunAAcmazGAtilganRAkkarOBKosarMI. The efficacy of bevacizumab, sorafenib, and retinoic acid on rat endometriosis model. Reprod Sci. 2013;20(1):26–32.
CarterCAChenCBrinkC. 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.
40.
TangTCManSLeeCRXuPKerbelRS. 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.
41.
KrajewskaJHandkiewicz-JunakDJarzabB. Sorafenib for the treatment of thyroid cancer: an updated review. Expert Opin Pharmacother. 2015;16(4):573–583.
42.
KimSYaziciYDCalzadaG. Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol Cancer Ther. 2007;6(6):1785–1792.
McLarenJPrenticeACharnock-JonesDS. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest. 1996;98(2):482–489.
45.
McLarenJPrenticeACharnock-JonesDSSmithSK. Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis. Hum Reprod. 1996;11(1):220–223.
46.
NapAWGriffioenAWDunselmanGA. Antiangiogenesis therapy for endometriosis. J Clin Endocrinol Metab. 2004;89(3):1089–1095.
47.
VodolazkaiaAEl-AalamatYPopovicD. Evaluation of a panel of 28 biomarkers for the non-invasive diagnosis of endometriosis. Hum Reprod. 2012;27(9):2698–2711.
48.
SantulliPChouzenouxSFioreseM. Protein oxidative stress markers in peritoneal fluids of women with deep infiltrating endometriosis are increased. Hum Reprod. 2015;30(1):49–60.
49.
BeckerCMRohwerNFunakoshiT. 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.
50.
XuMZhengYLXieXY. Sorafenib blocks the HIF-1alpha/VEGFA pathway, inhibits tumor invasion, and induces apoptosis in hepatoma cells. DNA Cell Biol. 2014;33(5):275–281.
