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Uterine fibroids (UFs) are associated with irregular or excessive uterine bleeding, pelvic pain or pressure, or infertility. Ovarian steroid hormones support the growth and maintenance of UFs. Ulipristal acetate (UPA) a selective progesterone receptor (PR) modulator (SPRM) reduce the size of UFs, inhibit ovulation and lead to amenorrhea. Recent liver toxicity concerns with UPA, diminished enthusiasm for its use and reinstate the critical need for a safe, efficacious SPRM to treat UFs. In the current study, we evaluated the efficacy of new SPRM, EC313, for the treatment for UFs using a NOD-SCID mouse model. EC313 treatment resulted in a dose-dependent reduction in the fibroid xenograft weight (p < 0.01). Estradiol (E2) induced proliferation was blocked significantly in EC313-treated xenograft fibroids (p < 0.0001). Uterine weight was reduced by EC313 treatment compared to UPA treatment. ER and PR were reduced in EC313-treated groups compared to controls (p < 0.001) and UPA treatments (p < 0.01). UF specific desmin and collagen were markedly reduced with EC313 treatment. The partial PR agonism and no signs of unopposed estrogenicity makes EC313 a candidate for the long-term treatment for UFs. Docking studies have provided a structure based explanation for the SPRM activity of EC313.

Titel:	EC313-a tissue selective SPRM reduces the growth and proliferation of uterine fibroids in a human uterine fibroid tissue xenograft model.
Autor/in / Beteiligte Person:	Nair, HB ; Santhamma, B ; Dileep, KV ; Binkley, P ; Acosta, K ; Zhang, KYJ ; Schenken, R ; Nickisch, K
Link:	Full Text Finder (Volltext)
Zeitschrift:	Scientific reports, Jg. 9 (2019-11-21), Heft 1, S. 17279
Veröffentlichung:	London : Nature Publishing Group, copyright 2011-, 2019
Medientyp:	academicJournal
ISSN:	2045-2322 (electronic)
DOI:	10.1038/s41598-019-53467-w
Schlagwort:	Animals Contraceptive Agents, Female adverse effects Contraceptive Agents, Female chemistry Estrenes administration & dosage Estrenes adverse effects Female Humans Leiomyoma pathology Mice Molecular Docking Simulation Molecular Structure Norpregnadienes administration & dosage Norpregnadienes adverse effects Oximes administration & dosage Oximes adverse effects Progesterone Congeners adverse effects Progesterone Congeners chemistry Receptors, Progesterone chemistry Receptors, Progesterone metabolism Structure-Activity Relationship Uterine Neoplasms pathology Uterus drug effects Uterus pathology Xenograft Model Antitumor Assays Cell Proliferation drug effects Contraceptive Agents, Female administration & dosage Leiomyoma drug therapy Progesterone Congeners administration & dosage Receptors, Progesterone agonists Uterine Neoplasms drug therapy
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Sci Rep] 2019 Nov 21; Vol. 9 (1), pp. 17279. <i>Date of Electronic Publication: </i>2019 Nov 21. MeSH Terms: Cell Proliferation / drug effects ; Contraceptive Agents, Female / administration & dosage ; Leiomyoma / drug therapy ; Progesterone Congeners / administration & dosage ; Receptors, Progesterone / agonists ; Uterine Neoplasms / drug therapy ; Animals ; Contraceptive Agents, Female / adverse effects ; Contraceptive Agents, Female / chemistry ; Estrenes / administration & dosage ; Estrenes / adverse effects ; Female ; Humans ; Leiomyoma / pathology ; Mice ; Molecular Docking Simulation ; Molecular Structure ; Norpregnadienes / administration & dosage ; Norpregnadienes / adverse effects ; Oximes / administration & dosage ; Oximes / adverse effects ; Progesterone Congeners / adverse effects ; Progesterone Congeners / chemistry ; Receptors, Progesterone / chemistry ; Receptors, Progesterone / metabolism ; Structure-Activity Relationship ; Uterine Neoplasms / pathology ; Uterus / drug effects ; Uterus / pathology ; Xenograft Model Antitumor Assays References: J Biol Chem. 2012 Jun 8;287(24):20333-43. (PMID: 22535964) ; Clin Obstet Gynecol. 2016 Mar;59(1):30-52. (PMID: 26756261) ; Cochrane Database Syst Rev. 2017 Nov 15;11:CD000547. (PMID: 29139105) ; Minim Invasive Ther Allied Technol. 2017 Oct;26(5):284-291. (PMID: 28635407) ; Ther Clin Risk Manag. 2019 Jan 23;15:157-178. (PMID: 30774352) ; Best Pract Res Clin Obstet Gynaecol. 2016 Jul;34:13-24. (PMID: 26725037) ; Oncotarget. 2017 Sep 28;9(4):4282-4300. (PMID: 29435103) ; Biomed Res Int. 2018 Jun 24;2018:1374821. (PMID: 30539001) ; Nucl Recept Signal. 2003;1:e004. (PMID: 16604176) ; Cochrane Database Syst Rev. 2001;(2):CD000547. (PMID: 11405968) ; J Clin Pharmacol. 2018 Feb;58(2):228-239. (PMID: 28940451) ; Cell. 1990 Jan 26;60(2):247-57. (PMID: 2153462) ; J Reprod Med. 2000 Jun;45(6):481-9. (PMID: 10900582) ; J Clin Endocrinol Metab. 2008 Dec;93(12):4664-71. (PMID: 18765509) ; J Biol Chem. 1996 Mar 15;271(11):6217-24. (PMID: 8626413) ; Endocr Rev. 2005 May;26(3):423-38. (PMID: 15857972) ; Hum Reprod. 2005 Apr;20(4):1090-9. (PMID: 15665012) ; Nature. 2015 Jul 16;523(7560):313-7. (PMID: 26153859) ; Annu Rev Biochem. 1994;63:451-86. (PMID: 7979245) ; Obstet Gynecol Clin North Am. 2006 Mar;33(1):41-58. (PMID: 16504805) ; Am J Obstet Gynecol. 2016 Nov;215(5):596.e1-596.e8. (PMID: 27177523) ; Best Pract Res Clin Obstet Gynaecol. 2008 Aug;22(4):615-26. (PMID: 18372219) ; Nat Struct Biol. 2002 May;9(5):359-64. (PMID: 11953755) ; Steroids. 2000 Oct-Nov;65(10-11):807-15. (PMID: 11108892) ; Expert Opin Pharmacother. 2008 Oct;9(14):2459-72. (PMID: 18778184) ; Bioinformatics. 2010 Oct 1;26(19):2398-405. (PMID: 20685958) ; Reprod Sci. 2007 Dec;14(8 Suppl):20-7. (PMID: 18089606) ; Hum Reprod. 2019 Apr 1;34(4):623-634. (PMID: 30865281) ; J Clin Endocrinol Metab. 2007 Feb;92(2):616-23. (PMID: 17105846) ; Fertil Steril. 2004 Oct;82 Suppl 3:1182-7. (PMID: 15474093) ; PLoS One. 2016 Mar 24;11(3):e0151182. (PMID: 27011208) ; Expert Opin Pharmacother. 2008 Oct;9(14):2473-85. (PMID: 18778185) ; Reproduction. 2016 Nov;152(5):467-80. (PMID: 27528771) ; Popul Health Manag. 2018 Mar;21(S1):S13-S20. (PMID: 29649369) ; J Clin Endocrinol Metab. 1993 May;76(5):1217-23. (PMID: 8496313) ; Bioinformatics. 2008 Sep 1;24(17):1865-73. (PMID: 18591193) ; Mol Endocrinol. 1999 Jun;13(6):910-24. (PMID: 10379890) ; Fertil Steril. 1988 Mar;49(3):538-41. (PMID: 3277869) ; Hum Reprod. 2008 Apr;23(4):944-51. (PMID: 18281245) ; Exp Biol Med (Maywood). 2002 Dec;227(11):969-80. (PMID: 12486206) ; Fertil Steril. 2017 Jul;108(1):152-160.e4. (PMID: 28579415) ; Endocr Rev. 1999 Jun;20(3):321-44. (PMID: 10368774) ; J Biol Chem. 2011 Oct 7;286(40):35079-86. (PMID: 21849509) ; Am J Obstet Gynecol. 2015 Aug;213(2):141-60. (PMID: 25771213) ; Expert Opin Pharmacother. 2008 Oct;9(14):2487-96. (PMID: 18778186) ; PLoS One. 2015 Nov 20;10(11):e0142429. (PMID: 26588841) ; J Mammary Gland Biol Neoplasia. 2000 Jul;5(3):307-24. (PMID: 14973393) ; Expert Opin Emerg Drugs. 2018 Mar;23(1):17-23. (PMID: 29486606) ; Radiology. 2016 Sep;280(3):675-92. (PMID: 27533290) ; Steroids. 2000 Oct-Nov;65(10-11):713-23. (PMID: 11108882) ; N Engl J Med. 2015 Apr 23;372(17):1646-55. (PMID: 25901428) ; Mol Endocrinol. 2007 May;21(5):1066-81. (PMID: 17356170) Substance Nomenclature: 0 (Contraceptive Agents, Female) ; 0 (Estrenes) ; 0 (Norpregnadienes) ; 0 (Oximes) ; 0 (Progesterone Congeners) ; 0 (Receptors, Progesterone) ; 0 (selective progesterone receptor modulator EC313) ; 72W09924WP (asoprisnil) ; YF7V70N02B (ulipristal acetate) Entry Date(s): Date Created: 20191123 Date Completed: 20201109 Latest Revision: 20210203 Update Code: 20231215 PubMed Central ID: PMC6872653

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EC313-a tissue selective SPRM reduces the growth and proliferation of uterine fibroids in a human uterine fibroid tissue xenograft model.