PMID- 26335175 OWN - NLM STAT- MEDLINE DCOM- 20170118 LR - 20181224 IS - 1933-7205 (Electronic) IS - 1933-7191 (Print) IS - 1933-7191 (Linking) VI - 23 IP - 1 DP - 2016 Jan TI - Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models. PG - 11-23 LID - 10.1177/1933719115600553 [doi] AB - Endometriosis is an estrogen (ER)-dependent gynecological disease caused by the growth of endometrial tissue at extrauterine sites. Current endocrine therapies address the estrogenic aspect of disease and offer some relief from pain but are associated with significant side effects. Immune dysfunction is also widely believed to be an underlying contributor to the pathogenesis of this disease. This study evaluated an inhibitor of c-Jun N-terminal kinase, bentamapimod (AS602801), which interrupts immune pathways, in 2 rodent endometriosis models. Treatment of nude mice bearing xenografts biopsied from women with endometriosis (BWE) with 30 mg/kg AS602801 caused 29% regression of lesion. Medroxyprogesterone acetate (MPA) or progesterone (PR) alone did not cause regression of BWE lesions, but combining 10 mg/kg AS602801 with MPA caused 38% lesion regression. In human endometrial organ cultures (from healthy women), treatment with AS602801 or MPA reduced matrix metalloproteinase-3 (MMP-3) release into culture medium. In organ cultures established with BWE, PR or MPA failed to inhibit MMP-3 secretion, whereas AS602801 alone or MPA + AS602801 suppressed MMP-3 production. In an autologous rat endometriosis model, AS602801 caused 48% regression of lesions compared to GnRH antagonist Antide (84%). AS602801 reduced inflammatory cytokines in endometriotic lesions, while levels of cytokines in ipsilateral horns were unaffected. Furthermore, AS602801 enhanced natural killer cell activity, without apparent negative effects on uterus. These results indicate that bentamapimod induced regression of endometriotic lesions in endometriosis rodent animal models without suppressing ER action. c-Jun N-terminal kinase inhibition mediated a comprehensive reduction in cytokine secretion and moreover was able to overcome PR resistance. CI - (c) The Author(s) 2015. FAU - Palmer, Stephen S AU - Palmer SS AD - EMD Serono Research Institute, Billerica, MA, USA TocopheRx, Inc, Burlington, MA, USA stephen@tocopherx.com. FAU - Altan, Melis AU - Altan M AD - EMD Serono Research Institute, Billerica, MA, USA. FAU - Denis, Deborah AU - Denis D AD - EMD Serono Research Institute, Billerica, MA, USA. FAU - Tos, Enrico Gillio AU - Tos EG AD - RBM, Ivrea, Italy. FAU - Gotteland, Jean-Pierre AU - Gotteland JP AD - PregLem SA, Geneva, Switzerland. FAU - Osteen, Kevin G AU - Osteen KG AD - Dept. of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA. FAU - Bruner-Tran, Kaylon L AU - Bruner-Tran KL AD - Dept. of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA. FAU - Nataraja, Selvaraj G AU - Nataraja SG AD - EMD Serono Research Institute, Billerica, MA, USA TocopheRx, Inc, Burlington, MA, USA. LA - eng GR - U54 HD037321/HD/NICHD NIH HHS/United States GR - U54 HD37321/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150902 PL - United States TA - Reprod Sci JT - Reproductive sciences (Thousand Oaks, Calif.) JID - 101291249 RN - 0 (Benzothiazoles) RN - 0 (Cytokines) RN - 0 (Enzyme Inhibitors) RN - 0 (Pyrimidines) RN - 4G7DS2Q64Y (Progesterone) RN - C2QI4IOI2G (Medroxyprogesterone Acetate) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 3.4.24.17 (MMP3 protein, human) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - TT3L4B4U0N (bentamapimod) SB - IM MH - Adult MH - Animals MH - Benzothiazoles/pharmacology/*therapeutic use MH - Cytokines/metabolism MH - Disease Models, Animal MH - Endometriosis/*drug therapy/metabolism MH - Endometrium/*drug effects/metabolism MH - Enzyme Inhibitors/pharmacology/*therapeutic use MH - Female MH - Humans MH - JNK Mitogen-Activated Protein Kinases/*antagonists & inhibitors MH - Killer Cells, Natural/drug effects/metabolism MH - MAP Kinase Signaling System/drug effects MH - Matrix Metalloproteinase 3/metabolism MH - Medroxyprogesterone Acetate/pharmacology/therapeutic use MH - Mice MH - Mice, Nude MH - Progesterone/pharmacology/therapeutic use MH - Pyrimidines/pharmacology/*therapeutic use MH - Rats PMC - PMC5933194 OTO - NOTNLM OT - JNK inhibitor OT - MMP OT - MPA. OT - bentamapimod OT - cytokine OT - endometriosis OT - progesterone COIS- Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SSP, MA, DD, J-PG, and SGN were employees of EMD/Merck Serono during the performance of these studies. EGT was employed at RBM (Istituto Di Ricerche Biomedicine "Antoine Marxer"), an affiliate of Merck Serono. SSP, MA, EGT, and SGN are no longer employees at EMD Serono or RBM and have no continuing interest in bentamapimod (PGL5001). J-PG is no longer employee of Merck Serono but affiliated with PreGlem, who holds rights to PGL5001, and is the contact for questions regarding bentamapimod. EDAT- 2015/09/04 06:00 MHDA- 2017/01/19 06:00 PMCR- 2017/01/01 CRDT- 2015/09/04 06:00 PHST- 2015/09/04 06:00 [entrez] PHST- 2015/09/04 06:00 [pubmed] PHST- 2017/01/19 06:00 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - 1933719115600553 [pii] AID - 10.1177_1933719115600553 [pii] AID - 10.1177/1933719115600553 [doi] PST - ppublish SO - Reprod Sci. 2016 Jan;23(1):11-23. doi: 10.1177/1933719115600553. Epub 2015 Sep 2.