Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models.
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.
EMD Serono Research Institute, Billerica, MA, USA TocopheRx, Inc, Burlington, MA, USA stephen@tocopherx.com.
Stephen S
SS
Palmer
EMD Serono Research Institute, Billerica, MA, USA.
Melis
M
Altan
EMD Serono Research Institute, Billerica, MA, USA.
Deborah
D
Denis
RBM, Ivrea, Italy.
Enrico Gillio
EG
Tos
PregLem SA, Geneva, Switzerland.
Jean-Pierre
JP
Gotteland
Dept. of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA.
Kevin G
KG
Osteen
Dept. of Obstetrics and Gynecology, Vanderbilt University, Nashville, TN, USA.
Kaylon L
KL
Bruner-Tran
EMD Serono Research Institute, Billerica, MA, USA TocopheRx, Inc, Burlington, MA, USA.
Selvaraj G
SG
Nataraja
D000328:Adult; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004715:Endometriosis / Q000188:drug therapy* / Q000378:metabolism; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D011374:Progesterone / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats
D052160:Benzothiazoles; D016207:Cytokines; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011374:Progesterone; D017258:Medroxyprogesterone Acetate; D048031:JNK Mitogen-Activated Protein Kinases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C000609147:bentamapimod
JNK inhibitor; MMP; MPA.; bentamapimod; cytokine; endometriosis; progesterone