Interruption of Inflammatory Pathways with JNK Inhibitors Induces Regression of Human Endometriotic Lesions and Restores Progesterone Receptor Sensitivity in Endometrium and Lesions.

Endometriosis is one of the most common causes of chronic pelvic pain, which affects over 70 million adult and adolescent women worldwide. The pathophysiology of endometriosis involves endocrine, inflammatory and angiogenic components and to date the endocrine axis has been the predominant axis for intervention, but most therapies are associated with >50% recurrence of disease or menopausal side effects. In the present study, an inhibitor of the c-jun-N-terminal-Kinase (JNK) has been evaluated for its ability to inhibit the inflammatory axis of disease and to restore hormone sensitivity to hormone-refractory lesions. The effect of AS01 on regression of endometriosis was evaluated in 2 animal models and in 2 cellular models. In a surgically-induced model of endometriosis, treatment of rats with AS01 (30 mg/kg, 60 mg/kg, bid) caused 45% - 48% regression of lesions, while Antide (GnRH antagonist) caused 85% regression of lesions. This decrease in lesion size by JNK was similar to inhibition obtained with tumor necrosis factor binding protein (TBP; 64%) in previous studies in rats. Phosphorylation of c-jun (P-c-jun) was eliminated in lesions at 60 mg/kg, while no change in P-c-jun was seen in control or Antide-treated rats. Levels of 6 inflammatory cytokines were significantly decreased by AS01 in the disease-affected uterine horn, while the same cytokines were unchanged in the unaffected uterine horn. In the second set of experiments, ovariectomized nude mice bearing endometriotic lesions established with human endometrial tissue fragments were treated daily with or without AS01. After 4 weeks of treatment, the mice were sacrificed and the lesions were counted. JNK caused 65% regression of lesions established from normal volunteers, but only 30% regression of lesions established in women with disease. Combination of progesterone with JNK inhibitor treatments in mice bearing lesions from women with disease caused 65% regression of lesions, whereas progesterone alone was without effect. In the third set of experiments, the mechanism of JNK action to reverse progesterone resistance was measured in cultures of human endometrium. AS01 restored progesterone sensitivity to the tissue as evidenced by suppression of MMP-3 production, a local biomarker of lesions. Furthermore, in cultures of endometriotic cells, JNK decreased the amount of N-cadherin and β-catenin associated with the cell surface. Results from these studies indicate that JNK inhibitor may be useful in the regression of endometriotic lesions, and control of the associated pelvic pain.