A Long-Acting Tumor Necrosis Factor α-Binding Protein Demonstrates Activity in Both In Vitro and In Vivo Models of Endometriosis

Altan, Z. Melis; Denis, Deborah; Kagan, David; Grund, Eric M.; Palmer, Stephen; Nataraja, Selvaraj

doi:10.1124/jpet.110.166488

Cited by 26 publications

(18 citation statements)

References 36 publications

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“…In contrast to the earlier study in rat endometriosis, 36 where Antide and TBP-1 showed no effect on NK cell activity, bentamapimod was able to reverse the effect of decreased NK cell cytotoxicity in endometriotic animals similar to earlier reports in mice 47 and human. 48 Reduced NK cell activity was observed in women with endometriosis.…”

Section: Discussioncontrasting

confidence: 49%

Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models

et al. 2016

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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.

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Section: Discussioncontrasting

confidence: 49%

Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models

et al. 2016

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“…suggested that the production of IL‐8 by the endometrial stromal cells is also stimulated by proinflammatory IL‐1 and TNF‐α and IFN‐γ, characteristic for the inflammatory response induced by endometriosis. Altan et al . as well as Grund et al .…”

Section: Il‐8 and Endometriosismentioning

confidence: 92%

Abnormal peritoneal regulation of chemokine activation—The role of IL‐8 in pathogenesis of endometriosis

Sikora

Smycz‐Kubańska

Mielczarek‐Palacz

et al. 2017

American J Rep Immunol

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“…Vitamin E is a lipid-soluble, chain-breaking antioxidant that prevents the propagation of lipid peroxidation by forming a vitamin E radial [42, 43]. Vitamin C is generally recommended to be included along with Vitamin E supplementation since vitamin C helps in the recycling of Vitamin E radical back to Vitamin E [44]. We chose the stated concentrations because of clinical trials on cardiovascular diseases that used these levels [45] and our own unpublished studies suggested that at these concentrations they were nontoxic and decreased inflammatory markers.…”

Section: Methodsmentioning

confidence: 99%

Antioxidant supplementation reduces endometriosis-related pelvic pain in humans

Santanam

Kavtaradze

Murphy

et al. 2013

Translational Research

118

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We had previously suggested that women with endometriosis have increased oxidative stress in the peritoneal cavity. In order to assess whether antioxidant supplementation would ameliorate endometriosis associated symptoms, we performed a randomized, placebo controlled trial of antioxidant vitamins (Vitamin E and C) in women with pelvic pain and endometriosis. Fifty nine women, ages 19–41 years, with pelvic pain and history of endometriosis and/or infertility were recruited for this study. Patients were randomly assigned to two groups: vitamin E (1200 IU) and vitamin C (1000 mg) combination or placebo, daily for eight weeks before surgery. Pain scales were administered at baseline and bi-weekly. Inflammatory markers were measured in the peritoneal fluid obtained from both groups of patients at the end of therapy. Our results indicated that, after treatment with antioxidants, chronic pain (“everyday pain”) improved in 43% of patients in antioxidant treatment group (p=0.0055) as compared to the placebo group. In the same group, dysmenorrhea (“pain associated with menstruation”) and dyspareunia (“pain with sex”) decreased in 37% and 24% patients, respectively. In the placebo group, dysmenorrhea associated pain decreased in 4 patients and no change was seen in chronic pain or dyspareunia. There was significant decrease in peritoneal fluid inflammatory markers, RANTES (p≤0.002), interleukin-6 (p≤0.056) and monocyte chemotactic protein-1 (p≤0.016) after antioxidant therapy compared to patients not on antioxidants. In conclusion, results of this clinical trial show that administration of antioxidants reduces chronic pelvic pain in women with endometriosis and inflammatory markers in the peritoneal fluid.

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A Long-Acting Tumor Necrosis Factor α-Binding Protein Demonstrates Activity in Both In Vitro and In Vivo Models of Endometriosis

Cited by 26 publications

References 36 publications

Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models

Bentamapimod (JNK Inhibitor AS602801) Induces Regression of Endometriotic Lesions in Animal Models

Abnormal peritoneal regulation of chemokine activation—The role of IL‐8 in pathogenesis of endometriosis

Antioxidant supplementation reduces endometriosis-related pelvic pain in humans

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