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Repurposing dichloroacetate for the treatment of women with endometriosis
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Horne, Andrew W., Ahmad, S. Furquan, Carter, Roderick, Simitsidellis, Ioannis, Greaves, Erin, Hogg, Chloe, Morton, Nicholas M. and Saunders, Philippa T. K. (2019) Repurposing dichloroacetate for the treatment of women with endometriosis. Proceedings of the National Academy of Sciences of the United States of America, 116 (51). pp. 25389-25391. doi:10.1073/pnas.1916144116
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WRAP-repurposing-dichloraacetate-treatment-women-endometriosis-Greaves-2019.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial No Derivatives 4.0. Download (736Kb) | Preview |
Official URL: http://dx.doi.org/10.1073/pnas.1916144116
Abstract
Endometriosis is a chronic pain condition affecting ∼176 million women worldwide. It is defined by the presence of endometrium-like tissue (lesions) outside the uterus, most commonly on the pelvic peritoneum. There is no cure for endometriosis. All endometriosis drug approvals to date have been contraceptive, limiting their use in women of child-bearing age. We have shown that human peritoneal mesothelial cells (HPMCs) recovered from the pelvic peritoneum of women with endometriosis exhibit significantly higher glycolysis, lower mitochondrial respiration, decreased enzymatic activity of pyruvate dehydrogenase (PDH), and increased production of lactate compared to HPMCs from women without disease. Transforming growth factor-β1 (TGF-β1) is elevated in the peritoneal fluid from women with endometriosis, and exposure of HPMCs to TGF-β1 exacerbates this abnormal phenotype. Treatment of endometriosis HPMCs with the pyruvate dehydrogenase kinase (PDK) inhibitor/PDH activator dichloroacetate (DCA) normalizes HPMC metabolism, reduces lactate secretion, and abrogates endometrial stromal cell proliferation in a coculture model. Oral DCA reduced peritoneal fluid lactate concentrations and endometriosis lesion size in a mouse model. These findings provide the rationale for targeting metabolic processes as a noncontraceptive treatment for women with endometriosis either as a primary nonhormonal treatment or to prevent recurrence after surgery.
| Item Type: | Journal Article | ||||||||||||
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| Subjects: | R Medicine > RG Gynecology and obstetrics | ||||||||||||
| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Endometriosis, Endometriosis -- Treatment -- Research, Glycolysis | ||||||||||||
| Journal or Publication Title: | Proceedings of the National Academy of Sciences of the United States of America | ||||||||||||
| Publisher: | National Academy of Sciences | ||||||||||||
| ISSN: | 0027-8424 | ||||||||||||
| Official Date: | 2 December 2019 | ||||||||||||
| Dates: |
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| Date of first compliant deposit: | 15 January 2020 | ||||||||||||
| Volume: | 116 | ||||||||||||
| Number: | 51 | ||||||||||||
| Page Range: | pp. 25389-25391 | ||||||||||||
| DOI: | 10.1073/pnas.1916144116 | ||||||||||||
| Status: | Peer Reviewed | ||||||||||||
| Publication Status: | Published | ||||||||||||
| Access rights to Published version: | Open Access | ||||||||||||
| RIOXX Funder/Project Grant: |
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