Oxidative phosphorylation inhibitors inhibit proliferation of endometriosis cells

in Reproduction
Authors:
Arvinder Kapur Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA

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Jose M Ayuso Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin, USA

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Shujah Rehman Morgridge Institute for Research, Madison, Wisconsin, USA

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Santosh Kumari Department of Dermatology, University of Wisconsin-Madison, Madison, Wisconsin, USA

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Mildred Felder Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA

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Zach Stenerson University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin, USA

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Melisa C Skala Morgridge Institute for Research, Madison, Wisconsin, USA
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA

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Dave Beebe Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA

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Lisa Barroilhet Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA

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Manish S Patankar Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin, USA
William S. Middleton Memorial Veterans’ Hospital, Madison, Wisconsin, USA

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https://orcid.org/0000-0002-8205-6432

Correspondence should be addressed to A Kapur or M S Patankar; Email: Arvinder.kapur@qiagen.com or patankar@wisc.edu
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In brief

Developing novel therapies to cure and manage endometriosis is a major unmet need that will benefit over 180 million women worldwide. Results from the current study suggest that inhibitors of oxidative phosphorylation may serve as novel agents for the treatment of endometriosis.

Abstract

Current therapeutic strategies for endometriosis focus on symptom management and are not curative. Here, we provide evidence supporting the inhibition of oxidative phosphorylation (OXPHOS) as a novel treatment strategy for endometriosis. Additionally, we report an organotypic organ-on-a-chip luminal model for endometriosis. The OXPHOS inhibitors, curcumin, plumbagin, and the FDA-approved anti-malarial agent, atovaquone, were tested against the endometriosis cell line, 12Z, in conventional as well as the new organotypic model. The results suggest that all three compounds inhibit proliferation and cause cell death of the endometriotic cells by inhibiting OXPHOS and causing an increase in intracellular oxygen radicals. The oxidative stress mediated by curcumin, plumbagin, and atovaquone causes DNA double-strand breaks as indicated by the elevation of phospho-γH2Ax. Mitochondrial energetics shows a significant decrease in oxygen consumption in 12Z cells. These experiments also highlight differences in the mechanism of action as curcumin and plumbagin inhibit complex I whereas atovaquone blocks complexes I, II, and III. Real-time assessment of cells in the lumen model showed inhibition of migration in response to the test compounds. Additionally, using two-photon lifetime imaging, we demonstrate that the 12Z cells in the lumen show decreased redox ratio (NAD(P)H/FAD) and lower fluorescence lifetime of NAD(P)H in the treated cells confirming major metabolic changes in response to inhibition of mitochondrial electron transport. The robust chemotoxic responses observed with atovaquone suggest that this anti-malarial agent may be repurposed for the effective treatment of endometriosis.

 

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