{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T23:21:27Z","timestamp":1783120887029,"version":"3.54.6"},"reference-count":41,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T00:00:00Z","timestamp":1651708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1R01CA238423-01A1"],"award-info":[{"award-number":["1R01CA238423-01A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["Reproductive Scientist Development Program (K12)"],"award-info":[{"award-number":["Reproductive Scientist Development Program (K12)"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018096","name":"GOG Foundation","doi-asserted-by":"publisher","award":["1R01CA238423-01A1"],"award-info":[{"award-number":["1R01CA238423-01A1"]}],"id":[{"id":"10.13039\/100018096","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018096","name":"GOG Foundation","doi-asserted-by":"publisher","award":["Reproductive Scientist Development Program (K12)"],"award-info":[{"award-number":["Reproductive Scientist Development Program (K12)"]}],"id":[{"id":"10.13039\/100018096","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone\u2019s potential as a gynecologic cancer therapeutic.<\/jats:p>","DOI":"10.3390\/cancers14092297","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T02:19:48Z","timestamp":1651717188000},"page":"2297","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers"],"prefix":"10.3390","volume":"14","author":[{"given":"Arvinder","family":"Kapur","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron D","family":"Simmons","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer S.","family":"Ericksen","sequence":"additional","affiliation":[{"name":"Drug Development Core, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5967-6425","authenticated-orcid":false,"given":"Geeta","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Biomedical Engineering, Macromolecular Sciences and Engineering, Precision Health, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean P.","family":"Palecek","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mildred","family":"Felder","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zach","family":"Stenerson","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amruta","family":"Nayak","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9414-1845","authenticated-orcid":false,"given":"Jose Maria Ayuso","family":"Dominguez","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53715, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8205-6432","authenticated-orcid":false,"given":"Manish","family":"Patankar","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Barroilhet","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.bbabio.2010.03.025","article-title":"The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies","volume":"1797","author":"Mathupala","year":"2010","journal-title":"Biochim. Biophys. Acta BBA Bioenerg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1126\/science.124.3215.269","article-title":"On respiratory impairment in cancer cells","volume":"124","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"26142","DOI":"10.18632\/oncotarget.15393","article-title":"Increased reactive oxygen species levels cause ER stress and cytotoxicity in andrographolide treated colon cancer cells","volume":"8","author":"Banerjee","year":"2017","journal-title":"Oncotarget"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"61890","DOI":"10.18632\/oncotarget.11301","article-title":"Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells","volume":"7","author":"Ippolito","year":"2016","journal-title":"Oncotarget"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.biocel.2018.03.011","article-title":"Mitochondria-related oxidative stress contributes to ovarian cancer-promoting activity of mesothelial cells subjected to malignant ascites","volume":"98","author":"Pakula","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.bbabio.2010.09.003","article-title":"Oxidative phosphorylation in cancer cells","volume":"1807","author":"Solaini","year":"2011","journal-title":"Biochim. Biophys. Acta BBA Bioenerg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e1969","DOI":"10.1038\/cddis.2015.305","article-title":"Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents","volume":"6","author":"Yadav","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/s41598-018-19261-w","article-title":"Oxidative stress via inhibition of the mitochondrial electron transport and Nrf-2-mediated anti-oxidative response regulate the cytotoxic activity of plumbagin","volume":"8","author":"Kapur","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27530","DOI":"10.1038\/srep27530","article-title":"Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation","volume":"6","author":"Kapur","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1158\/1078-0432.CCR-17-3070","article-title":"Oxidative Phosphorylation as an Emerging Target in Cancer Therapy","volume":"24","author":"Ashton","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3390\/cancers10090337","article-title":"Oxidative Phosphorylation: A target for novel therapeutic strategies against ovarian cancer","volume":"10","author":"Mayak","year":"2018","journal-title":"Cancers"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11471","DOI":"10.1038\/s41598-019-47261-x","article-title":"Plumbagin-induced oxidative stress leads to inhibition of Na(+)\/K(+)-ATPase (NKA) in canine cancer cells","volume":"9","author":"Alharbi","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"34084","DOI":"10.18632\/oncotarget.9122","article-title":"Repurposing atovaquone: Targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells","volume":"7","author":"Fiorillo","year":"2016","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12308","DOI":"10.1038\/ncomms12308","article-title":"The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia","volume":"7","author":"Ashton","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6934","DOI":"10.1158\/1078-0432.CCR-17-0133","article-title":"Personalized Medicine-Based Approach to Model Patterns of Chemoresistance and Tumor Recurrence Using Ovarian Cancer Stem Cell Spheroids","volume":"23","author":"Raghavan","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_17","first-page":"e59696","article-title":"Physiologic Patient Derived 3D Spheroids for Anti-neoplastic Drug Screening to Target Cancer Stem Cells","volume":"149","author":"Bregenzer","year":"2019","journal-title":"JoVE J. Vis. Exp."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/978-1-4939-7401-6_6","article-title":"Self-Renewal and CSCs In Vitro Enrichment: Growth as Floating Spheres","volume":"1692","author":"Mehta","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_20","unstructured":"(2021, July 31). PubChem Database. Atovaquone, CID = 74989, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/#query=atovaquone."},{"key":"ref_21","unstructured":"(2021, July 31). PubChem Database. 1,4-Naphthoquinone, CID = 8530, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/1_4-Naphthoquinone."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.bbabio.2008.04.033","article-title":"Exploring the inhibitor binding pocket of respiratory complex I","volume":"1777","author":"Fendel","year":"2008","journal-title":"Biochim. Biophys. Acta BBA Bioenerg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1007\/s11306-015-0831-6","article-title":"Metabolic responses induced by DNA damage and poly (ADP-ribose) polymerase (PARP) inhibition in MCF-7 cells","volume":"11","author":"Bhute","year":"2015","journal-title":"Metabolomics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1093\/jac\/dkx198","article-title":"Plasma concentrations of atovaquone given to immunocompromised patients to prevent Pneumocystis jirovecii","volume":"72","author":"Robin","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S0891-5849(00)00317-8","article-title":"Mitochondrial free radical generation, oxidative stress, and aging","volume":"29","author":"Cadenas","year":"2000","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20081386","article-title":"How mitochondria produce reactive oxygen species","volume":"417","author":"Murphy","year":"2009","journal-title":"Biochem. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nature05572","article-title":"Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum","volume":"446","author":"Painter","year":"2007","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5281","DOI":"10.1128\/AAC.00937-10","article-title":"Mitochondrial electron transport inhibition and viability of intraerythrocytic Plasmodium falciparum","volume":"54","author":"Painter","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4305","DOI":"10.18632\/oncotarget.2010","article-title":"Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation","volume":"5","author":"Pasto","year":"2014","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1103\/PhysRev.47.777","article-title":"Can Quantum-Mechanical Description of Physical Reality Be Considered Complete?","volume":"47","author":"Einstein","year":"1935","journal-title":"Phys. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.neo.2019.06.005","article-title":"Engineered 3D Model of Cancer Stem Cell Enrichment and Chemoresistance","volume":"21","author":"Mehta","year":"2019","journal-title":"Neoplasia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ygyno.2015.04.014","article-title":"Formation of stable small cell number three-dimensional ovarian cancer spheroids using hanging drop arrays for preclinical drug sensitivity assays","volume":"138","author":"Raghavan","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1634\/theoncologist.2015-0438","article-title":"Clinical Application of Poly(ADP-Ribose) Polymerase Inhibitors in High-Grade Serous Ovarian Cancer","volume":"21","author":"Parkes","year":"2016","journal-title":"Oncologist"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.celrep.2015.12.046","article-title":"Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer","volume":"14","author":"Choi","year":"2016","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"55771","DOI":"10.18632\/oncotarget.9908","article-title":"Targeting epithelial-mesenchymal transition and cancer stem cells for chemoresistant ovarian cancer","volume":"7","author":"Deng","year":"2016","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/nrm3772","article-title":"Metabolic requirements for the maintenance of self-renewing stem cells","volume":"15","author":"Ito","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4029","DOI":"10.1038\/ncomms5029","article-title":"Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action","volume":"5","author":"Birth","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12964-018-0252-z","article-title":"Inhibition of CRM1 activity sensitizes endometrial and ovarian cell lines to TRAIL-induced cell death","volume":"16","author":"Fabi","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"650","DOI":"10.21037\/tcr.2016.08.40","article-title":"TP53 mutations in epithelial ovarian cancer","volume":"5","author":"Zhang","year":"2016","journal-title":"Transl. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Felippe Goncalves-de-Albuquerque, C., Ribeiro Silva, A., Ignacio da Silva, C., Caire Castro-Faria-Neto, H., and Burth, P. (2017). Na\/K Pump and Beyond: Na\/K-ATPase as a Modulator of Apoptosis and Autophagy. Molecules, 22.","DOI":"10.3390\/molecules22040578"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1158\/0008-5472.CAN-18-2723","article-title":"NRF2 Activation in Cancer: From DNA to Protein","volume":"79","author":"Cloer","year":"2019","journal-title":"Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/9\/2297\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:06:10Z","timestamp":1760137570000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/9\/2297"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,5]]},"references-count":41,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["cancers14092297"],"URL":"https:\/\/doi.org\/10.3390\/cancers14092297","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,5]]}}}