Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers
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 clini...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/9/2297 |
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| author | Arvinder Kapur Pooja Mehta Aaron D Simmons Spencer S. Ericksen Geeta Mehta Sean P. Palecek Mildred Felder Zach Stenerson Amruta Nayak Jose Maria Ayuso Dominguez Manish Patankar Lisa M. Barroilhet |
| author_facet | Arvinder Kapur Pooja Mehta Aaron D Simmons Spencer S. Ericksen Geeta Mehta Sean P. Palecek Mildred Felder Zach Stenerson Amruta Nayak Jose Maria Ayuso Dominguez Manish Patankar Lisa M. Barroilhet |
| author_sort | Arvinder Kapur |
| collection | DOAJ |
| description | 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’s potential as a gynecologic cancer therapeutic. |
| first_indexed | 2024-03-10T04:17:26Z |
| format | Article |
| id | doaj.art-e72fa9a2fafb4b76b5a5fa756edeb127 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:17:26Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e72fa9a2fafb4b76b5a5fa756edeb1272023-11-23T07:57:39ZengMDPI AGCancers2072-66942022-05-01149229710.3390/cancers14092297Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic CancersArvinder Kapur0Pooja Mehta1Aaron D Simmons2Spencer S. Ericksen3Geeta Mehta4Sean P. Palecek5Mildred Felder6Zach Stenerson7Amruta Nayak8Jose Maria Ayuso Dominguez9Manish Patankar10Lisa M. Barroilhet11Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USADepartment of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USADrug Development Core, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USADepartment of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USADepartment of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USADepartment of Dermatology, University of Wisconsin-Madison, Madison, WI 53715, USADepartment of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USAOxidative 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’s potential as a gynecologic cancer therapeutic.https://www.mdpi.com/2072-6694/14/9/2297metabolismoxidative phosphorylationmitochondria |
| spellingShingle | Arvinder Kapur Pooja Mehta Aaron D Simmons Spencer S. Ericksen Geeta Mehta Sean P. Palecek Mildred Felder Zach Stenerson Amruta Nayak Jose Maria Ayuso Dominguez Manish Patankar Lisa M. Barroilhet Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers Cancers metabolism oxidative phosphorylation mitochondria |
| title | Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers |
| title_full | Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers |
| title_fullStr | Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers |
| title_full_unstemmed | Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers |
| title_short | Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers |
| title_sort | atovaquone an inhibitor of oxidative phosphorylation as studied in gynecologic cancers |
| topic | metabolism oxidative phosphorylation mitochondria |
| url | https://www.mdpi.com/2072-6694/14/9/2297 |
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