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OvCa cells metastasize to the peritoneum, which is covered by mesothelial cells, and invade into the underlying stroma, composed of extracellular matrices (ECM) and stromal cells. In a study using a three-dimensional quantitative high-throughput screening platform (3D-qHTS), we found that \u03b2-escin, a component of horse chestnut seed extract, inhibited OvCa adhesion\/invasion. Here, we determine whether \u03b2-escin and structurally similar compounds have a therapeutic potential against OvCa metastasis. Different sources of \u03b2-escin and horse chestnut seed extract inhibited OvCa cell adhesion\/invasion, both in vitro and in vivo. From a collection of 160 structurally similar compounds to \u03b2-escin, we found that cardiac glycosides inhibited OvCa cell adhesion\/invasion and proliferation in vitro, and inhibited adhesion\/invasion and metastasis in vivo. Mechanistically, \u03b2-escin and the cardiac glycosides inhibited ECM production in mesothelial cells and fibroblasts. The oral administration of \u03b2-escin inhibited metastasis in both OvCa prevention and intervention mouse models. Specifically, \u03b2-escin inhibited ECM production in the omental tumors. Additionally, the production of HIF1\u03b1-targeted proteins, lactate dehydrogenase A, and hexokinase 2 in omental tumors was blocked by \u03b2-escin. This study reveals that the natural compound \u03b2-escin has a therapeutic potential because of its ability to prevent OvCa dissemination by targeting both cancer and stromal cells in the OvCa tumor microenvironment.<\/jats:p>","DOI":"10.3390\/cancers13163931","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T08:47:52Z","timestamp":1628066872000},"page":"3931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The Natural Product \u03b2-Escin Targets Cancer and Stromal Cells of the Tumor Microenvironment to Inhibit Ovarian Cancer Metastasis"],"prefix":"10.3390","volume":"13","author":[{"given":"Hilary A.","family":"Kenny","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1843-9102","authenticated-orcid":false,"given":"Peter C.","family":"Hart","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasjusz","family":"Kordylewicz","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhu","family":"Lal","sequence":"additional","affiliation":[{"name":"Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), NIH, Rockville, MD 20852, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Shen","sequence":"additional","affiliation":[{"name":"Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), NIH, Rockville, MD 20852, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6064-1772","authenticated-orcid":false,"given":"Betul","family":"Kara","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Ju","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Grassl","sequence":"additional","affiliation":[{"name":"Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Alharbi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53792, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5385-358X","authenticated-orcid":false,"given":"Bikash R.","family":"Pattnaik","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8260-0098","authenticated-orcid":false,"given":"Karen M.","family":"Watters","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8205-6432","authenticated-orcid":false,"given":"Manish S.","family":"Patankar","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53792, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ferrer","sequence":"additional","affiliation":[{"name":"Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), NIH, Rockville, MD 20852, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8624-1507","authenticated-orcid":false,"given":"Ernst","family":"Lengyel","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.2174\/1871520620666200705220307","article-title":"Natural Products: Implication in Cancer Prevention and Treatment through Modulating Various Biological Activities","volume":"20","author":"Anwar","year":"2020","journal-title":"Anticancer. 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