The Natural Product β-Escin Targets Cancer and Stromal Cells of the Tumor Microenvironment to Inhibit Ovarian Cancer Metastasis

SIMPLE SUMMARY: β-escin, a component of horse chestnut seed extract, was first identified as an inhibitor of ovarian cancer (OvCa) adhesion/invasion in our high-throughput screening program using a three-dimensional organotypic model assembled from primary human cells and extracellular matrix. The goal of the study presented here is to determine if β-escin and structurally-similar compounds have a therapeutic potential against OvCa metastasis. β-escin and cardiac glycosides inhibit ovarian cancer adhesion/invasion to the omental microenvironment in vivo, and β-escin inhibits ovarian cancer metastasis in the prevention and intervention setting. Additionally, β-escin was found to decrease the stemness of ovarian cancer cells, inhibit extracellular matrix production in the tumor microenvironment, and inhibit HIF1α stability in ovarian cancer cells and the tumor microenvironment. This study reveals that the natural compound β-escin has therapeutic potential because of its ability to prevent OvCa dissemination by targeting both cancer and stromal cells in the OvCa tumor microenvironment. ABSTRACT: The high mortality of OvCa is caused by the wide dissemination of cancer within the abdominal cavity. 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 β-escin, a component of horse chestnut seed extract, inhibited OvCa adhesion/invasion. Here, we determine whether β-escin and structurally similar compounds have a therapeutic potential against OvCa metastasis. Different sources of β-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 β-escin, we found that cardiac glycosides inhibited OvCa cell adhesion/invasion and proliferation in vitro, and inhibited adhesion/invasion and metastasis in vivo. Mechanistically, β-escin and the cardiac glycosides inhibited ECM production in mesothelial cells and fibroblasts. The oral administration of β-escin inhibited metastasis in both OvCa prevention and intervention mouse models. Specifically, β-escin inhibited ECM production in the omental tumors. Additionally, the production of HIF1α-targeted proteins, lactate dehydrogenase A, and hexokinase 2 in omental tumors was blocked by β-escin. This study reveals that the natural compound β-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.