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

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 beta-escin, a component of horse chestnut seed extract, inhibited OvCa adhesion/invasion. Here, we determine whether beta-escin and structurally similar compounds have a therapeutic potential against OvCa metastasis. Different sources of beta-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 beta-escin, we found that cardiac glycosides inhibited OvCa cell adhesion/invasion and proliferation in vitro, and inhibited adhesion/invasion and metastasis in vivo. Mechanistically, beta-escin and the cardiac glycosides inhibited ECM production in mesothelial cells and fibroblasts. The oral administration of beta-escin inhibited metastasis in both OvCa prevention and intervention mouse models. Specifically, beta-escin inhibited ECM production in the omental tumors. Additionally, the production of HIF1 alpha-targeted proteins, lactate dehydrogenase A, and hexokinase 2 in omental tumors was blocked by beta-escin. This study reveals that the natural compound beta-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