Eupenifeldin Triggers Cell Death in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer is the most common and aggressive form of ovarian cancer. There is an urgent need to develop novel drugs that could improve patient outcomes. Eupenifeldin was recently produced in large yields by the Oberlies lab, which allowed for extensive biological characterization. In three high-grade serous ovarian cancer cell lines (OVCAR3, OVCAR5, OVCAR8), eupenifeldin was found to have an IC50 of ~10 nM, with a therapeutic index 10X lower in fallopian tube secretory epithelial cell lines (FTSEC), indicating that there may be a specificity for tumor cells. In a clonogenic assay, incubation of 10 nM eupenifeldin for 8 hours was found to significantly hinder the ability of these cells to undergo expansion 5-fold suggesting cytotoxicity. To evaluate if cell death occurred by apoptosis, the annexin-V/propidium iodide assay was performed. It was found that eupenifeldin induced early apoptotic events in OVCAR3 and OVCAR8. These findings were confirmed in a western blot by evaluating cleaved PARP in OVCAR3. Cell-cycle arrest assay determined that treatment with eupenifeldin in OVCAR5 and OVCAR8 cell lines induced cell cycle arrest at 50 nM. A decrease in phosphorylated retinoblastoma confirms this via immunoblot. Eupenifeldin was found to act as a weak autophagy activator in HeLa cells. Natural products with nM activity that induce apoptosis may provide new therapies for ovarian cancer.