Abstract
Ovarian cancer is the leading cause of gynecological cancer-related mortality. The anticancer effect of eupatilin, a family of flavonoids, is known in many cancer types, but it is unclear what mechanism it plays in ovarian cancer. In this study, eupatilin promoted cell death of ovarian cancer cells by activating caspases, cell cycle arrest, reactive oxygen species (ROS) generation, calcium influx, disruption of the endoplasmic reticulum (ER)–mitochondria axis with SERPINB11 inhibition, and downregulation of phosphoinositide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways. Additionally, eupatilin-reduced SERPINB11 expression enhanced the effect of conventional chemotherapeutic agents against ovarian cancer cell progression. Cotreatment with siSERPINB11 and eupatilin increased calcium-ion-dependent apoptotic activity in ovarian cancer cells. Although there were no significant toxic effects of eupatilin on embryos, eupatilin completely inhibited tumorigenesis in a zebrafish xenograft model. In addition, eupatilin suppressed angiogenesis in zebrafish transgenic models. Collectively, downregulating SERPINB11 with eupatilin against cancer progression may improve therapeutic activity.
Highlights
Ovarian cancer is the leading cause of gynecological cancer-related mortality, with a 10-year survival rate below 30%
We assessed annexin/propidium iodide (PI) staining to analyze the features of eupatilin-induced cell death, and our results revealed that Propidium Iodide (PI)- and annexin-positive apoptotic populations were increased
Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells showed that eupatilin induced DNA fragmentation, indicating that eupatilin-mediated cytotoxicity was based on apoptotic cell death in both cell lines (Figure 1C)
Summary
Ovarian cancer is the leading cause of gynecological cancer-related mortality, with a 10-year survival rate below 30%. In spite of many efforts with numerous drug screenings and therapeutic strategies, the survival rate has not increased over the last three decades [1,2]. The various genetic variations of ovarian cancer and their different sensitivity to chemotherapy make it difficult to formulate treatment strategies for ovarian cancer [3]. Evidence has shown that compounds derived from herbs, fruits, and vegetables can reduce the risk of ovarian cancer and have synergistic effects with chemically synthesized anticancer drugs [4]. Eupatilin is a bioactive flavonoid derived from Artemisia asiatica. It has been reported that eupatilin has anticancer effects by regulating cell cycle or Cancers 2020, 12, 1459; doi:10.3390/cancers12061459 www.mdpi.com/journal/cancers
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