Abstract
BackgroundOvarian cancer therapy generally involves systemic chemotherapy with anticancer drugs; however, chemotherapy with a platinum-based drug has often been shown to cause adverse reactions and drug resistance in ovarian cancer patients. Evodia rutaecarpa (ER) reportedly shows anticancer activity against various types of cancer cells. However, the effects of ER have not yet been fully uncovered in ovarian cancer.MethodsIn the present study, we investigated the anticancer effects of an ER extract and its components against the ovarian cancer cell lines SKOV-33, A2780, RMUG-S and a cisplatin-resistant SKOV-3 cell line (CisR SKOV-3). Cell viability and colony formation assays along with subcellular fractionation analysis, immunoblotting, and immunofluorescence staining were performed.ResultsER treatment led to a significant reduction in the viability of SKOV-3 cells. Moreover, limonin, a compound found in ER, reduced the viability of both serous-type (SKOV-3 and A2780) and mucinous-type (RMUG-S) ovarian cancer cells by inducing apoptosis via activation of the p53 signaling pathway. Furthermore, limonin reversed the drug resistance through activation of apoptosis in CisR SKOV-3.ConclusionTaken together, our findings suggest that limonin contributes to the anti-ovarian cancer effects of ER by inducing apoptosis via activation of the p53 signaling pathway.
Highlights
Ovarian cancer therapy generally involves systemic chemotherapy with anticancer drugs; chemotherapy with a platinum-based drug has often been shown to cause adverse reactions and drug resistance in ovarian cancer patients
Evodia rutaecarpa (ER) extract exerted anticancer effects in SKOV-3 cells We found that ER treatment reduced cell density and increased membrane blebbing in SKOV-3 cells (Fig. 1a)
We investigated the effect of limonin on the cellular levels of p53 and p65 proteins in ovarian cancer cells and found that the limonin-induced apoptotic cell death was initiated by the activation of the p53 protein, subsequently leading to an increase in the level of p53 as well as to its nuclear translocation, thereby resulting in the activation of proteins involved in the process of apoptosis (Figs. 3 and 4)
Summary
Ovarian cancer therapy generally involves systemic chemotherapy with anticancer drugs; chemotherapy with a platinum-based drug has often been shown to cause adverse reactions and drug resistance in ovarian cancer patients. In patients with ovarian cancer, chemotherapy with existing anticancer drugs, such as cisplatin, leads to adverse reactions and the development of chemoresistance. Together with chemoresistance, contribute to the failure of anticancer therapy. To address these problems, development of drugs using natural products has been on the rise, Evodia rutaecarpa (ER), an oriental medicine, has traditionally been used for the treatment of headaches, gastrointestinal diseases, amenorrhea, and postpartum hemorrhage [4,5,6]. Several studies have reported that ER and its derivatives exhibit multiple biological activities, including anti-inflammatory, anti-obesity, antihypertensive, and anti-allergic effects [8,9,10].
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