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Background: Ovarian 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. Methods: In 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 (Cis R SKOV-3). Cell viability and colony formation assays along with subcellular fractionation analysis, immunoblotting, and immunofluorescence staining were performed. Results: ER 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 Cis R SKOV-3. Conclusion: Taken 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.

Aim: To evaluate the effects of the combination of calcitriol and chemotherapy and to identify the molecular mechanisms underlying the effect of calcitriol on ovarian cancer cells. Materials and Methods: SKOV-3 cells were treated with calcitriol and cisplatin, and their effects alone and in combination in a dose-dependent manner were compared. Cell viability, cell proliferation, and apoptosis were assessed using the following assays: PrestoBlue, intracellular adenosine triphosphate, caspase-3/7 activity, annexin V, and immunoblotting, respectively. Results: Calcitriol alone caused dose-dependent inhibition of cell survival and proliferation, and induced apoptotic cell death of SKOV-3 cells. We confirmed that the expression of vitamin D receptor was increased in a dose-dependent manner by calcitriol. Combination treatment using calcitriol at a physiological concentration of 10-100 nM plus cisplatin significantly suppressed cell survival and induced apoptosis. Furthermore, when calcitriol was administered alone, the activity of vascular endothelial growth factor decreased in a dose-dependent manner, and when combined with cisplatin, activity was more suppressed. Conclusion: In SKOV-3 ovarian cancer cells, calcitriol plus cisplatin exerted greater antiproliferative, apoptotic, and anti-angiogenic effects than cisplatin alone. Adding calcitriol to platinum-based chemotherapy might be beneficial to patients with ovarian cancer.Ovarian cancer is the main cause of mortality in women with cancer (1). The 5-year survival rate for women with epithelial ovarian cancer (EOC) is less than 40% because, in most cases, the disease is diagnosed at an advanced stage (2, 3). Patients with advanced EOC are treated with cytoreductive surgery and platinum-based chemotherapy; those who receive adjuvant chemotherapy or preoperative chemotherapy will also undergo cytoreductive surgery (2, 4). Patients with advanced EOC respond well to initial platinum-based therapy but the disease eventually recurs in more than 75% of patients (5). Patients with recurrent EOC receive additional chemotherapy, which increases the survival rate, but does not ultimately cure the disease. The treatment modalities for ovarian cancer have not significantly progressed over the past few decades, so there is growing interest in new approaches for EOC treatment (6). The growing biological understanding of EOC has led to the development of several targeted molecules and biological treatments, including angiogenesis inhibitors, immune modulators and poly (ADPribose) polymerase (PARP) inhibitors (7).Vitamin D has a well-established role in maintaining calcium and bone homeostasis. Nearly 3% of the human genome is affected by the endocrine system of vitamin D (8). Calcitriol is an activated hormone of vitamin D that binds to the vitamin D receptor (VDR) in the cell nucleus (9, 10). Studies have reported mechanisms by which VDR can suppress tumor growth, including genomic and non-genomic signaling pathways (8,10,11). In addition, calcitriol regulates important biologica...

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Purpose This study aimed to evaluate anticancer effects of combination treatment with poly(ADP-ribose) polymerase (PARP) and checkpoint kinase 1 (Chk1) inhibitors in BRCA wild-type ovarian cancer. PARP inhibitors can function as DNA-damaging agents in BRCA wild-type cancer, even if clinical activity is limited. Most epithelial ovarian cancers are characterized by a TP53 mutation causing dysfunction at the G1/S checkpoint, which makes tumor cells highly dependent on Chk1-mediated G/M phase cell-cycle arrest for DNA repair.Materials and Methods We investigated the anticancer effects of combination treatment with prexasertib (LY2606368), a selective ATP competitive small molecule inhibitor of Chk1 and Chk2, and rucaparib, a PARP inhibitor, in BRCA wild-type ovarian cancer cell lines (OVCAR3 and SKOV3).Results We found that combined treatment significantly decreased cell viability in all cell lines and induced greater DNA damage and apoptosis than in the control and/or using monotherapies. Moreover, we found that prexasertib significantly inhibited homologous recombination–mediated DNA repair and thus showed a marked anticancer effect in combination treatment with rucaparib. The anticancer mechanism of prexasertib and rucaparib was considered to be caused by an impaired G2/M checkpoint due to prexasertib treatment, which forced mitotic catastrophe in the presence of rucaparib.Conclusion Our results suggest a novel effective therapeutic strategy for BRCA wild-type epithelial ovarian cancer using a combination of Chk1 and PARP inhibitors.