Screening And Mechanism Study Of Anti-epithelial Ovarian Cancer Compounds Through Cell And Tumor Xenograft Models

Ovarian cancer is the most lethal gynecologic tumor with only 30%-40% 5-year survival rate.Epithelial ovarian cancer accounts for more than 85% of ovarian cancer,which is a subtype with the highest proportion and malignancy.The development of effective targeted therapy drugs is urgently needed to improve the 5-year survival rates of epithelial ovarian cancer.Cell models in vitro and tumor transplantation models in vivo are critic for screening of chemotherapeutic drugs.The widely used epithelial ovarian cancer cell lines are mainly derived from foreign ethnic populations,such as SKOV3 and OVCAR3 cell lines are both Caucasian race in the United States and A2780 cell line is from Australian.However,there are still no cell line derived from Chinese population.In this study,a variety of primary epithelial ovarian cancer cells were isolated from the epithelial ovarian cancer tissues from Chinese patients and a cell line SHOV4 was successfully established.SHOV4 is an epithelial high grade serous ovarian cancer cell line from Chinese Han,which is now frozen in China Center for Type Culture Collection(CCTCC).SHOV4 has not only strong proliferation,migration,clone formation abilities in vitro but also high tumorigenesis ability in vivo,that represents a typical and valuable cell line model of epithelial ovarian cancer.Using primary cells,cell lines and PDX models of epithelial ovarian cancer,an anti-epithelial ovarian cancer small molecule compound WG-391 D was identified.WG-391 D can effectively inhibit the proliferation and migration of epithelial ovarian cancer cells and the tumor growth of transplanted mouse models.Mechanismly,we demonstrated that WG-391 D can induce G2/M cell cycle arrest and apoptosis of epithelial ovarian cancer cells by inhibiting the expression of CDC25 B and inactivation of its downstream targets CDC2(CDK1)and AKT.Based on this study and our previous publications,we speculate that WG-391 D inhibits epithelial ovarian cancer tumorigenesis in a TGFBR1/CDC25B/AKT dependent manner.WG-391 D may be a good lead compound for the development of targeted therapeutics against epithelial ovarian cancer.