Senolytic Elimination of Senescent Ovarian Clear Cell Carcinoma Cells Induced by CEP-1347 With the BH3 Mimetic Navitoclax

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Background/Aim: Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer characterized by infrequent TP53 mutations. We recently reported that the MDM4 inhibitor CEP-1347 effectively activated the p53 – p21 axis and inhibited the proliferation of OCCC cells with wild-type TP53. We also recently found that CEP-1347 induced senescence-like phenotypes in glioma stem cells and sensitized them to senolytics, such as BH3 mimetics represented by navitoclax. In the present study, we investigated whether CEP-1347 induced senescence-like phenotypes in OCCC cells and if combinations with BH3 mimetics enhanced the anti-cancer activity of CEP-1347 by promoting senolysis in OCCC cells. Materials and Methods: Senescence-like phenotypes were analyzed using microscopy, flow cytometry, and western blotting. Combined effects with senolytics were evaluated using cell death assays, colony formation assays, and western blot analysis. Results: CEP-1347 induced cellular senescence in OCCC cells with wild-type TP53. Furthermore, in combination with senolytics, particularly navitoclax, CEP-1347 strongly induced apoptotic death in these OCCC cells under conditions that were not toxic to normal cells. Conclusion: CEP-1347 induced cellular senescence in OCCC cells with wild-type TP53. The combination of CEP-1347 with senolytics, such as navitoclax, represents a rational strategy to ensure the selective elimination of senescent OCCC cells and enhance therapeutic efficacy.

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