Apigenin modulates cell survival pathways and restores olaparib sensitivity in high-grade serous ovarian cancer cells

OBJECTIVE: High-grade serous ovarian cancer (HGSOC) presents significant therapeutic challenges, particularly due to acquired resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) such as olaparib. This study examines the potential of apigenin (API), a naturally occurring flavonoid, to modulate survival pathways and restore olaparib sensitivity in HGSOC cell lines. MATERIALS AND METHODS: Four human HGSOC cell lines (TYK-nu, Kuramochi, CAOV3, and OVCAR3) and their olaparib-resistant derivatives were used. Olaparib resistance was induced by gradually exposing cells to increasing concentrations of olaparib. Cells were treated with API, and cell viability, apoptosis, and cell cycle distribution were assessed using MTT assays and flow cytometry. Western blotting was performed to analyze STAT3 and AKT phosphorylation, apoptotic markers, and cell cycle regulators, while immunofluorescence was used to evaluate STAT3 subcellular localization. RESULTS: API reduced cell viability in all HGSOC cell lines in a dose-dependent manner, exhibiting differential sensitivity. It induced cell death in TYK-nu and OVCAR3, while causing G2/M phase arrest in Kuramochi and CAOV3. API selectively inhibited pSTAT3 (Y705) and pAKT (S308) without altering total protein levels or STAT3 nuclear localization. Additionally, it downregulated key cell cycle regulators, including p53, p27, p21, and p16 across all lines. Cyclin B1 levels decreased universally, while CDC2 (CDK1) downregulation was specific to Kuramochi and CAOV3, correlating with G2/M arrest. Notably, API restored olaparib sensitivity in resistant Kuramochi and CAOV3 cells by reducing pSTAT3 (Y705) levels, indicating that STAT3 modulation may be a potential mechanism for overcoming resistance. CONCLUSION: API suppresses HGSOC progression by inducing apoptosis, arresting the cell cycle, and modulating survival pathways. It also restores olaparib sensitivity in resistant cells, supporting its potential as an adjuvant therapy to enhance olaparib efficacy in combination treatments.