Nelfinavir Synergizes with Cisplatin and Promotes GSDME-Associated Lytic Cell Death in Platinum-Resistant Ovarian Cancer Cells

Background/Objectives: Platinum resistance limits the efficacy of ovarian cancer treatment and arises through multiple mechanisms, including enhanced DNA repair, activation of stress responses, and increased survival signaling. Nelfinavir (NFV), an HIV protease inhibitor with reported anti-tumor activity, is a candidate for drug repurposing, but its interaction with cisplatin (CDDP) in ovarian cancer has not been established. Here, we investigated whether NFV enhances CDDP cytotoxicity in platinum (Pt)-resistant ovarian cancer cells and characterized the associated cell death response.

Methods

Drug interaction was assessed using cell vitality and viability assays and Loewe additivity modeling together with Bliss and ZIP analyses. Cell death was characterized by Annexin V/7-AAD staining, mitochondrial membrane potential analysis, lactate dehydrogenase (LDH) release, immunoblotting, pharmacological caspase inhibition, and bulk mRNA sequencing with differential expression and gene set enrichment analyses.