Introduction: Cisplatin (CDDP) resistance is a major challenge in ovarian cancer (OC) therapy, with over 80% of patients becoming CDDP-resistant. CDDP-resistant patients have limited treatment options, and therefore, therapeutics which can re-sensitize resistant OC to CDDP are essential. In this study, we examine the ability of the HIV protease inhibitor nelfinavir (NFV) to sensitize resistant OC cells to CDDP through activation of endoplasmic reticulum (ER) stress and simultaneous downregulation of the PI3K-AKT survival pathway.

Methods: Experiments were completed using CDDP-resistant OC cell lines PEO4 and IGROV-1/CP. Cell viability following treatment was assessed through cytometric cell counting. Induction of apoptosis was measured through annexin V staining and caspase-3/7 activation assays. Oxidative stress was measured through flow cytometry with superoxide indicator dyes. Immunoblotting was used to assess the DNA damage marker γH2AX, phosphorylation of AKT, and markers of ER stress.

Results: Co-treatment with NFV and CDDP reduced the IC50 of CDDP in PEO4 cells from 50 μM to 13 μM, and from >200 μM to 25 μM in IGROV-1/CP cells. Similarly, the combination of NFV and CDDP resulted in increased oxidative stress and DNA damage compared to either drug alone. Furthermore, co-treatment of the drugs increased caspase-3/7 activation and annexin V staining. The presence of NFV triggered the ER stress pathway, resulting in upregulation of pro-apoptotic proteins such as BAX, PUMA, and CHOP. Finally, NFV reduced phosphorylation of AKT, thereby downregulating the PI3K-AKT survival pathway.

Conclusions:  In this study, NFV sensitized CDDP-resistant OC cells to CDDP in cell viability experiments. In addition, the combination of CDDP and NFV was able to induce oxidative stress, DNA damage, ER stress, and apoptosis, while simultaneously downregulating the PI3K-AKT survival pathway. These results suggest that NFV may provide an option for CDDP-resistant patients.