Investigation of novel therapeutic strategies for epithelial ovarian cancer

Abstract

Objective: PRIMA-1MET is a small molecule compound that restores wild-type p53 to mutant p53, and is recently confirmed to be safe at therapeutic plasma levels. The aims of this study were to identify the anti-tumour activity of PRIMA-1MET on epithelial ovarian cancer (EOC) cells and elucidate the underlying mechanism in vitro. Methods: We used nine EOC cell lines and their chronic cisplatin/paclitaxel-resistant cells and performed cell viability assay and cell apoptosis assay to evaluate the efficacy of PRIMA-1MET. Moreover, we assessed the functional role of reactive oxygen species (ROS) and their scavenger in the EOC cells. Results: We examined the viability of the total 13 EOC cells after 48 h treatment with PRIMA-1MET. Measuring the half maximal inhibitory concentration (IC₅₀) of EOC cells revealed that the sensitivity was heterogeneous, and did not correlate with TP53 status. PRIMA-1MET induced apoptosis, PARP cleavage, and intracellular ROS accumulation in a p53-independent manner. The anti-tumour effects of PRIMA-1MET were completely rescued by a ROS scavenger, N-acetyl cysteine. Furthermore, PRIMA-1MET reduced the expression of antioxidant enzymes, PRX3 and GPX1, in a dose-dependent manner. Conclusion: We demonstrated that PRIMA-1MET had an anti-tumour effect on EOC cells regardless of TP53 status and chemo-resistance. PRIMA-1MET is a promising therapeutic agent for chemo-resistant EOC patients and may contribute to a better prognosis in the future.