PRIMA-1 ^MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells

There is an intensive need for the development of novel drugs for the treatment of epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy due to the high recurrence rate. TP53 mutation is a common event in EOC, particularly in high-grade serous ovarian cancer, where it occurs in more than 90% of cases. Recently, PRIMA-1 and PRIMA-1 ^MET (p53 reactivation and induction of massive apoptosis and its methylated form) were shown to have an antitumor effect on several types of cancer. Despite that PRIMA-1 ^MET is the first compound evaluated in clinical trials, the antitumor effects of PRIMA-1 ^MET on EOC remain unclear. In this study, we investigated the therapeutic potential of PRIMA-1 ^MET for the treatment of EOC cells. PRIMA-1 ^MET treatment of EOC cell lines (n=13) resulted in rapid apoptosis at various concentrations (24 h IC50 2.6-20.1 μM). The apoptotic response was independent of the p53 status and chemo-sensitivity. PRIMA-1 ^MET treatment increased intracellular reactive oxygen species (ROS), and PRIMA-1 ^MET -induced apoptosis was rescued by an ROS scavenger. Furthermore, RNA expression analysis revealed that the mechanism of action of PRIMA-1 ^MET may be due to inhibition of antioxidant enzymes, such as Prx3 and GPx-1. In conclusion, our results suggest that PRIMA-1 ^MET represents a novel therapeutic strategy for the treatment of ovarian cancer irrespective of p53 status and chemo-sensitivity.