Synergistic suppression of ovarian cancer by combining NRF2 and GPX4 inhibitors: in vitro and in vivo evidence.

ABSTRACT

Ovarian cancer is a significant challenge in women's health due to the lack of effective screening and diagnostic methods, often leading to late detection and the highest mortality rate among all gynecologic tumors worldwide. Recent research has shown that ovarian cancer has an "iron addiction" phenotype which makes it vulnerable to ferroptosis inducers. We tested the combination of NRF2-targeted inhibitors with GPX4-targeted inhibitors in ovarian cancer through in vitro and in vivo experiment. The data showed that combination treatment effectively suppressed adherent cell growth, inhibited suspended cell spheroid formation, and restrained the ability of spheroid formation in 3D-culture. Mechanistically, the combination induced accumulation of ROS, 4-HNE, as well as activation of caspase-3 which indicates that this combination simultaneously increases cell ferroptosis and apoptosis. Notably, inhibition of GPX4 or NRF2 can suppress ovarian cancer spreading and growth in the peritoneal cavity of mice, while the combination of NRF2 inhibitor ML385 with GPX4 inhibitors showed a significant synergistic effect compared to individual drug treatment in a syngeneic mouse ovarian cancer model. Overall, these findings suggest that combining NRF2 inhibitors with GPX4 inhibitors results in a synergy suppression of ovarian cancer in vitro and in vivo, and maybe a promising therapeutic strategy for the treatment of ovarian cancer.