AKR1C inhibitors medroxyprogesterone acetate and mefenamic acid exhibit antitumor activity alone and combined with carboplatin in platinum-resistant high-grade serous ovarian cancer models

High-grade serous ovarian carcinoma (HGSOC) is the most lethal form of ovarian carcinoma, primarily because of its tendency to develop platinum resistance. The genes AKR1C1-3 and NFE2L2 are involved in steroid metabolism and cellular detoxification, but their roles in HGSOC remain unclear. Here, we show that AKR1C1-3 co-expression is elevated in platinum-resistant HGSOC tumors. Kaplan-Meier analysis revealed that high AKR1C1-3 expression and low NFE2L2 expression impact survival in serous ovarian cancer. Evaluation of mRNA and protein levels of AKR1C1-3 in six HGSOC cell lines showed the highest expression in the two most resistant lines. Next, we investigated medroxyprogesterone acetate (MPA) and mefenamic acid (MEF), both with AKR1C inhibitory activity, to assess their potential antitumor effects in HGSOC cells. Both drugs reduced proliferation and migration in resistant cells, with MPA showing strong single-agent effects and synergy with carboplatin, while MEF enhanced carboplatin activity at higher concentrations. To further investigate the migration potential of resistant HGSOC cells, we also examined the effect of estrogen precursor (estrone sulfate) alone or in combination with MPA, MEF, or carboplatin. Estrone sulfate modulated migration in a cell line-dependent manner; in COV362 cells, its combination with MPA completely inhibited migration. Importantly, MPA and MEF consistently induced apoptosis, whereas carboplatin induced delayed necrosis. In 3D spheroids, both agents disrupted tumor architecture and reduced viability, alone or in combination with carboplatin. Our findings highlight that platinum resistance in HGSOC can be tackled by repurposing MEF and MPA that act also as AKR1C inhibitors.