AKR1C1/2 inhibition by MPA resensitizes platinum resistant ovarian cancer towards platinum-based chemotherapy

Background Platinum resistance is a major problem limiting sufficient treatment of epithelial ovarian cancer (EOC). During development of chemoresistance nuclear factor E2-related factor 2 (NRF2) and its target genes are induced. Here we focus on this pathway to further characterize the molecular basis of chemoresistance and propose a combination therapy with carboplatin and medroxyprogesterone acetate (MPA).

Methods In an established EOC collective with 156 patients aldo-keto reductase family 1 member C1 and 2 (AKR1C1/2) expression was investigated by immunohistochemistry. NRF2 and AKR1C1/2 expression was further compared between six ovarian cancer cell lines and platinum-resistant clones. Functional assays have been conducted to assess the therapeutic effect of carboplatin, MPA and their combination on viability, proliferation and apoptosis of OV90 and OV90cp cells. Molecular mechanisms of MPA action were investigated by NRF2 silencing and AKR activity measurements.

Results AKR1C1/2 expression was upregulated in patients with serous EOC and those patients showed an impaired progression free survival. Expression analyses proved that NRF2 and its target genes AKRC1/2 are induced in platinum resistant ovarian cancer cells. MPA administration led to a potent inhibition of AKR activity and to a concentration- and time-dependent decline of OV90 viability. Combination of carboplatin and MPA enhanced this effect significantly. Proliferation of OV90 and OV90cp was further inhibited, while the apoptosis rate increased. By NRF2 silencing however, the effects of MPA treatment were reduced.

Conclusion Our data suggest that a combination therapy with MPA and carboplatin might be a promising therapeutic approach to increase response rates of EOC patients.

Publication History

Article published online:
07 October 2020