AKR1C1/2 inhibition by MPA sensitizes platinum resistant ovarian cancer towards carboplatin.

Abstract

In recurrent epithelial ovarian cancer (EOC) most patients develop platinum-resistance. On molecular level the NRF2 pathway, a cellular defense mechanism against reactive oxygen species, is induced. In this study, we investigate AKR1C1/2, target of NRF2, in a well-established EOC collective by immunohistochemistry and in a panel of ovarian cancer cell lines including platinum-resistant clones. The therapeutic effect of carboplatin and MPA as monotherapy or in combination was assessed by functional assays, using OV90 and OV90cp cells. Molecular mechanisms of action of MPA were investigated by NRF2 silencing and AKR activity measurements. Immunohistochemical analysis revealed that AKR1C1/2 is a key player in the development of chemoresistance and an independent indicator for short PFS (23.5 vs. 49.6 months, p = 0.013). Inhibition of AKR1C1/2 by MPA led to a concentration- and time-dependent decline of OV90 viability and to an increased response to CP in vitro. By NRF2 silencing, however, the effects of MPA treatment were reduced. Concludingly, our data suggest that a combination therapy of carboplatin and MPA might be a promising therapeutic approach to increase response rates of EOC patients, which should be explored in clinical context.

• Authors: Susann Badmann, Doris Mayr, Elisa Schmoeckel, Anna Hester, Christina Buschmann, Susanne Beyer, Thomas Kolben, Fabian Kraus, Anca Chelariu-Raicu, Alexander Burges, Sven Mahner, Udo Jeschke, Fabian Trillsch, Bastian Czogalla
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 1862 (02 03 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35115586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Antineoplastic Agents, Hormonal
• Enzyme Inhibitors
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Carboplatin
• Medroxyprogesterone Acetate
• Hydroxysteroid Dehydrogenases
• 20-Hydroxysteroid Dehydrogenases
• 3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase
• AKR1C2 protein, human

Topics

• 20-Hydroxysteroid Dehydrogenases (antagonists & inhibitors, metabolism)
• Antineoplastic Agents, Hormonal (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Carboplatin (pharmacology)
• Carcinoma, Ovarian Epithelial (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Hydroxysteroid Dehydrogenases (antagonists & inhibitors, metabolism)
• Medroxyprogesterone Acetate (pharmacology)
• Middle Aged
• NF-E2-Related Factor 2 (genetics, metabolism)
• Ovarian Neoplasms (drug therapy, enzymology, genetics, pathology)