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Kafka, M.* ; Mayr, F.* ; Temml, V.* ; Möller, G. ; Adamski, J. ; Höfer, J.* ; Schwaiger, S.* ; Heidegger, I.* ; Matuszczak, B.* ; Schuster, D.* ; Klocker, H.* ; Bektic, J.* ; Stuppner, H.* ; Eder, I.E.*

Dual inhibitory action of a novel AKR1C3 inhibitor on both full-length AR and the variant AR-V7 in enzalutamide resistant metastatic castration resistant prostate cancer.

Cancers 12:2092 (2020)

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	Open Access Gold

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The expanded use of second-generation antiandrogens revolutionized the treatment landscape of progressed prostate cancer. However, resistances to these novel drugs are already the next obstacle to be solved. Various previous studies depicted an involvement of the enzyme AKR1C3 in the process of castration resistance as well as in the resistance to 2nd generation antiandrogens like enzalutamide. In our study, we examined the potential of natural AKR1C3 inhibitors in various prostate cancer cell lines and a three-dimensional co-culture spheroid model consisting of cancer cells and cancer-associated fibroblasts (CAFs) mimicking enzalutamide resistant prostate cancer. One of our compounds, named MF-15, expressed strong antineoplastic effects especially in cell culture models with significant enzalutamide resistance. Furthermore, MF-15 exhibited a strong effect on androgen receptor (AR) signaling, including significant inhibition of AR activity, downregulation of androgen-regulated genes, lower prostate specific antigen (PSA) production, and decreased AR and AKR1C3 expression, indicating a bi-functional effect. Even more important, we demonstrated a persisting inhibition of AR activity in the presence of AR-V7 and further showed that MF-15 non-competitively binds within the DNA binding domain of the AR. The data suggest MF-15 as useful drug to overcome enzalutamide resistance.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Enzalutamide Resistance ; Prostate Cancer ; Ar-v7 ; Spheroid Culture ; Cancer-associated Fibroblasts (cafs); Receptor Splice Variants; Circulating Tumor-cells; Androgen-receptor; 17-beta-hydroxysteroid-dehydrogenase Akr1c3; Expression; Abiraterone; Therapy; Binding; Target; Domain

ISSN (print) / ISBN 2072-6694

Journal Cancers

Quellenangaben Volume: 12, Issue: 8, Article Number: 2092

Publisher MDPI

Publishing Place St Alban-anlage 66, Ch-4052 Basel, Switzerland

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Molekulare Endokrinologie und Metabolismus (MEM)

Grants FWF Hertha Firnberg Project
GECT Euregio Tirol-Sudtirol-Trentino