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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Sprache englisch
Veröffentlichungsjahr 2020
HGF-Berichtsjahr 2020
ISSN (print) / ISBN 2072-6694
Zeitschrift Cancers
Quellenangaben Band: 12, Heft: 8, Seiten: , Artikelnummer: 2092 Supplement: ,
Verlag MDPI
Verlagsort St Alban-anlage 66, Ch-4052 Basel, Switzerland
Begutachtungsstatus Peer reviewed
Institut(e) Molekulare Endokrinologie und Metabolismus (MEM)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-505600-001
G-505600-003
Förderungen FWF Hertha Firnberg Project
GECT Euregio Tirol-Sudtirol-Trentino
DOI 10.3390/cancers12082092
WOS ID WOS:000578908300001
Scopus ID 85090656849
PubMed ID 32731472
Erfassungsdatum 2020-09-21
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