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 (Basel). 2020 Jul 28;12(8):2092. doi: 10.3390/cancers12082092.
Mona Kafka  1 ,  Fabian Mayr  2 ,  Veronika Temml  2 ,  Gabriele Möller  3 ,  Jerzy Adamski  3  4  5 ,  Julia Höfer  1 ,  Stefan Schwaiger  2 ,  Isabel Heidegger  1 ,  Barbara Matuszczak  6 ,  Daniela Schuster  6  7 ,  Helmut Klocker  1 ,  Jasmin Bektic  1 ,  Hermann Stuppner  2 ,  Iris E Eder  1
Affiliations
  • 1. Department of Urology, Medical University Innsbruck, 6020 Innsbruck, Austria.
  • 2. Institute of Pharmacy/Pharmacognosy, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria.
  • 3. Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 4. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 637551, Singapore.
  • 5. Lehrstuhl für Experimentelle Genetik, Technische Universität München, 85354 Freising-Weihenstephan, Germany.
  • 6. Institute of Pharmacy/Pharmaceutical Chemistry, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria.
  • 7. Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Paracelsus Medical University, 5020 Salzburg, Austria.
PMID: 32731472 DOI: 10.3390/cancers12082092
Abstract

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.

Keywords
AR-V7; ARK1C3; cancer-associated fibroblasts (CAFs); enzalutamide resistance; prostate cancer; spheroid culture.
Products