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.

Mona Kafka,Barbara Matuszczak,Fabian Mayr,Gabriele Möller,Veronika Temml,Jasmin Bektic,Daniela Schuster,Iris E Eder,Isabel Heidegger,Jerzy Adamski,Helmut Klocker,Julia Höfer,Hermann Stuppner,Stefan Schwaiger

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.

Highlights

Because of the strong relevance of androgens in all stages of prostate cancer (PCa), androgen deprivation therapy (ADT) is a mainstay in the treatment of metastatic PCa
The aim of our study was to investigate the anti-neoplastic effects of three natural aldo-keto reductase family 1 member C3 (AKR1C3) inhibitors, which originated from the plant Melodorum fruticosum, in PCa with an emphasis on their efficacy in overwhelming enzalutamide resistance
We demonstrated that prostate cancer cells become enzalutamide-resistant upon spheroid co-culture with cancer-associated fibroblasts (CAFs), associated with increased production of pro-inflammatory cytokines and elevation of steroid biosynthesis with significant upregulation of AKR1C3 in particular [23]

Summary

Introduction

Because of the strong relevance of androgens in all stages of prostate cancer (PCa), androgen deprivation therapy (ADT) is a mainstay in the treatment of metastatic PCa. The process of CRPC is connected to various mechanisms, as reactivation of androgen signaling under castrated conditions, gain-of-function mutations within the androgen receptor (AR) gene, increased AR expression [3,4,5], and elevated intratumoral androgen biosynthesis through upregulation of androgen-synthesizing enzymes like aldo-keto reductase family 1 member C3 (AKR1C3) [6]. The development of novel anti-androgens such as abiraterone acetate or enzalutamide significantly improved the management of CRPC. These anti-androgens intervene with the AR signaling pathway via different mechanisms. Abiraterone acetate inhibits androgen biosynthesis by targeting cytochrome

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