Intracrine androgen biosynthesis and drug resistance

Abstract

Castration-resistant prostate cancer is the lethal form of prostate cancer and most commonly remains dependent on androgen receptor (AR) signaling. Current therapies use AR signaling inhibitors (ARSI) exemplified by abiraterone acetate, a P450c17 inhibitor, and enzalutamide, a potent AR antagonist. However, drug resistance to these agents occurs within 12-18 months and they only prolong overall survival by 3-4 months. Multiple mechanisms can contribute to ARSI drug resistance. These mechanisms can include but are not limited to germline mutations in the AR, post-transcriptional alterations in AR structure, and adaptive expression of genes involved in the intracrine biosynthesis and metabolism of androgens within the tumor. This review focuses on intracrine androgen biosynthesis, how this can contribute to ARSI drug resistance, and therapeutic strategies that can be used to surmount these resistance mechanisms.

Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

“…In the search for AKR1C3 inhibitors, many steroidal and non-steroidal inhibitors have been isolated or generated and analysed [16,29]. Among them, plant-derived chalcones, flavonoids, alkaloids, and/or their derivatives have also been investigated.…”

“…One of these studies focused especially on the inhibitory influence of a series of naturally occurring chalcones on 17β-HSD and aromatase activities and was performed using human placental microsomes [47]. We included 2 of the 11 investigated chalcones-namely, isoliquiritigenin (16) and naringenin chalcone (29), in our study. Using placental microsomes and compound concentration of 10 µM, the authors reported 17β-HSD inhibition of 10% ( 16) and 2.4% (29), respectively.…”

“…We included 2 of the 11 investigated chalcones-namely, isoliquiritigenin (16) and naringenin chalcone (29), in our study. Using placental microsomes and compound concentration of 10 µM, the authors reported 17β-HSD inhibition of 10% ( 16) and 2.4% (29), respectively. This is less than what was measured in our study, with 16 and 29 reaching 31.1 ± 3.2% and 40.6 ± 7.7% inhibition of AKR1C3, respectively.…”

“…Many steroidal or non-steroidal AKR1C3 inhibitors have already been developed and characterised [17,25,29]. Most were developed to target AKR1C3 only, but some are both AKR1C3 inhibitors and AR antagonists [13,30,31].…”

“…Our current research aimed to further explore and clarify the importance of the substitution pattern on the inhibitory activity against AKR1C3 for a set of 12 synthetic chalcones (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29), along with isoliquiritigenin (16) and butein (17) obtained from commercial sources. Our goal was to better understand the AKR1C3-chalcone interaction and to develop an efficient chalcone-based AKR1C3 inhibitor.…”