STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model

Abstract

Abstract17b-Hydroxysteroid dehydrogenases (17b-HSDs) catalyse the 17-position reduction/oxidation of steroids. 17b-HSD type 3 (17b-HSD3) catalyses the reduction of the weakly androgenic androstenedione (adione) to testosterone, suggesting that specific inhibitors of 17b-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia. STX2171 is a novel selective non-steroidal 17b-HSD3 inhibitor with an IC 50 of w200 nM in a whole-cell assay. It inhibits adione-stimulated proliferation of 17b-HSD3-expressing androgen receptor-positive LNCaP(HSD3) prostate cancer cells in vitro. An androgen-stimulated LNCaP(HSD3) xenograft proof-of-concept model was developed to study the efficacies of STX2171 and a more established 17b-HSD3 inhibitor, STX1383 (SCH-451659, Schering-Plough), in vivo. Castrated male MF-1 mice were inoculated s.c. with 1!10 7 cells 24 h after an initial daily dose of testosterone propionate (TP) or vehicle. After 4 weeks, tumours had not developed in vehicle-dosed mice, but were present in 50% of those mice given TP. One week after switching the stimulus to adione, mice were dosed additionally with the vehicle or inhibitor for a further 4 weeks. Both TP and adione efficiently stimulated tumour growth and increased plasma testosterone levels; however, in the presence of either 17b-HSD3 inhibitor, adione-dependent tumour growth was significantly inhibited and plasma testosterone levels reduced. Mouse body weights were unaffected. Both inhibitors also significantly lowered plasma testosterone levels in intact mice. In conclusion, STX2171 and STX1383 significantly lower plasma testosterone levels and inhibit androgen-dependent tumour growth in vivo, indicating that 17b-HSD3 inhibitors may have application in the treatment of hormone-dependent prostate cancer.

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

“…In the testes,this enzyme catalyses the last step in the biosynthesis of T, by stereoselectively reducing the C17 ketone STX2171 and 31 (later named STX1383) were also tested in a hormone-dependent PCa LNCaP(HSD3) xenografts, which were established in castrated male mice and using AD to stimulate tumour proliferation [83] . Both compounds were able to inhibit the proliferation of androgen-dependent prostate tumours (when stimulated by AD) and to reduce but not completely inhibit plasma T levels.…”

Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases

“…These molecules decreased plasma T levels and inhibited the in vivo growth of an androgen-stimulated LNCaPwt (HSD3) xenograft in castrated mice. This fact indicated that HSD3 inhibitors may have applications in the treatment of prostate cancer [99-100]. …”

“…( 13 ) displays several steroidal derivatives ( 54 , 55 , Fig. 13 ) that inhibit HSD3 and HSD5 [92, 97-100]. …”

“…Several reports have indicated that the inhibition of 17β-HSD5 could activate the peroxisome proliferator-activator, which is a nuclear receptor that functions as a transcriptional factor for encoding gene expression. As a consequence, cell differentiation and apoptosis of various different cell types and prostate cancers have been observed [99-100]. …”

“…( 13 ), several different steroidal lactones exhibited 17β-HSD3 inhibitory activity. However, the most potent lactone ( 57 ) is an inhibitor of 17β-HSD5; this has an IC 50 value of 2.9 nM in HEK-293 cells, which over-express human 17β-HSD5 enzyme; this lactone ( 57 ) was identified by Schuster et al in 2007 [100-111]. …”