17β-hydroxysteroid dehydrogenases (17β-HSDs) catalyse the 17-position reduction / oxidation of steroids.
17β-HSD type 3 (17β-HSD3) catalyses the reduction of the weakly-androgenic androstenedione (adione) to testosterone, suggesting that specific inhibitors of 17β-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia. STX2171 is a novel selective non-steroidal 17β-HSD3 inhibitor with an IC50 of ~200 nM in a whole cell assay. It inhibits adione-stimulated proliferation of 17β-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 17β-HSD3 inhibitor, STX1383 (SCH-451659, Schering-Plough), in vivo. Castrated male MF-1 mice were inoculated s.c. with 1 x 107 cells 24 hours after an initial daily dose of testosterone propionate (TP) or vehicle. After 4 weeks tumors 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 vehicle or inhibitor for a further 4 weeks. Both TP and adione efficiently stimulated tumor growth and increased plasma testosterone levels, but in the presence of either 17β-HSD3 inhibitor, adione-dependent tumor growth was significantly inhibited and plasma testosterone levels reduced. Mouse bodyweights 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 tumor growth in vivo, indicating that 17β-HSD3 inhibitors may have application in the treatment of hormone-dependent prostate cancer.
Written by:
Day JM, Foster PA, Tutill HJ, Schmidlin F, Sharland CM, Hargrave JD, Vicker N, Potter BV, Reed MJ, Purohit A. Are you the author?
Oncology Drug Discovery & Women's Health Group, Imperial College London, London, United Kingdom.
Reference: Endocr Relat Cancer. 2012 Nov 6. Epub ahead of print.
PubMed Abstract
PMID: 23132791
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