Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17β-hydroxysteroid dehydrogenase Type 3

Reference:

Day, J. M., Tutill, H. J., Foster, P. A., Bailey, H. V., Heaton, W. B., Sharland, C. M., Vicker, N., Potter, B. V. L., Purohit, A. and Reed, M. J., 2009. Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17β-hydroxysteroid dehydrogenase Type 3. Molecular and Cellular Endocrinology, 301 (1-2), pp. 251-258.

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Official URL:

http://dx.doi.org/10.1016/j.mce.2008.08.014

Abstract

17β-Hydroxysteroid dehydrogenases (17β-HSDs) are responsible for the pre-receptor reduction/oxidation of steroids at the 17-position into active/inactive hormones, and the 15 known enzymes vary in their substrate specificity, localisation, and directional activity. 17β-HSD Type 3 (17β-HSD3) has been seen to be over-expressed in prostate cancer, and catalyses the reduction of androstenedione (Adione) to testosterone (T), which stimulates prostate tumour growth. Specific inhibitors of 17β-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia, and also have potential as male anti-fertility agents. A 293-EBNA-based cell line with stable expression of transfected human 17β-HSD3 was created and used to develop a whole cell radiometric TLC-based assay to assess the 17β-HSD3 inhibitory potency of a series of compounds. STX2171 and STX2624 (IC50 values in the 200–450 nM range) were two of several active inhibitors identified. In similar TLC-based assays these compounds were found to be inactive against 17β-HSD1 and 17β-HSD2, indicating selectivity. A novel proof of concept model was developed to study the efficacy of the compounds in vitro using the androgen receptor positive hormone-dependent prostate cancer cell line, LNCaPwt, and its derivative, LNCaP[17β-HSD3], transfected and selected for stable expression of 17β-HSD3. The proliferation of the parental cell line was most efficiently stimulated by 5α-dihydrotestosterone (DHT), but the LNCaP[17β-HSD3] cells were equally stimulated by Adione, indicating that 17β-HSD3 efficiently converts Adione to T in this model. Adione-stimulated proliferation of LNCaP[17β-HSD3] cells was inhibited in the presence of either STX2171 or STX2624. The compounds alone neither stimulated proliferation of the cells nor caused significant cell death, indicating that they are non-androgenic with low cytotoxicity. STX2171 inhibited Adione-stimulated growth of xenografts established from LNCaPwt cells in castrated mice in vivo. In conclusion, a primary screening assay and proof of concept model have been developed to study the efficacy of 17β-HSD3 inhibitory compounds, which may have a role in the treatment of hormone-dependent cancer. Active compounds are selective for 17β-HSD3 over 17β-HSD1 and 17β-HSD2, non-androgenic with low toxicity, and efficacious in both an in vitro proof of concept model and in an in vivo tumour model.

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