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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.

Details

Item Type Articles
CreatorsDay, 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.
DOI10.1016/j.mce.2008.08.014
Uncontrolled Keywordsenzyme inhibition, testosterone, prostate cancer, (17 beta-hsd), androgen, 17 beta-hydroxysteroid, dehydrogenase
DepartmentsFaculty of Science > Pharmacy & Pharmacology
RefereedYes
StatusPublished
ID Code13994

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