Effects of new 17alpha-hydroxylase/C(17,20)-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo.

Abstract

Our laboratory has been developing new inhibitors of a key regulatory enzyme of testicular and adrenal androgen synthesis 17alpha-hydroxylase/C(17,20)-lyase (P450c17), with the aim of improving prostate cancer treatment. We designed and evaluated two groups of azolyl steroids: delta5-non-competitive inhibitors (delta5NCIs), VN/63-1, VN/85-1, VN/87-1 and their corresponding delta4 derivatives (delta4NCIs), VN/107-1, VN/108-1 and VN/109-1. The human P450c17 gene was transfected into LNCaP human prostate cancer cells, and the resultant LNCaP-CYP17 cells were utilized to evaluate the inhibitory potency of the new azolyl steroids. VN/85-1 and VN/108-1 had the lowest IC50 values of 1.25 +/- 0.44 nM and 2.96 +/- 0.78 nM respectively, which are much lower than that of the known P450 inhibitor ketoconazole (80.7 +/- 1.8 nM). To determine whether the compounds had direct actions on proliferation of wild-type LNCaP cells, cell growth studies were performed. All of the delta5NCIs and VN/108-1 blocked the growth-stimulating effects of androgens. In steroid-free media, the delta5NCIs decreased the proliferation of LNCaP cells by 35-40%, while all of the delta4NCIs stimulated LNCaP cells growth 1.5- to 2-fold. In androgen receptor (AR) binding studies, carried out to determine the mechanism of this effect, all of the delta4NCIs (5 microM) displaced 77-82% of synthetic androgen R1881 (5 nM) from the LNCaP AR. The anti-androgen flutamide and the delta5NCIs displaced 53% and 32-51% of R1881 bound to AR respectively. These results suggested that the delta5NCIs may also be acting as anti-androgens. We further evaluated our inhibitors in male severe combined immunodeficient mice bearing LNCaP tumour xenografts. In this model VN/85-1 was as effective as finasteride at inhibiting tumor growth (26% and 28% inhibition, respectively) and the inhibitory effect of VN/87-1 was similar to that of castration (33% and 36% inhibition respectively). These results suggest that VN/85-1 and VN/87-1 may be potential candidates for treatment of prostate cancer.

• Authors: D N Grigoryev, B J Long, I P Nnane, V C Njar, Y Liu, A M Brodie
• Journal: British journal of cancer (Br J Cancer) Vol. 81 Issue 4 Pg. 622-30 (Oct 1999) ISSN: 0007-0920 [Print] England
• PMID: 10574247 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Steroids
• Metribolone
• Steroid 17-alpha-Hydroxylase
• Prostate-Specific Antigen

Topics

• Animals
• Cell Division (drug effects)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Humans
• Male
• Metribolone (metabolism)
• Mice
• Mice, SCID
• Prostate-Specific Antigen (blood)
• Prostatic Neoplasms (drug therapy, pathology)
• Steroid 17-alpha-Hydroxylase (antagonists & inhibitors)
• Steroids (therapeutic use)
• Tumor Cells, Cultured