Abstract
Our laboratory has been developing new inhibitors of a key regulatory enzyme of testicular and adrenal androgen synthesis 17α-hydroxylase/C17,20-lyase (P450c17), with the aim of improving prostate cancer treatment. We designed and evaluated two groups of azolyl steroids: Δ5-non-competitive inhibitors (Δ5NCIs), VN/63-1, VN/85-1, VN/87-1 and their corresponding Δ4 derivatives (Δ4NCIs), 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 Δ5NCIs and VN/108-1 blocked the growth-stimulating effects of androgens. In steroid-free media, the Δ5NCIs decreased the proliferation of LNCaP cells by 35-40%, while all of the Δ4NCIs 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 Δ4NCIs (5 μM) displaced 77-82% of synthetic androgen R1881 (5 nM) from the LNCaP AR. The anti-androgen flutamide and the Δ5NCIs displaced 53% and 32-51% of R1881 bound to AR respectively. These results suggested that the Δ5NCIs 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.
Original language | English (US) |
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Pages (from-to) | 622-630 |
Number of pages | 9 |
Journal | British journal of cancer |
Volume | 81 |
Issue number | 4 |
DOIs | |
State | Published - 1999 |
Externally published | Yes |
Keywords
- 17α-hydroxylase/C-lyase inhibitors
- Androgens synthesis
- Azolyl steroids
- LNCaP cells
- SCID mice
ASJC Scopus subject areas
- Oncology
- Cancer Research