Effects of new 17α-hydroxylase/C17,20-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo

D. N. Grigoryev, B. J. Long, I. P. Nnane, V. C.O. Njar, Y. Liu, A. M.H. Brodie

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)622-630
Number of pages9
JournalBritish journal of cancer
Volume81
Issue number4
DOIs
StatePublished - 1999

Keywords

  • 17α-hydroxylase/C-lyase inhibitors
  • Androgens synthesis
  • Azolyl steroids
  • LNCaP cells
  • SCID mice

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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