Inhibition of spontaneous and androgen-induced prostate growth by a nonhypercalcemic calcitriol analog

Endocrinology. 2003 Jul;144(7):3046-57. doi: 10.1210/en.2002-0210.


We have recently found that analog V (BXL-353, a calcitriol analog) inhibits growth factor (GF)-stimulated human benign prostate hyperplasia (BPH) cell proliferation by disrupting signal transduction, reducing Bcl-2 expression, and inducing apoptosis. We now report that BXL-353 blocks in vitro and in vivo testosterone (T) activity. BPH cells responded to T and dihydrotestosterone (DHT) with dose-dependent growth and reduced apoptosis. Exposure of BPH cells to BXL-353 significantly antagonized both T- and DHT-induced proliferation and induced apoptosis, even in the presence of T. To verify whether BXL-353 reduced prostate growth in vivo, we administered it orally to either intact or castrated rats, supplemented with T enanthate. Nonhypercalcemic doses of BXL-353 time- and dose-dependently reduced the androgen effect on ventral prostate weight, similarly to finasteride. Comparable results were obtained after chronic administration of BXL-353 to intact rats. Clusterin (an atrophy marker) gene and protein were up-regulated by BXL-353 in rat prostate, and nuclear fragmentation was widely present. The antiandrogenic properties of BXL-353 did not interfere with pituitary and testis function, as assessed by serum determination of rat LH and T. BXL-353 did not compete for androgen binding to BPH homogenates and failed to inhibit 5alpha-reductase type 1 and type 2 activities. In conclusion, BXL-353 blocks in vitro and in vivo androgen-stimulated prostate cell growth, probably acting downstream from the androgen receptor, without affecting calcemia or sex hormone secretion. BXL-353 and other vitamin D(3) analogs might thus represent an interesting class of compounds for treating patients with BPH.

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
  • Aging / pathology
  • Androgen Antagonists / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Atrophy
  • CHO Cells
  • Calcitriol / analogs & derivatives*
  • Clusterin
  • Cricetinae
  • Dihydrotestosterone / pharmacology
  • Gene Expression / drug effects
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Gonadal Steroid Hormones / blood
  • Gonadal Steroid Hormones / pharmacology*
  • Humans
  • Luteinizing Hormone / blood
  • Male
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Prostate / drug effects
  • Prostate / pathology*
  • Prostatic Hyperplasia / drug therapy*
  • Prostatic Hyperplasia / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptors, Androgen / genetics
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Stromal Cells / cytology
  • Stromal Cells / drug effects
  • Testosterone / blood
  • Testosterone / pharmacology*
  • Up-Regulation / drug effects


  • Androgen Antagonists
  • CLU protein, human
  • Clusterin
  • Glycoproteins
  • Gonadal Steroid Hormones
  • Molecular Chaperones
  • Receptors, Androgen
  • Receptors, Fibroblast Growth Factor
  • Dihydrotestosterone
  • Testosterone
  • Luteinizing Hormone
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • Receptor, Fibroblast Growth Factor, Type 2
  • keratinocyte growth factor receptor
  • Calcitriol