A low-calcemic vitamin D analog (Ro 25-4020) inhibits the growth of LNCaP human prostate cancer cells with increased potency by producing an active 24-oxo metabolite (Ro 29-9970).

Abstract

In this study, we have characterized a novel less-calcemic vitamin D analog Ro 25-4020 (1alpha, 25 dihydroxy-16-ene-5,6-trans-vitamin D3) and investigated the mechanisms underlying its enhanced growth inhibitory properties. We found that Ro 25-4020 (IC50 = 0.3 nM) exhibited greater inhibitory activity than 1,25(OH)2D3 (IC50 = 1 nM) on LNCaP human prostate cancer cell growth. However, Ro 25-4020 was tenfold less active than 1,25(OH)2D3 in receptor-binding assays, ligand-induced heterodimerization and transactivation assays using VDR. HPLC and GC-MS analyses revealed that 1,25(OH)2D3 is converted to a 24-hydroxy metabolite, which has been shown to be less potent than 1,25(OH)2D3. In contrast, Ro 25-4020 was converted to a major 24-oxo metabolite that was more stable. Ligand-binding assays reveal that both Ro 25-4020 and its 24-oxo metabolite have similar affinity for VDR. Synthetic 24-oxo-Ro 25-4020, however, inhibited LNCaP cell proliferation as potently as 1,25(OH)2D3 and was more potent in transactivation of two out of three vitamin D target genes tested. These results suggest that conversion of Ro 25-4020 into an active and more stable 24-oxo metabolite with longer half-life contributes significantly to its potent antiproliferative actions on the LNCaP cells.

• Authors: Srilatha Swami, Xian-Yan Zhao, Stephen Sarabia, Mei-Lung Siu-Caldera, Milan Uskokovic, Satya G Reddy, David Feldman
• Journal: Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer (Recent Results Cancer Res) Vol. 164 Pg. 349-52 ( 2003) ISSN: 0080-0015 [Print] Germany
• PMID: 12899533 (Publication Type: Journal Article)

Chemical References

• 1,25-dihydroxy-16,23-diene vitamin D3
• Receptors, Calcitriol
• Receptors, Retinoic Acid
• Osteocalcin
• Cholecalciferol
• Luciferases
• Prostate-Specific Antigen
• Calcitriol

Topics

• Animals
• COS Cells
• Calcitriol (pharmacology)
• Cell Differentiation (drug effects)
• Cell Division (drug effects)
• Chlorocebus aethiops
• Cholecalciferol (analogs & derivatives, pharmacology)
• Chromatography, High Pressure Liquid
• Gas Chromatography-Mass Spectrometry
• Humans
• Luciferases (metabolism)
• Male
• Osteocalcin (genetics, metabolism)
• Prostate-Specific Antigen (genetics, metabolism)
• Prostatic Neoplasms (metabolism, pathology)
• Receptors, Calcitriol (metabolism)
• Receptors, Retinoic Acid (metabolism)
• Saccharomyces cerevisiae
• Transcription, Genetic (drug effects)
• Transcriptional Activation
• Tumor Cells, Cultured
• Two-Hybrid System Techniques