title: 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.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Swami
authors.forename: Xian-Yan
authors.initials: XY
authors.lastname: Zhao
authors.forename: Stephen
authors.initials: S
authors.lastname: Sarabia
authors.forename: Mei-Lung
authors.initials: ML
authors.lastname: Siu-Caldera
authors.forename: Milan
authors.initials: M
authors.lastname: Uskokovic
authors.forename: Satya G
authors.initials: SG
authors.lastname: Reddy
authors.forename: David
authors.initials: D
authors.lastname: Feldman
mesh_terms: D000818:Animals; D019556:COS Cells; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002522:Chlorocebus aethiops; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
chemical_list: C116777:1,25-dihydroxy-16,23-diene vitamin D3; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D015675:Osteocalcin; D002762:Cholecalciferol; D008156:Luciferases; D017430:Prostate-Specific Antigen; D002117:Calcitriol