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Inhibition of Proliferation and Induction of Apoptosis by 25-Hydroxyvitamin D₃-3ß-(2)-Bromoacetate, a Nontoxic and Vitamin D Receptor-Alkylating Analog of 25-Hydroxyvitamin D₃ in Prostate Cancer Cells

¹ Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; ² Department of Endocrine, Neoplasia and Hormonal Disorder, M. D. Anderson Cancer Center, and ³ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; ⁴ Department of Biochemistry and Molecular Biology, New Jersey Medical School, Newark, New Jersey; and ⁵ Department of Surgical Oncology, University of Illinois Medical School, Chicago, Illinois

The 25-hydroxyvitamin D₃ (25-OH-D₃) is a nontoxic and low-affinity vitamin D receptor (VDR)-binding metabolic precursor of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]. We hypothesized that covalent attachment of a 25-OH-D₃ analog to the hormone-binding pocket of VDR might convert the latter into transcriptionally active holo-form, making 25-OH-D₃ biologically active. Furthermore, it might be possible to translate the nontoxic nature of 25-OH-D₃ into its analog. We showed earlier that 25-hydroxyvitamin D₃-3-bromoacetate (25-OH-D₃-3-BE) alkylated the hormone-binding pocket of VDR. In this communication we describe that 10^–6 mol/L of 25-OH-D₃-3-BE inhibited the growth of keratinocytes, LNCaP, and LAPC-4 androgen-sensitive and PC-3 and DU145 androgen-refractory prostate cancer cells, and PZ-HPV-7 immortalized normal prostate cells with similar or stronger efficacy as 1,25(OH)₂D₃. But its effect was strongest in LNCaP, PC-3, LAPC-4, and DU145 cells. Furthermore, 25-OH-D₃-3-BE was toxic to these prostate cancer cells and caused these cells to undergo apoptosis as shown by DNA-fragmentation and caspase-activation assays. In a reporter assay with COS-7 cells, transfected with a 1,25-dihydroxyvitamin D₃-24-hydroxylase (24-OHase)-construct and VDR-expression vector, 25-OH-D₃-3-BE induced 24-OHase promoter activity. In a "pull down assay" with PC-3 cells, 25-OH-D₃-3-BE induced strong interaction between VDR and general transcription factors, retinoid X receptor, and GRIP-1. Collectively, these results strongly suggested that the cellular effects of 25-OH-D₃-3-BE were manifested via 1,25(OH)₂D₃/VDR signaling pathway. A toxicity study in CD-1 mice showed that 166 µg/kg of 25-OH-D₃-3-BE did not raise serum-calcium beyond vehicle control. Collectively, these results strongly suggested that 25-OH-D₃-3-BE has a strong potential as a therapeutic agent for androgen-sensitive and androgen-refractory prostate cancer.

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