Inhibition of proliferation and induction of apoptosis by 25-hydroxyvitamin D3-3beta-(2)-Bromoacetate, a nontoxic and vitamin D receptor-alkylating analog of 25-hydroxyvitamin D3 in prostate cancer cells.
Clin Cancer Res
; 10(23): 8018-27, 2004 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-15585637
ABSTRACT
The 25-hydroxyvitamin D(3) (25-OH-D(3)) is a nontoxic and low-affinity vitamin D receptor (VDR)-binding metabolic precursor of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. We hypothesized that covalent attachment of a 25-OH-D(3) analog to the hormone-binding pocket of VDR might convert the latter into transcriptionally active holo-form, making 25-OH-D(3) biologically active. Furthermore, it might be possible to translate the nontoxic nature of 25-OH-D(3) into its analog. We showed earlier that 25-hydroxyvitamin D(3)-3-bromoacetate (25-OH-D(3)-3-BE) alkylated the hormone-binding pocket of VDR. In this communication we describe that 10(-6) mol/L of 25-OH-D(3)-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)(2)D(3). But its effect was strongest in LNCaP, PC-3, LAPC-4, and DU145 cells. Furthermore, 25-OH-D(3)-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 1alpha,25-dihydroxyvitamin D(3)-24-hydroxylase (24-OHase)-construct and VDR-expression vector, 25-OH-D(3)-3-BE induced 24-OHase promoter activity. In a "pull down assay" with PC-3 cells, 25-OH-D(3)-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-D(3)-3-BE were manifested via 1,25(OH)(2)D(3)/VDR signaling pathway. A toxicity study in CD-1 mice showed that 166 microg/kg of 25-OH-D(3)-3-BE did not raise serum-calcium beyond vehicle control. Collectively, these results strongly suggested that 25-OH-D(3)-3-BE has a strong potential as a therapeutic agent for androgen-sensitive and androgen-refractory prostate cancer.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
/
Calcitriol
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Apoptose
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Proliferação de Células
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Neoplasias Hormônio-Dependentes
Limite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Clin Cancer Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos