Mechanistic and pharmacodynamic studies of a 25-hydroxyvitamin D3 derivative in prostate cancer cells.
1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active form of vitamin D has strong antiproliferative effects in cancer cells. But it is highly toxic at therapeutic doses. We have observed that 25-hydroxyvitamin D(3)-3-bromoacetate (25-OH-D(3)-3-BE), a derivative of 25-hydroxyvitamin D(3), the pro-hormonal form of 1,25(OH)(2)D(3) has strong growth-inhibitory and proapoptotic properties in hormone-sensitive and hormone-refractory prostate cancer cells. In the present investigation we demonstrate that the antiproliferative effect of 25-OH-D(3)-3-BE is predominantly mediated by VDR in ALVA-31 prostate cancer cells. In other mechanistic studies we show that the proapoptotic property of 25-OH-D(3)-3-BE is related to the inhibition of phosphorylation of Akt, a pro-survival protein. Furthermore, we carried out cellular uptake and serum stability studies of 25-OH-D(3)-3-BE to demonstrate potential therapeutic applicability of 25-OH-D(3)-3-BE in hormone-sensitive and hormone-insensitive prostate cancer.
Lambert
James R
JR
Department of Pathology, University of Colorado Health Science Center, Aurora, CO, USA.
Young
Christian D
CD
Persons
Kelly S
KS
Ray
Rahul
R
D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D001692:Biological Transport; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism
C101470:25-hydroxyvitamin D3-bromoacetate; D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; D051057:Proto-Oncogene Proteins c-akt; D002112:Calcifediol