Mechanistic and pharmacodynamic studies of a 25-hydroxyvitamin D3 derivative in prostate cancer cells

Biochem Biophys Res Commun. 2007 Sep 14;361(1):189-95. doi: 10.1016/j.bbrc.2007.07.012. Epub 2007 Jul 16.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / blood
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Biological Transport
  • Calcifediol / analogs & derivatives*
  • Calcifediol / blood
  • Calcifediol / metabolism
  • Calcifediol / pharmacology
  • Cell Line, Tumor
  • Humans
  • Male
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Calcitriol / metabolism

Substances

  • 25-hydroxyvitamin D3-bromoacetate
  • Antineoplastic Agents
  • Receptors, Calcitriol
  • Proto-Oncogene Proteins c-akt
  • Calcifediol