A 24-phenylsulfone analog of vitamin D inhibits 1alpha,25-dihydroxyvitamin D(3) degradation in vitamin D metabolism-competent cells

J Pharmacol Exp Ther. 2007 Mar;320(3):1119-26. doi: 10.1124/jpet.106.115451. Epub 2006 Dec 20.

Abstract

The antimitotic, prodifferentiating, and proapoptotic steroid hormone, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25-(OH)(2)D(3)], at supraphysiological levels has potential for tumor therapy. However, epithelial cells from tumor-prone organs such as colon, prostate, and breast express not only the vitamin D receptor, but also vitamin D hydroxylases. In contrast to normal cells, malignant cells have high basal levels of the hydroxylase 25-hydroxyvitamin D(3)-24-hydroxylase (CYP24) and, in addition, have the potential to induce CYP24 in response to 1alpha,25-(OH)(2)D(3). Because 24-hydroxylation by CYP24 would rapidly degrade the steroid hormone in the course of therapy, the enzyme activity in tumor cells should be inhibited. We demonstrate that a 24-phenylsulfone analog of 1alpha,25-(OH)(2)D(3), KRC-24SO(2)Ph-1 (S-4a), rapidly and potently inhibits 24-hydroxylase activity in human tumor cells derived from colon, prostate, and mammary gland. Although enzymatic inhibition is a consequence of direct interaction, S-4a as a vitamin D analog apparently binds to the vitamin D receptor and induces CYP24 mRNA, which, however, is not translated into increased enzymatic activity. 25-Hydroxyvitamin D(3)-1alpha-hydroxylase expression is not affected at all by S-4a. When both 1alpha,25-(OH)(2)D(3) and S-4a are added to the cell culture, transcription of CYP24 is increased, possibly because of an increase in the half-life of the hormone. The colon cell line COGA-13 has very high levels of CYP24 and is, therefore, resistant to the action of vitamin D. Yet, S-4a imparts antimitotic activity to 1alpha,25-(OH)(2)D(3) and may therefore constitute a therapeutic to stimulate the antiproliferative potential of vitamin D-based antitumor activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / biosynthesis*
  • Blotting, Western
  • Calcitriol / antagonists & inhibitors*
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Cyclin D1 / metabolism
  • Humans
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Steroid Hydroxylases / biosynthesis*
  • Sulfones / pharmacology*
  • Vitamin D* / analogs & derivatives
  • Vitamin D* / metabolism
  • Vitamin D* / pharmacology
  • Vitamin D3 24-Hydroxylase

Substances

  • RNA, Messenger
  • Sulfones
  • Cyclin D1
  • Vitamin D
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
  • Calcitriol