A 24-phenylsulfone analog of vitamin D inhibits 1alpha,25-dihydroxyvitamin D(3) degradation in vitamin D metabolism-competent cells.
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.
Lechner
Daniel
D
Department of Pathophysiology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Manhardt
Teresa
T
Bajna
Erika
E
Posner
Gary H
GH
Cross
Heide S
HS
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis*; D015153:Blotting, Western; D002117:Calcitriol / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000096:biosynthesis*; D013450:Sulfones / Q000494:pharmacology*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase
D012333:RNA, Messenger; D013450:Sulfones; D019938:Cyclin D1; D014807:Vitamin D; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol