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CELLULAR AND MOLECULAR

A 24-Phenylsulfone Analog of Vitamin D Inhibits 1,25-Dihydroxyvitamin D₃ Degradation in Vitamin D Metabolism-Competent Cells

Department of Pathophysiology, Medical University of Vienna, Austria (D.L., T.M., E.B., H.S.C.); and Department of Chemistry, Johns Hopkins University, Baltimore, Maryland (G.H.P.).

The antimitotic, prodifferentiating, and proapoptotic steroid hormone, 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃], 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 D₃-24-hydroxylase (CYP24) and, in addition, have the potential to induce CYP24 in response to 1,25-(OH)₂D₃. 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 1,25-(OH)₂D₃, KRC-24SO₂Ph-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 D₃-1-hydroxylase expression is not affected at all by S-4a. When both 1,25-(OH)₂D₃ 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 1,25-(OH)₂D₃ and may therefore constitute a therapeutic to stimulate the antiproliferative potential of vitamin D-based antitumor activity.

Address correspondence to: Heide S. Cross, Department of Pathophysiology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: heide.cross{at}meduniwien.ac.at

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