A 24-Phenylsulfone Analog of Vitamin D Inhibits 1α,25-Dihydroxyvitamin D3 Degradation in Vitamin D Metabolism-Competent Cells
2006
The antimitotic, prodifferentiating, and proapoptotic steroid hormone, 1α,25-dihydroxyvitamin D3 [1α,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 1α,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 1α,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 D3-1α-hydroxylase expression is not affected at all by S-4a. When both 1α,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 1α,25-(OH)2D3 and may therefore constitute a therapeutic to stimulate the antiproliferative potential of vitamin D-based antitumor activity.
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