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25-Hydroxyvitamin D₃, the Prohormone of 1,25-Dihydroxyvitamin D₃, Inhibits the Proliferation of Primary Prostatic Epithelial Cells

Departments of Cancer Biology [A. M. B., G. G. S., S. D. C.], Urology [S. D. C.] and Pathology [R. W.], Wake Forest University School of Medicine, Winston-Salem, North Carolina 27105

The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] is known to inhibit the proliferation of prostatic epithelial cells. This has stimulated interest in vitamin D compounds as therapeutic agents for prostate cancer. However, the therapeutic use of 1,25(OH)₂D₃ is limited because elevations in serum 1,25(OH)₂D₃ can cause dangerous elevations in serum calcium levels. We wondered whether the prohormone of 1,25(OH)₂D₃, 25-hydroxyvitamin D₃ (25-OH-D₃), which is much less calcemic, could also achieve antiproliferative effects in prostatic cells. 25-OH-D₃ is converted to 1,25(OH)₂D₃ by the mitochondrial enzyme 1--hydroxylase. We have recently shown that human prostatic cells also possess significant 1--hydroxylase activity (Schwartz et al., Cancer Epidemiol. Biomark. Prev., 7: 391–395, 1998). We studied 1--hydroxylase gene expression in four strains of primary human prostatic epithelial cells by reverse transcription PCR amplification (RT-PCR) of 1--hydroxylase. Human prostatic stromal cells were negative for 1--hydroxylase by RT-PCR. This led us to hypothesize that 25-OH-D₃ would inhibit the proliferation of prostatic epithelial cells because 25-OH-D₃ would be converted to 1,25(OH)₂D₃ intracellularly. We studied the effects of 25-OH-D₃ and 1,25(OH)₂D₃ on the proliferation of prostatic epithelial cells using high density growth and clonal growth assays on two different primary cell strains derived from normal human prostatic peripheral zone. 25-OH-D₃ and 1,25(OH)₂D₃ each inhibited growth in a dose- and time-dependent manner. Growth inhibition was evident at 1 nM, and maximal inhibition was observed at 100 nM within 10–12 days of exposure. The potencies of 25-OH-D₃ and 1,25(OH)₂D₃ were not significantly different. These data demonstrate that 25-OH-D₃, which previously was thought to have little biological activity, can become a potent antiproliferative hormone for prostatic cells that express 1--hydroxylase. Because 25-OH-D₃ exhibits similar potency to 1,25(OH)₂D₃ but is less calcemic, 25-OH-D₃ may offer a safer option than 1,25(OH)₂D₃ for prostate cancer therapy. Moreover, because 25-OH-D₃ is produced endogenously from vitamin D, these findings support a potential role for vitamin D in the chemoprevention of prostate cancer.

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