Prostate cancer cells contain specific
receptors [vitamin D receptors (VDRs)] for 1alpha,25-dihydroxyvitamin D3 (1alpha,25(
OH)2D3), which is known to inhibit the proliferation and invasiveness of these cells. These findings support the use of 1alpha,25(
OH)2D3 for
prostate cancer therapy. However, because 1alpha,25(
OH)2D3 can cause
hypercalcemia, analogues of 1alpha,25(
OH)2D3 that are less calcemic but that exhibit potent antiproliferative activity would be attractive as therapeutic agents. We investigated the effects of two different types of less calcemic
vitamin D compounds,
25-hydroxyvitamin D3 [25(
OH)D3] and
19-nor-1alpha,25-dihydroxyvitamin D2 [19-nor-1,25(
OH)2D2], and compared their activity to 1alpha,25(
OH)2D3 on (a) the proliferation of primary cultures and cell lines of human
prostate cancer cells; and (b) the transactivation of the VDRs in the
androgen-insensitive PC-3
cancer cell line stably transfected with VDR (PC-3/ VDR). 19-nor-1alpha,25(OH)2D2, an analogue of 1alpha,25(
OH)2D3 that was originally developed for the treatment of
parathyroid disease, has been shown to be less calcemic than 1alpha,25(
OH)2D3 in clinical trials. Additionally, we recently showed that human prostate cells in primary culture possess 25(OH)D3-1alpha-hydroxylase, an
enzyme that hydroxylates the inactive prohormone, 25(
OH)D3, to the active
hormone, 1alpha,25(
OH)2D3, intracellularly. We reasoned that the
hormone that is formed intracellularly would inhibit prostate cell proliferation in an autocrine fashion. We found that 1alpha,25(
OH)2D3 and 19-nor-1alpha,25(OH)2D2 caused similar dose-dependent inhibition in the cell lines and primary cultures in the [3H]
thymidine incorporation assay and that both compounds were significantly more active in the primary cultures than in LNCaP cells. Likewise, 25(
OH)D3 had inhibitory effects comparable to those of 1alpha,25(
OH)2D3 in the primary cultures. In the
chloramphenicol acetyltransferase (CAT) reporter gene transactivation assay in PC-3/ VDR cells, 1alpha,25(
OH)2D3 and 19-nor-1alpha,25(OH)2D2 caused similar increases in CAT activity between 10(-11)and 10(-9) M. Incubation of PC-3/VDR cells with 5 x 10(-8) M 25(
OH)D3 induced a 29-fold increase in CAT activity, similar to that induced by 10(-8) M 1alpha,25(
OH)2D3. In conclusion, our data indicate that 25(
OH)D3 and 19-nor-1alpha,25(OH)2D2 represent two different solutions to the problem of
hypercalcemia associated with
vitamin D-based
therapies: 25(
OH)D3 requires the presence of 1alpha-hydroxylase, whereas 19-nor-1alpha,25(OH)2D2 does not. Both drugs are approved for human use and may be good candidates for human clinical trials in
prostate cancer.