Growth inhibitory effects of 1alpha, 25-dihydroxyvitamin D(3) are mediated by increased levels of p21 in the prostatic carcinoma cell line ALVA-31.

1alpha, 25-Dihydroxyvitamin D(3) [1alpha, 25-(OH)(2)D(3)] is recognized to have significant antiproliferative effects on certain prostatic carcinoma (PC) cell lines, although the precise mechanisms of action remain in question. We have evaluated the role of the cell cycle-dependent kinase inhibitor p21. In the PC cell lines ALVA-31 and LNCaP, 1alpha, 25-(OH)(2)D(3) inhibits growth and induces both p21 mRNA and protein levels. Growth inhibition of ALVA-31 cells was abolished by stable transfection with a p21 antisense construct. This effect was not attributable to a reduction in functional vitamin D receptors as measured by transcriptional activity with a luciferase-vitamin D response element reporter construct. Therefore, increased p21 expression appears necessary to mediate the antiproliferative effects of this hormone in ALVA-31 cells. Cell lines that are insensitive to the growth inhibitory properties of 1alpha, 25-(OH)(2)D(3) failed to up-regulate p21 expression after hormone treatment; these include sublines of ALVA-31 as well as the cell lines TSU-Pr1 and JCA-1. In the latter two lines, adenovirus-mediated expression of a sense p21 cDNA significantly reduced their proliferation as compared with a control adenoviral construct. This suggests that the signaling pathway downstream of p21 is intact in TSU-Pr1 and JCA-1 cells, although p21 expression appears unregulated by 1alpha, 25-(OH)(2)D(3). We propose a model in which the antiproliferative effect of 1alpha, 25-(OH)(2)D(3) on PC cells is mediated through increased p21 expression. Elucidation of why this effect is absent in select cell lines may provide valuable insight into the variability of responses observed in PC patients treated with vitamin D.

1Alpha,25dihydroxyvitamin D3 and platinum drugs act synergistically to inhibit the growth of prostate cancer cell lines.

The majority of men who die from prostate cancer (PC) have hormone-refractory disease. To date, chemotherapeutic agents have had little or no impact on the survival of such patients. To explore a new approach for the treatment of hormone-refractory PC, we examined the combination effects of cis- or carboplatin with vitamin D. 1alpha,25-Dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its synthetic analogue, Ro 25-6760, have an antiproliferative effect on some prostate cancer cell lines. Consequently, the growth-inhibitory effects of the drugs were measured, both singularly and in combination with cis- or carboplatin, on PC cells. Our results show that although each of the drugs alone displayed antiproliferative activity, the growth inhibition of PC cells was further enhanced by the combination of 1alpha,25(OH)2D3 or Ro 25-6760 and either platinum agent. The greatest enhancement of inhibition occurred using smaller concentrations of the platinum compound in combination with higher concentrations of 1alpha,25(OH)2D3. Isobologram analysis revealed that 1alpha,25(OH)2D3 and platinum acted in a synergistic manner to inhibit the growth of PC cells. Our findings suggest that there is potential clinical value in combining 1alpha,25(OH)2D3 with platinum compounds for the treatment of advanced-stage human PC.