seocalcitol and Ovarian-Neoplasms

Ovarian cancer is the leading cause of death among gynecological malignancies in the US and the poor outcome of current treatments necessitates the development of novel therapeutic strategies to fight against it. Epidemiological data indicate a positive association between higher latitude and ovarian cancer incidence and mortality rates, suggesting that vitamin D insufficiency may contribute to ovarian cancer development. Recent studies in the authors' laboratory showed that multiple ovarian cancer cell lines respond to the active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3), for growth suppression. Mechanistic studies identified vitamin D-regulated genes with established functions in ovarian tumorigenesis as mediators for the growth suppression. While increased p27 protein stability and transcriptional up-regulation of GADD45 are responsible for 1alpha,25-dihydroxyvitamin D(3)-induced cell cycle arrest at G1/S and G2/M checkpoints, respectively, the hormone-induced apoptosis in ovarian cancer cells involves the down regulation of the mRNA stability of telomerase catalytic subunit. More importantly, preclinical studies showed that the synthetic vitamin D analog EB1089 effectively suppressed the growth of human ovarian tumor xenografts in mice. The tumor suppression is associated with an increase in apoptotic rate and a decrease in cell proliferation, suggesting that the molecular information can be translated into ovarian tumor suppression in animals. Based on these studies, we conclude that the vitamin D receptor that mediates these anti-tumor effects represents a novel molecular target for the development of new drugs for ovarian cancer. We predict that receptor-based drug discovery will lead to the successful development of more potent and safer vitamin D analogs for the treatment of this deadly disease.

Topics: Animals; Antineoplastic Agents; Calcitriol; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Receptors, Calcitriol; Transcription Factors; Vitamin D; Vitamin D Deficiency

The poor response of advanced epithelial ovarian cancer to current treatments necessitates the development of alternative therapeutic strategies. Inhibition of cancer growth by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] compounds represents an innovative approach for cancer therapy. The current study evaluated the therapeutic potential of a synthetic 1,25(OH)2D3 analogue EB1089 in the treatment of ovarian cancer.. The response of human ovarian cancer cells to 1,25(OH)2D3 and EB1089 were first compared in cell growth, gene transcription, and apoptotic assays. Then, nude mice bearing OVCAR3 tumor xenografts were treated with EB1089 at different dosages, and tumor volumes were monitored. The effect of EB1089 and 1,25(OH)2D3 on the level of serum calcium was also examined. After the treatment, tumors were excised and processed for histologic examination, Ki-67 staining, and tissue terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays to evaluate the morphologic, proliferative, and apoptotic changes induced by EB1089, respectively.. The study shows that EB1089 suppresses the in vitro growth of ovarian cancer cells and transcriptionally activates the GADD45 reporter gene more effectively than 1,25(OH)2D3. Clinically more importantly, EB1089 suppresses the growth of OVCAR3 tumor xenografts in nude mice without inducing hypercalcemia. Ki-67 staining and tissue TUNEL assays showed that both inhibition of cell proliferation and induction of apoptosis contribute to the EB1089-induced tumor suppression in vivo.. This study is the first demonstration that ovarian cancer responds positively in vivo to treatment with a 1,25(OH)2D3 compound and thus supports continued development of 1,25(OH)2D3 analogues for possible use as an alternative or complementary therapy for human ovarian cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Calcitriol; Calcium; Cell Line, Tumor; Cell Proliferation; Female; GADD45 Proteins; Genes, Reporter; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Intracellular Signaling Peptides and Proteins; Ki-67 Antigen; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Time Factors; Transcriptional Activation

Vitamin D and its analogues are potent regulators of cell growth and differentiation both in vivo and in vitro. We studied the effects of 25-hydroxyvitamin D(3) [25(OH)D(3)], 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and vitamin D analogue, EB 1089, on the growth of a human ovarian cancer cell line, OVCAR-3. We also studied the expression of vitamin D metabolising enzymes 24-hydroxylase (24OHase) and 1alpha-hydroxylase (1alphaOHase). Our results showed that high concentrations (10 and 100 nM) of 1,25(OH)(2)D(3) inhibited a cell proliferation, whereas low concentration (0.1 nM) stimulated growth of the OVCAR-3 cells. In the concentration range of 10-500 nM a prohormone, 25(OH)D(3), stimulated growth. An amount of 1 nM EB 1089 and 100 nM 1,25(OH)(2)D(3) inhibited growth with an equal magnitude. The expression of 24OHase was strongly induced by 1,25(OH)(2)D(3) and EB 1089 in OVCAR-3 cells, and analysis of vitamin D metabolites showed the functionality of 24OHase. An inhibition of 24OHase activity with a novel 24OHase inhibitor enhanced growth-inhibiting effects of 1,25(OH)(2)D(3) and suppressed the growth stimulation of 100 nM 25(OH)D(3). We also report the expression of a vitamin D activating enzyme, 1alphaOHase, in 7 ovarian cancer cell lines. The production of 1,25(OH)(2)D(3) in OVCAR-3 cells was low, possibly due to an extensive activity of 24OHase or a low 1alphaOHase activity. These results suggest that in ovarian cancer cells vitamin D metabolizing enzymes might play a key role in modulating the growth response to vitamin D. The possible mitogenic effects of vitamin D should be considered when evaluating treatment of ovarian cancer with vitamin D.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Calcifediol; Calcitriol; Cell Division; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Female; Humans; Ovarian Neoplasms; Steroid Hydroxylases; Tumor Cells, Cultured; Vitamin D3 24-Hydroxylase