seocalcitol and Vitamin-D-Deficiency

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

Conditions of disuse in bed rest patients, as well as microgravity experienced by astronauts are accompanied by reduced mechanical loading, reduced calcium absorption, and lower serum levels of 1,25(OH)2D3 (1,25-D), the active metabolite of vitamin D, all contributing to bone loss. To determine whether 1,25-D or a less calcemic analog, Seocalcitol or EB1089 (1 alpha,25-dihydroxy-22,24-diene-24,26,27-trihomovitamin D3) can alleviate bone loss in a rat hindlimb unloading model of disuse osteopenia, mature male rats originally on a vitamin D replete diet containing 1.01% calcium were transferred to a vitamin D-deficient diet containing 0.48% calcium and then tail suspended and treated for 28 days with vehicle, 0.05 microg/kg 1,25-D, or 0.05 microg/kg EB1089. The vitamin D-deficient diet caused a substantial decrease in bone mineral density (-8%), which may be compounded by hindlimb unloading (-10%). Exogenous 1,25-D not only prevented the bone loss but also increased the bone mineral density to greater than the baseline level (+7%). EB1089 was less effective in preventing bone loss. Analysis of site and cell-specific effects of 1,25-D and EB1089 revealed that 1,25-D was more active than EB1089 in the intestine, the site of calcium absorption, and in inducing osteoclastogenesis and bone resorption whereas EB1089 was more effective in inducing osteoblast differentiation. These studies suggest that elevating circulating 1,25-D levels presumably increasing calcium absorption can counteract bone loss induced by disuse or microgravity with its associated reductions in circulating 1,25-D and decreased calcium absorption.

Topics: Animals; Bone and Bones; Bone Density; Bone Resorption; Calcitriol; Calcium, Dietary; Cell Differentiation; Diet; Hindlimb Suspension; Intestinal Mucosa; Male; Osteoblasts; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Tomography, X-Ray Computed; Vitamin D Deficiency