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PubMed2006

Immunomodulation by 1,25-dihydroxyvitamin D3: therapeutic implications in hemodialysis and renal transplantation.

The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, is a secosteroid hormone that regulates calcium and bone metabolism, controls cell proliferation and differentiation, and plays an important role as an immunomodulator. Recent advances in understanding the mechanisms underlying 1,25(OH)2D3 immune actions expand the range of the therapeutic implications of 1,25(OH)2D3 and its analogs. This review will cover the current knowledge on vitamin D-mediated immunotolerance and recent advances in vitamin D-based therapies for the treatment of autoimmune disease and the prevention of graft rejection in renal transplantation. Initiation of vitamin D-based therapies at earlier stages of chronic kidney disease may impact the immune status of patients who progress to require dialysis or transplantation.

Animals↗
PubMed2002

1,25-Dihydroxyvitamin D3 analogs as potential therapies in transplantation.

While immunosuppressive drugs now permit good control of acute allograft rejection, chronic rejection remains an important medical problem, and the induction of stable transplantation tolerance has not yet been achieved in patients. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), a secosteroid hormone that controls cell proliferation and differentiation and exerts immunoregulatory activities in addition to regulating calcium and bone metabolism, has the potential to contribute to the management of allograft rejection. Recent advances in understanding the immunomodulatory properties of 1,25(OH)2D3 and its analogs suggest the clinical application of these hormones in transplantation, with the aim of facilitating tolerance induction and preventing chronic graft rejection.

Acute Disease↗
PubMed1992

Combined differentiation therapy in myelodysplastic syndrome with retinoid acid, 1 alpha,25 dihydroxyvitamin D3, and prednisone.

The myelodysplastic syndrome (MDPS) provides an opportunity for identifying host factors (genetic, endocrine, immune) involved in initiation and progression of preleukemia into frank acute myeloid leukemia. The aim of this study was to identify bone marrow (BM) cellular and humoral dysfunctions central to the development of MDPS and useful in therapeutic follow-up studies. Our preclinical studies have shown that (1) the characteristic stromal cell composition of the normal BM microenvironment was impaired in MDPS and in AML in 67 and 86% of the cases, respectively; (2) the 1 alpha,25(OH)2D3 concentration in BM plasma was abnormal in 50% of MDPS and 30% of AML; and (3) an inverse correlation existed in MDPS between the 1 alpha,25(OH)2D3 concentration and the frequency of F-CFU, (r = 0.41, p < 0.02), suggestive of a regulatory interaction between this secosteroid hormone and BM stromal cells. The analysis of clonal extinction of BM blast cells in response to all trans retinoic acid (RA), 1 alpha,25(OH)2D3, and colony stimulating factors (PHA-LCM), either alone or in various combinations, revealed individual patterns of responses in the cases of MDPS or AML. The results indicate the necessity for preclinical studies to select patients for combined differentiation therapy. Our ongoing clinical trials suggest that RA (Roaccutan, 20 mg/day continuously) as induction therapy, followed at weeks 6 to 8 by prednisone (40 mg/day for 15 days) and 1 alpha,25(OH)2D3 (Rocaltrol, 3 x 0.25 micrograms/day for 3 months) may induce a long-lasting hematological remission in MDPS.

Bone Marrow↗
PubMedDate not supplied

The third multidisciplinary conference on drug research, Piła 2002. Effects of 1alpha,25-dihydroxyvitamin D3 and some putative steroid neuroprotective agents on the hydrogen peroxide-induced damage in neuroblastoma-glioma hybrid NG108-15 cells.

Steroids are implicated in the regulation of neurodegenerative processes including oxidative stress. The aim of this study was to compare the effects of 1alpha,25-dihydroxyvitamin D3 (calcitriol) and its low-calcemic analogue (24R)-1,24-dihydroxycholecalciferol (tacalcitol, PRI-2191) and some putative neuroprotective steroids belonging to various pharmacological groups on the hydrogen peroxide-induced cytotoxicity in NG108-15 cell line. Both secosteroids prevented in a concentration-dependent manner (50-500 nM) the hydrogen peroxide-induced lactate dehydrogenase release in the NG108-15 cells. Estrogens (17beta-estradiol and estriol, 100 and 1000 nM) also protected these cells. Of the two neurosteroids tested at micromolar concentrations, dehydroepiandrosterone sulphate markedly reduced cell damage, whereas the allopregnanolone showed a weak neuroprotective effect. These data support some previous observations on the antineurotoxic action of neurosteroids and indicate that calcitriol and its low-calcemic analogue PRI-2191 have neuroprotective properties comparable to those of estrogens. Considering the undesired effects of estrogens, it seems that some calcitriol analogues may be alternative drugs in the treatment of some oxidative stress-related neurodegenerative disorders.

Animals↗
PubMed1992

Protection from chemotherapy-induced alopecia by 1,25-dihydroxyvitamin D3.

We have previously reported that several biological agents, when given simultaneously with cytosine arabinoside or cytoxan, will protect from cytosine arabinoside-induced but not from cytoxan-induced alopecia. In the present study we used the secosteroid 1,25-dihydroxyvitamin D3 in a different timing schedule to protect from chemotherapy-induced alopecia. In three separate experiments, 0.2 microgram of topical, 1,25-dihydroxyvitamin D3 protected rats from alopecia induced by etoposide, cytoxan, and an Adriamycin-cytoxan combination. In another experiment, 0.1 microgram protected rats from etoposide-induced alopecia at the site of application. 1,25-Dihydroxyvitamin D3 may offer a new and exciting approach to the prevention of chemotherapy-induced alopecia.

Alkylating Agents↗
PubMed2005

Vitamin D in normal and pathological parathyroid glands: new prospects for treating hyperparathyroidism (review).

The secosteroid hormone active vitamin D [1,25(OH)2D3] is a key player in the regulation of calcium homeostasis and bone mineralization. In addition, it has antiproliferative and prodifferentiating effects on various cells in vitro and in vivo. The action of 1,25(OH)2D3 is mediated through the vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. VDR is expressed in the intestine, bone, kidney, parathyroid glands, and in many other tissues and cell types. In the parathyroid glands, 1,25(OH)2D3 markedly decreases parathyroid hormone gene transcription and parathyroid cell proliferation and induces parathyroid cell differentiation. Diminished VDR expression is frequent in parathyroid tumors and probably contributes to parathyroid tumorigenesis. The enzyme responsible for catalyzing synthesis of 1,25(OH)2D3 (1alpha-hydroxylase) has lately been demonstrated in the parathyroid glands. This indicates a new role for 1alpha-hydroxylase as an intracrine modulator of vitamin D function in non-renal tissues, which recently has been recognized as crucial in parathyroid tumor development. The growth-inhibitory properties of 1,25(OH)2D3 are prospects for treatment of hyperparathyroidism.

Animals↗
PubMed2003

[Regulation of vitamin D biosynthesis by calcium].

Vitamin D is a secosteroid that is made in the skin by the action of sunlight. Vitamin D is biologically insert and must undergo two successive hydroxylations in the liver and kidney to become the biologically active vitamin D [1alpha,25 (OH)(2)D]. Recently it was appreciated that 1alpha,25 (OH)(2)D not only regulates calcium but also is capable of inhibiting the proliferation and inducing terminal differentiation of variety of cells. The renal production of 1alpha,25 (OH)(2)D is tightly regulated by serum calcium levels through the action of parathyroid hormone.

English Abstract↗
PubMedDate not supplied

Vitamin D analogs and coactivators.

The secosteroid hormone 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has potent antiproliferative and prodifferentiating actions on a wide variety of normal as well as malignant cell types. Strong calcemic effects obstruct the actual application of 1,25-(OH)2D3 for the treatment of hyperproliferative disorders such as cancer. To overcome this problem, structural analogs of 1,25-(OH)2D3 have been designed with a clear dissociation between antiproliferative and calcemic effects. This review focuses on the molecular mode of action of different 1,25-(OH)2D3 analogs and, in particular, on the recruitment of cofactor molecules to the vitamin D receptor by these analogs.

Acetyltransferases↗
PubMedDate not supplied

Involvement of PI3-K in neuroprotective effects of the 1,25-dihydroxyvitamin D3 analogue - PRI-2191.

The active form of 1,25-dihydroxyvitamin D(3) prevents neuronal damage in vitro and in vivo , however, it induces also hypercalcemia and hyperphosphatemia. Side-chain-modified analogues of 1,25-dihydroxyvitamin D(3), which show low calcemic activity, may be potentially useful in the treatment of some neurodegenerative diseases. Previously, we have found that PRI-2191 more potently than 1,25-dihydroxyvitamin D(3) protects human neuroblastoma (SH-SY5Y) cells against hydrogen-peroxide-induced toxicity. In the present study, we evaluated effects of two other 1,25-dihydroxyvitamin D(3) analogues - PRI-1890 and PRI-1901 on the neuronal degeneration in the same cell model. In line with the previous study, 24-h incubation with hydrogen peroxide (0.5 mM) was toxic to cells, as evidenced by an enhanced efflux of lactate dehydrogenase into the culture medium, and these effects were prevented by PRI-1890 and PRI-1901 at concentration of 5, 50 and 500 nM. Comparing the neuroprotective effects of secosteroids, we found that all three analogues were efficient at lower concentration than 1,25-dihydroxyvitamin D(3) and among them the PRI-2191 showed the most evident concentration-dependent effect. In the second part of this study, an involvement of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K), kinases which play a crucial role in neurodegenerative processes, in neuroprotective action of 1,25 dihydroxyvitamin D(3) and its the most potent analogue PRI-2191 has been investigated. The inhibitor of c-Jun N-terminal kinase (JNK)-MAPK (SP600125, 1 microM), inhibitor of p38-MAPK (SB-203580, 1 and 10 microM) and inhibitor of extracellular signal-regulated kinase (ERK)-MAPK (PD-98059, 15 and 30 microM) attenuated the hydrogen peroxide-induced toxicity. Moreover, PD-98059 (30 microM) enhanced neuroprotective effects of 1,25 dihydroxyvitamin D(3) but not that of PRI-2191. In contrast, the inhibitor of PI3-K (wortmannin, 10, 100 nM) did not affect hydrogen peroxide-induced cell damage itself, however, it significantly antagonized the effect of PRI-2191. On the other hand, wortmannin did not affect the neuroprotective effects of 1,25 dihydroxyvitamin D(3) This suggests that the activation of PI3-K/Akt signaling pathway plays an important role in the mechanism of inhibitory action of PRI-2191 on hydrogen peroxide-evoked toxicity in SH-SY5Y cells. Furthermore, these data point to differential involvement of ERK-MAPK and PI3-K in neuroprotective effects of 1,25 dihydroxyvitamin D(3) and its low-calcemic analogue - PRI-2191.

Androstadienes↗
PubMed1980

In vitro regulation of kidney 25-hydroxyvitamin D3-hydroxylase enzyme activities by vitamin D3 metabolites. Molecular specificity and mechanism of action.

An acute chick kidney tubule model was used to evaluate the molecular specificity of steroids which act to inhibit kidney 25-hydroxyvitamin D3-1-hydroxylase and induce 25-hydroxyvitamin D3-24-hydroxylase enzyme activities. Such hydroxylase-regulatory activity was confined to the vitamin D family of secosteroids. Vitamin D3 per se was not active. Rather, expression of hydroxylase-regulatory activity required acquisition of a C-25 hydroxyl grouping. Of the metabolites tested, 25-hydroxyvitamin D3 demonstrated the greatest hydroxylase-regulatory activity. Metabolites of 25-hydroxyvitamin D3 which contained hydroxyl groups at carbon atoms 1, or 24, or both, were also active in regulating the kidney hydroxylase enzymes. The hydroxylase-regulatory action of 1,25-dihydroxyvitamin D3 was blocked by inhibitors of RNA or protein synthesis, implicating a requirement for de novo protein synthesis. It was suggested that the regulatory process involves both hydroxylase-enzyme synthesis and turnover as well as enzyme-level modulation of endogenous enzyme activities.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1984

Induction of a high phagocytic capability in P388D1, a macrophage-like tumor cell line, by 1 alpha, 25-dihydroxyvitamin D3.

1 alpha, 25-Dihydroxyvitamin D3 [1,25-(OH)2D3] was shown to induce a high phagocytic capability in the macrophage-like murine tumor cell line P388D1. Induction of phagocytic capability by 1,25-(OH)2D3 was dose-dependent in the range of 0.2 to 5.0 ng/ml, required the continuous presence of the secosteroid in culture, and was reversible. 25-Hydroxyvitamin D3 was an effective inducer only at about 500 ng/ml, while 24R,25-dihydroxyvitamin D3 was ineffective. The induction of the high phagocytic capability was neither accompanied by increased synthesis of lysozyme nor closely associated with an inhibitory effect on cellular proliferation. P388D1 cells bound (without ingestion) nonopsonized sheep erythrocytes (sheep RBC), and the binding increased in 1,25-(OH)2D3-treated cells. Fc-receptor-mediated binding of immunoglobulin G-coated sheep RBC was not modulated in 1,25-(OH)2D3-treated cells, but the cells acquired an Fc-receptor-mediated phagocytic capability that was expressed only when preformed P388D1-sheep RBC rosettes were further exposed to immunoglobulin G. Several differentiation agents of myeloid leukemia cells (including dexamethasone) were not effective in inducing the high-phagocytic phenotype, while retinoic acid was very effective. Different myeloid or macrophage-like tumors (WEHI-265, J774.2, PU-5, and WEHI-3) were variable in their response to 1,25-(OH)2D3.

Animals↗
PubMed1993

Demonstration that 1 beta,25-dihydroxyvitamin D3 is an antagonist of the nongenomic but not genomic biological responses and biological profile of the three A-ring diastereomers of 1 alpha,25-dihydroxyvitamin D3.

The steroid hormone 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3) generates biological responses via both genomic and nongenomic mechanisms. This article reports the biological profile of four A-ring diastereomers of this secosteroid (results are expressed as percentage of the response of 1 alpha,25-(OH)2D3. The activity of the compounds, 1 alpha,25-(OH)2D3, 1 alpha,25-(OH)2-3-epivitamin D3, 1 beta,25-(OH)2D3, 1 beta,25-(OH)2-3-epivitamin D3, for in vivo intestinal Ca2+ absorption and bone Ca2+ mobilization and in vitro binding to the nuclear receptor (genomic responses) was, respectively, 100, 2.8, < 0.1, and < 0.1% (intestinal Ca2+ absorption); 100, 1.5, < 0.1, and < 0.1% (bone Ca2+ mobilization); 100, 24, 0.2, and 0.8% (receptor binding). In the in vivo nongenomic transcaltachia assay the results were 100, 80, 0, and 20-30%, and in ROS 17/2.8 cells (45Ca2+ uptake through voltage-gated Ca2+ channels) 1 alpha,25-(OH)2D3 had 100% activity and 1 beta,25-(OH)2D3 (the only diastereomer evaluated) had no agonist activity. Keratinocyte proliferation was inhibited in the order 1 alpha,25-(OH)2D3 > 1 alpha,25-(OH)2-3-epivitamin D3 > 1 beta,25-(OH)2D3 > 1 beta,25-(OH)2-3-epivitamin D3. 1 beta,25-(OH)2D3 was a potent antagonist of 1 alpha,25-(OH)2D3-mediated transcaltachia and 45Ca2+ uptake in ROS 17/2.8 cells but was unable to block the genomic 1 alpha,25-(OH)2D3 induction of chick calbindin-D28k (in vivo), induction of MG-63 cell osteocalcin, and HL-60 cell differentiation. These results suggest that analogs of 1 alpha,25-(OH)2D3 may be synthesized which are selective agonists or antagonists of genomic or nongenomic responses in the vitamin D endocrine system.

Animals↗
PubMedDate not supplied

1 alpha, 25-dihydroxyvitamin D3 and all-trans-retinoic acid inhibit the growth of a lung cancer cell line.

The secosteroid 1 alpha, 25-dihydroxyvitamin D3 (calcitriol) and retinoic acid are the major biologically active metabolites of vitamins D and A, respectively. Their antitumor activity has been observed in several cancer cells in vitro apart from lung cancer cells. The purpose of this study was to examine the possible effects of the agents on lung cancer cell lines. The responses of five lung cancer cell lines to calcitriol or all-transretinoic acid (RA) were assessed by a colorimetric MTT assay. Calcitriol inhibited growth in one of the tested cell lines, i.e. EBC-1 squamous cell carcinoma, dose dependently. RA also exhibited the same effect in EBC-1 cells. However neither agent affected the growth of other lung cancer cell lines. Subsequently we examined the mRNA expression of vitamin D receptor (VDR) and retinoic acid receptor (RAR alpha) in these lung cancer cells by quantitative RT-PCR. EBC-1 cells expressed high levels of mRNA for both VDR and RAR alpha, while other cell lines expressed much lower mRNA levels for the receptors. These data suggest that the growth inhibitory effects of the vitamins are associated with mRNA expression for VDR and RAR alpha.

Actins↗
PubMed1997

Three synthetic vitamin D analogues induce prostate-specific acid phosphatase and prostate-specific antigen while inhibiting the growth of human prostate cancer cells in a vitamin D receptor-dependent fashion.

Numerous studies have indicated that the secosteroid hormone 1alpha, 25-dihydroxyvitamin D3 protects against the development of clinical prostate cancer (PC). Whether this hormone also has therapeutic potential for patients with advanced PC has not yet been evaluated. Several synthetic vitamin D analogues are now available that have reduced hypercalcemic effects and yet effectively induce differentiation in some cell types. For these reasons, these analogues may be safer and more effective for cancer therapy than the natural hormone. In the current study, 13 such analogues were screened for their abilities to inhibit the growth of PC cell lines. Three of the most consistently effective analogues (Ro 23-7553, Ro 24-5531, and Ro 25-6760) were then chosen for further analysis. Growth studies using clones of the JCA-1 cell line that were transfected with the vitamin D receptor cDNA indicate that the antiproliferative effects of these analogues require vitamin D receptor expression. Furthermore, these three analogues induce the secretion of prostate-specific acid phosphatase and prostate-specific antigen (two markers of the differentiated prostatic phenotype) in the cell line LNCaP. These in vitro studies suggest that Ro 23-7553, Ro 24-5531, and Ro 25-6760 should be further evaluated as therapeutic agents for the treatment of PC.

Acid Phosphatase↗
PubMed1977

The mass spectral fragmentation of 9alpha-hydroxy steroids and related compounds.

The fragmentation processes occurring in various 9alpha-hydroxy steroids upon electron ionization have been studied. The mechanisms proposed for the formation of the prominent ions in these spectra have been confirmed with the aid of deuterium labelling, measurements on metastable ion decompositions, low eV spectra and high resolution mass measurements. The fragmentation of the corresponding 9-oxo-9,10-seco steroids, which shows analogy to that of the 9alpha-hydroxy compounds in many respects, has also been discussed.

Hydroxysteroids↗