1α,25‐Dihydroxy vitamin D3, the active form of vitamin D3, protects against allergeninduced airway constriction

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor, with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evidence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infiltrative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the expression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show, using in vitro limiting dilution assays, quantitative real-time PCR, quantitative proteomics and ex vivo adult organotypic brain slice transplantation cultures, that therapeutic doses of calcitriol, the hormonally active form of vitamin D3, reduce stemness to varying extents in a panel of investigated GSC lines, and that it effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to completely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in follow-up studies.

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1,25-Dihydroxycholecalciferol: Identification of the Proposed Active Form of Vitamin D3 in the Intestine

Science ◽

10.1126/science.173.3991.51 ◽

1971 ◽

Vol 173 (3991) ◽

pp. 51-54 ◽

Cited By ~ 156

Author(s):

A. W. Norman ◽

J. F. Myrtle ◽

R. J. Miogett ◽

H. G. Nowicki ◽

V. Williams ◽

...

Keyword(s):

Vitamin D3 ◽

Active Form

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Oral Administration of an Active Form of Vitamin D3(Calcitriol) Decreases Atherosclerosis in Mice by Inducing Regulatory T Cells and Immature Dendritic Cells With Tolerogenic Functions

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.110.215459 ◽

2010 ◽

Vol 30 (12) ◽

pp. 2495-2503 ◽

Cited By ~ 120

Author(s):

Masafumi Takeda ◽

Tomoya Yamashita ◽

Naoto Sasaki ◽

Kenji Nakajima ◽

Tomoyuki Kita ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Oral Administration ◽

Vitamin D3 ◽

Active Form ◽

Immature Dendritic Cells

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1,25-Dihydroxycholecalciferol—A Hormonally Active Form of Vitamin D3

Proceedings of the 1973 Laurentian Hormone Conference ◽

10.1016/b978-0-12-571130-2.50015-8 ◽

1974 ◽

pp. 431-480 ◽

Cited By ~ 2

Author(s):

W. NORMAN ANTHONY ◽

HENRY HELEN

Keyword(s):

Vitamin D3 ◽

Active Form

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Key Vitamin D Target Genes with Functions in the Immune System

Nutrients ◽

10.3390/nu12041140 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1140 ◽

Cited By ~ 6

Author(s):

Oona Koivisto ◽

Andrea Hanel ◽

Carsten Carlberg

Keyword(s):

Vitamin D ◽

Adaptive Immunity ◽

Vitamin D3 ◽

Target Genes ◽

Mononuclear Cells ◽

Active Form ◽

Biologically Active ◽

Monocytic Cell ◽

Monocytic Cell Line ◽

Innate And Adaptive Immunity

The biologically active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), modulates innate and adaptive immunity via genes regulated by the transcription factor vitamin D receptor (VDR). In order to identify the key vitamin D target genes involved in these processes, transcriptome-wide datasets were compared, which were obtained from a human monocytic cell line (THP-1) and peripheral blood mononuclear cells (PBMCs) treated in vitro by 1,25(OH)2D3, filtered using different approaches, as well as from PBMCs of individuals supplemented with a vitamin D3 bolus. The led to the genes ACVRL1, CAMP, CD14, CD93, CEBPB, FN1, MAPK13, NINJ1, LILRB4, LRRC25, SEMA6B, SRGN, THBD, THEMIS2 and TREM1. Public epigenome- and transcriptome-wide data from THP-1 cells were used to characterize these genes based on the level of their VDR-driven enhancers as well as the level of the dynamics of their mRNA production. Both types of datasets allowed the categorization of the vitamin D target genes into three groups according to their role in (i) acute response to infection, (ii) infection in general and (iii) autoimmunity. In conclusion, 15 genes were identified as major mediators of the action of vitamin D in innate and adaptive immunity and their individual functions are explained based on different gene regulatory scenarios.

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Novel vitamin D analogs that modulate leukemic cell growth and differentiation with little effect on either intestinal calcium absorption or bone mobilization

Blood ◽

10.1182/blood.v74.1.82.82 ◽

1989 ◽

Vol 74 (1) ◽

pp. 82-93 ◽

Cited By ~ 103

Author(s):

JY Zhou ◽

AW Norman ◽

M Lubbert ◽

ED Collins ◽

MR Uskokovic ◽

...

Keyword(s):

Vitamin D ◽

Mechanism Of Action ◽

Vitamin D3 ◽

Clonal Growth ◽

Calcium Absorption ◽

Active Form ◽

Intestinal Calcium Absorption ◽

Leukemic Cells ◽

Binding Studies ◽

Vitamin D Analogs

Abstract Induction of terminal differentiation of leukemic and preleukemic cells is a therapeutic approach to leukemia and preleukemia. The 1 alpha, 25- dihydroxyvitamin D3 [1,25(OH)2D3], the hormonally active form of vitamin D3, can induce differentiation and inhibit proliferation of leukemia cells, but concentrations required to achieve these effects cause life-threatening hypercalcemia. Seven new analogs of 1,25(OH)2D3 were discovered to be either equivalent or more potent than 1,25(OH)2D3 as assessed by: (a) inhibition of clonal proliferation of HL-60, EM-2, U937, and patients' myeloid leukemic cells: and (b) induction of differentiation of HL-60 promyelocytes. Furthermore, these analogs stimulated clonal growth of normal human myeloid stem cells. The most potent analog, 1,25-dihydroxy-16ene-23yne-vitamin D3, was about fourfold more potent than 1,25(OH)2D3. This analog decreased clonal growth and expression of c-myc oncogene in HL-60 cells by 50% within ten hours of exposure. Effects on calcium metabolism of these novel analogs in vivo was assessed by intestinal calcium absorption (ICA) and bone calcium mobilization (BCM). Each of the analogs mediated markedly less (10 to 200-fold) ICA and BCM as compared with 1,25(OH)2D3. To gain insight into the possible mechanism of action of these new analogs, receptor binding studies were done with 1,25(OH)2–16ene-23yne-D3 and showed that it competed only about 60% as effectively as 1,25(OH)2D3 for 1,25(OH)2D3 receptors present in HL-60 cells and 98% as effective as 1,25(OH)2D3 for receptors present in chick intestinal cells. In summary, we have discovered seven novel vitamin D analogs that are more potent than the physiologic 1,25(OH)2D3 as measured by a variety of hematopoietic assays. In contrast, these compounds appear to have the potential to be markedly less toxic (induction of hypercalcemia). These novel vitamin D compounds may be superior to 1,25(OH)2D3 in a number of clinical situations including leukemia/preleukemia; they will provide a tool to dissect the mechanism of action of vitamin D seco-steroids in promoting cellular differentiation.

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