Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the biological activity of two sets of ring A stereoisomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) (2-methyl-1alpha,25(OH)(2)D(3)) and 2-methyl-20-epi-1alpha, 25-dihydroxyvitamin D(3) (2-methyl-20-epi-1alpha,25(OH)(2)D(3)) in terms of the following: transactivation of a rat 25-hydroxyvitamin D(3)-24-hydroxylase gene promoter including two vitamin D response elements (VDREs) and a human osteocalcin gene promoter including a VDRE in transfected human osteosarcoma (MG-63) cells; a vitamin D receptor (VDR)-mediated response using a VDR-GAL4 one-hybrid luciferase reporter system and a retinoid X receptor alpha (RXRalpha)-mediated response using an expressed VDR/RXRalpha-GAL4 modified two-hybrid luciferase reporter system in transfected human epitheloid carcinoma, cervix (HeLa) cells; and modulation of cell surface CD11b antigen expression in human leukemia (HL-60) cells. All the diastereomers of both analogues exhibited unique biological activity profiles depending upon the configurations of the C-1 and C-3 hydroxyl groups, the C-2 methyl group in ring A, and the C-20 methyl group in the side chain. Of the eight possible diastereomers of the 2-methyl analogues, 2alpha-methyl-1alpha,25(OH)(2)D(3) was the most potent and exhibited comparable or even greater biological potency than 1alpha,25(OH)(2)D(3). Of the eight possible diastereomers of the 2-methyl-20-epi analogues, 2alpha-methyl-20-epi-1alpha,25(OH)(2)D(3) was the most potent and exhibited 100- to 200-fold higher transcriptional potencies than 1alpha,25(OH)(2)D(3) and exceptionally high cell regulatory activities. 2beta-methyl-20-epi-1alpha,25(OH)(2)D(3) was nearly as potent as its 2-epimer, 2alpha-methyl-20-epi-1alpha,25(OH)(2)D(3), whereas its 20-epimer, 2beta-methyl-1alpha,25(OH)(2)D(3), was almost completely biologically inactive. In these respects, it can be postulated that the double modification of 2-methyl substitution and 20-epimerization to 1alpha,25(OH)(2)D(3) induces remarkable changes in a VDR/RXRalpha/VDRE-mediated signaling response and greatly enhances biological activity. The other striking finding was that 2beta-methyl-20-epi-3-epi-1beta,25(OH)(2)D(3) is transcriptionally more active than 1alpha,25(OH)(2)D(3) despite lacking the 1alpha-hydroxyl group, which was believed to be essential for expressing VDR-mediated gene transcription. Since the C-20 natural counterpart, 2beta-methyl-3-epi-1beta,25(OH)(2)D(3), was almost completely biologically inactive, 20-epimerization is probably responsible for activation of gene expression. Although earlier extensive structure-activity studies of vitamin D analogues showed stereochemistry at the C-1, C-3, and C-20 of 1alpha,25(OH)(2)D(3) to be the key structural motif for vitamin D action, our results clearly demonstrated that stereochemistry at the C-2 is also an important structural motif for vitamin D action and imply that 2-methyl substitution possibly induces conformational changes in ring A depending upon the combinations of configurations of the C-1 and C-3 hydroxyl groups with C-20 stereochemistry. Consequently, several of these analogues exhibit exceptionally high or unexpected biological activities at the molecular and cellular levels. These results suggest that 2-methyl substitution together with alterations of stereochemistry in both ring A and the side chain of 1alpha, 25(OH)(2)D(3) will provide useful analogues for structure-activity studies and development of therapeutic agents with unique biological activity profiles.
 ...
PMID:Novel ring A stereoisomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) and 2-methyl-20-epi-1alpha,25-dihydroxyvitamin D(3): transactivation of target genes and modulation of differentiation in human promyelocytic leukemia (HL-60) cells. 1067 86

Calcitriol (1,25-dihydroxyvitamin D3) induces differentiation and inhibits proliferation of human promyelocytic leukemia cells. The mechanisms involved in the regulation of these processes are not clearly understood. Previous studies have shown that calcitriol mediates cell differentiation not only by interaction with nuclear vitamin D receptor, but also by numerous rapid, membrane--mediated effects. Since in the light of past studies, involvement of raf/MEK1,2/erk1,2 signal transduction pathway in calcitriol-induced cell differentiation was questionable, another attempt was undertaken in this study in order to investigate the problem. PD 98059, the specific inhibitor of MEK1 and MEK2 was found to inhibit calcitriol-induced monocytic differentiation of HL-60 cells. This finding proves that activation of the raf/MEK1,2/erk1,2 signal transduction pathway is essential for monocytic differentiation of human leukemia cells. The results reported in this paper suggest that inhibition of protein kinase C, which upstream regulates activation of erk1 and erk2, may be bypassed during the process of calcitriol-induced leukemia cell differentiation.
 ...
PMID:Evidence that activation of MEK1,2/erk1,2 signal transduction pathway is necessary for calcitriol-induced differentiation of HL-60 cells. 1129 87

Numerous in vitro and in vivo observations, demonstrating that 1,25-dihydroxyvitamin D(3) is a potent inhibitor of tumor cell growth, provided the rationale for using this seco-steroid hormone to treat patients with leukemia and various types of cancer. However, the therapeutic efficacy of systemically applied vitamin D analogs for treating cancer has not yet fulfilled its promise. A main reason for these disappointing results is that the use of systemically applied vitamin D analogs is limited by severe side effects, mostly hypercalcemia, at the supraphysiological doses needed to reach clinical improvement. New concepts for the development of cancer treatment strategies that are based on the use of vitamin D(3) compounds are discussed in this manuscript. At the moment, different strategies that may enable the application of vitamin D analogs for the treatment of various malignancies, including malignant skin tumors, are employed. It has been shown that certain vitamin D analogs differ in their intracellular metabolism, nongenomic actions, pharmacokinetics, interaction with the vitamin D binding protein (DBP) or the vitamin D receptor (VDR). Several of these new concepts are based on recent laboratory results demonstrating that VDR requires heterodimerisation with additional nuclear cofactors such as the retinoid-X receptor (RXR) for sufficient DNA-binding or are based on new findings in the metabolism of vitamin D. Taken together, these new strategies hold promise that analogs of 1,25-dihydroxyvitamin D(3) may herald a new era in the treatment of various malignancies, including skin cancer.
 ...
PMID:Will analogs of 1,25-dihydroxyvitamin D(3) (calcitriol) open a new era in cancer therapy? 1144 Dec 91

Exposure of leukemia cells to the physiologically active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25D3) normalizes their phenotype to cells that resemble mature monocytes. One of the earliest detectable events in this process is an upregulation of the nuclear receptor for 1,25D3, the vitamin D receptor (nVDR). In contrast, the novel analog of 1,25D3, 1,25-dihydroxy-5,6 trans-16-ene-vitamin D3 (5,6-16D3), which has recently been reported to have low calcium-mobilizing activity in vivo, rapidly induced the expression of CD14, CD11b, and monocyte-specific esterase (MSE), classical markers of the mature monocyte, but upregulated nVDR expression less than 1,25D3. This upregulation was shown to be the result of altered degradation of the nVDR protein, while the levels of nVDR mRNA were constant. Knock-out of nVDR transcriptional activity by a decoy VDRE double-stranded deoxyoligonucleotide, markedly abrogated 1,25D3-induced differentiation, but incompletely inhibited 5,6-16D3-induced differentiation. These findings suggest that the unique ability of 5,6-16D3 to induce cell differentiation but not systemic hypercalcemia, may be due to the activation of pathways which initiate differentiation independently of nVDR.
 ...
PMID:Signaling of monocytic differentiation by a non-hypercalcemic analog of vitamin D3, 1,25(OH)2-5,6 trans-16-ene-vitamin D3, involves nuclear vitamin D receptor (nVDR) and non-nVDR-mediated pathways. 1206 63

Synthetic analogs of vitamin D for potential use in differentiation therapy should selectively regulate genes necessary for differentiation without inducing any perturbations in calcium homeostasis. PRI-1906, an analog of vitamin D2, and PRI-2191, an analog of vitamin D3 bind nuclear vitamin D receptor (nVDR) with substantially lower affinity than 1,25-dihydroxyvitamin D3 (1,25-D3), but have higher differentiation-inducing activity as estimated in HL-60 leukemia cellmodel. To examine how their increased differentiation-inducing activity is regulated we tested the hypothesis that membrane-mediated events, unrelated to nVDR, take part in the differentiation in response to PRI-1906 and PRI-2191. The induction of leukemia cell differentiation in response to the analogs of vitamin D was inhibited by LY294002 (phosphatidylinositol 3-kinase inhibitor), PD98059 (inhibitor of MEK1,2, an upstream regulator of extracellular-signal regulated kinase) and rapamycin (p70S6K inhibitor) pointing out that activation of signal transduction pathways unrelated to nVDR is necessary for differentiation. On the other hand, inhibition of cytosolic phospholipase A2 accelerated the differentiation of HL-60 cells induced by either 1,25-D3 or by the vitamin D analogs suggesting possible existence of a feedback loop between extracellular-signal regulated kinases and phospholipase A2.
 ...
PMID:Side-chain modified vitamin D analogs require activation of both PI 3-K and erk1,2 signal transduction pathways to induce differentiation of human promyelocytic leukemia cells. 1236 81

Maxacalcitol (Oxarol) is a derivative of vitamin D compounds applied for the secondary hyperparathyroidism (2 degrees HPT) of hemodialysis (HD) patients as an injection and psoriasis as an ointment. 2 degrees HPT is one of the complications in HD patients with hyperplasia of parathyroid glands and elevated serum parathyroid hormone (PTH) levels. On the other hand, vitamin D compounds are known to have multiple actions in many organs (promotion of calcium absorption from the small intestine, induction of differentiation of leukemia cells, differentiation and proliferation of the chondrocyte, muscle cells and epidermal cells, immunosuppressive activities) and their activities on parathyroid glands seem to be mediated by the vitamin D receptor (genomic action). It was reported that both serum PTH and PTH mRNA levels were suppressed by Maxacalcitol with less calcemic action and also Maxacalcitol could ameliorate high-turnover bone and marked osteitis fibrosa in uremic rats. Here I review many reports focused on the effects of Maxacalcitol on the 2 degrees HPT.
 ...
PMID:[Maxacalcitol, a medicine for secondary hyperparathyroidism (2 degrees HPT)]. 1261 40

Differentiation therapy of cancer remains an only partially attained goal. Agents currently under active investigation include derivatives of vitamin D, modeled on its physiological hormone form, 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)), but the calcemic effects of these compounds preclude their use in the clinic. An approach that may obviate this problem is to combine 1,25D(3) or its derivatives with other agents that increase the antineoplastic effects of low, nontoxic concentrations of vitamin D compounds. We have recently used the plant-derived polyphenolic antioxidant, carnosic acid (CA), to demonstrate an increase in the differentiating action of 1,25D(3) on human leukemia cells under these conditions (M. Danilenko et al., JNCI, 93: 1224-1233, 2001). We now show that treatment of HL60-G cells with either CA or 1,25D(3) alone resulted in a decrease in the intracellular levels of reactive oxygen species. Furthermore, the combination of 10 micro M CA and a low concentration of 1,25D(3) (1 nM) produced an enhanced antioxidant effect, which correlated with the potentiation of monocytic differentiation. Other plant antioxidants tested (curcumin, silibinin, and the organoselenium antioxidant ebselen) also potentiated differentiation induced by 1,25D(3), although alone, they had only minor differentiating effects. Differentiation induced by CA/1,25D(3) combinations was associated with increased intracellular glutathione content, whereas buthionine sulfoxime decreased both differentiation and the cellular glutathione content. This combination also enhanced the activation of the Raf-mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase mitogen-activated protein kinase module and increased the binding of the activator protein-1 (AP-1) transcription factor to its cognate DNA element in the promoter regions of vitamin D receptor gene, suggesting that the mechanism of potentiation is at least in part attributable to induction and activation of components of this mitogen-activated protein kinase pathway. Cell treatment with a high concentration of 1,25D(3) (100 nM) resulted in a substantial elevation of basal intracellular calcium concentration. In contrast, importantly for an eventual clinical application of these studies, the potentiating action of CA on differentiation induced by a low concentration of 1,25D(3) (1 nM) was not accompanied by an elevation of basal intracellular calcium concentration. These findings suggest that combinations of CA with derivatives of vitamin D should be evaluated for use in differentiation therapy of myeloid leukemias.
 ...
PMID:Carnosic acid potentiates the antioxidant and prodifferentiation effects of 1alpha,25-dihydroxyvitamin D3 in leukemia cells but does not promote elevation of basal levels of intracellular calcium. 1264 94

The 20-epi form of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)-20-epi-D(3)) is expected as drugs for leukemia, other cancers or psoriasis, because it shows several-hundred fold enhanced ability to induce cell differentiation and growth inhibition than 1alpha,25-dihydroxyvitamin D(3) while its calcemic activity is only slightly elevated. In this study, we compared the human and rat CYP24-dependent metabolism of 1alpha,25(OH)(2)-20-epi-D(3) by using the Escherichia coli expression system. The HPLC and LC-MS analyses of the metabolites revealed that rat CYP24 converted 1alpha,25(OH)(2)-20-epi-D(3) to 25,26,27-trinor-1alpha(OH)-24(COOH)-20-epi-D(3) through 1alpha,24,25(OH)(3)-20-epi-D(3) and 1alpha,25(OH)(2)-24-oxo-20-epi-D(3). The binding affinity of trinor-1alpha(OH)-24(COOH)-20-epi-D(3) for vitamin D receptor (VDR) was less than 1/4000 of that of 1alpha,25(OH)(2)-20-epi-D(3). These results suggest that rat CYP24 can almost completely inactivate 1alpha,25(OH)(2)-20-epi-D(3). On the other hand, human CYP24 mainly converted 1alpha,25(OH)(2)-20-epi-D(3) to its putative demethylated compound with a hydroxyl group, via 1alpha,24,25(OH)(3)-20-epi-D(3), 1alpha,25(OH)(2)-24-oxo-20-epi-D(3), and 1alpha,23,25(OH)(3)-24-oxo-20-epi-D(3). All of these metabolites showed considerable affinity for vitamin D receptor. These results clearly demonstrate the species-based difference between human and rat on the CYP24-dependent metabolism of 1alpha,25(OH)(2)-20-epi-D(3).
 ...
PMID:Metabolism of 20-epimer of 1alpha,25-dihydroxyvitamin D3 by CYP24: species-based difference between humans and rats. 1367 56

Derivatives of vitamin D (deltanoids) are well known to have the ability to induce differentiation of a variety of malignant cells, including human leukemia cells, but the signaling pathways that lead to such an outcome are unclear. In this study we investigated the role of the retinoblastoma protein (pRb) and the CCAAT/enhancer-binding protein (C/EBP) beta in 1,25-dihydroxyvitamin D(3) (1,25D(3))-induced monocytic differentiation of human leukemia HL60 cells. It was found that in this system, pRb is up-regulated within 12 h of exposure to the inducer, and the kinetics of its increase parallel the appearance of the early markers of differentiation, CD14 and monocyte-specific esterase. The increase in pRb expression was accompanied by a similar increase in C/EBPbeta protein, and these two proteins coimmunoprecipitated, suggesting formation of a complex. Oligonucleotides antisense to pRb or C/EBPbeta (but not to C/EBPalpha) or containing the C/EBP-binding sequence ("decoys"), all inhibited 1,25D(3)-induced differentiation. Inhibition of signaling by vitamin D receptor or by mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase pathways using pharmacological inhibitors ZK159222, PD98059, or SP600125, respectively, inhibited pRb and C/EBPbeta expression and differentiation in a coordinate manner. In contrast, inhibition of the p38MAPK pathway by SB202190 potentiated differentiation and the up-regulation of pRb and C/EBPbeta. We suggest that 1,25D(3) may signal monocytic differentiation of HL60 cells in a vitamin D receptor-dependent manner that includes activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase MAPK pathways, which then up-regulate pRb and C/EBPbeta expression and in turn initiate the differentiation process.
 ...
PMID:Retinoblastoma protein and CCAAT/enhancer-binding protein beta are required for 1,25-dihydroxyvitamin D3-induced monocytic differentiation of HL60 cells. 1472 47

The steroid hormone 1 alpha,25(OH)(2)-vitamin D(3) (1,25D) regulates gene transcription through a nuclear receptor [vitamin D receptor (VDR)] and initiation of rapid cellular responses through a putative plasma membrane-associated receptor (VDR(mem)). This study characterized the VDR(mem) present in a caveolae-enriched membrane fraction (CMF), a site of accumulation of signal transduction agents. Saturable and specific [(3)H]-1,25D binding in vitro was found in CMF of chick, rat, and mouse intestine; mouse lung and kidney; and human NB4 leukemia and rat ROS 17/2.8 osteoblast-like cells; in all cases the 1,25D K(D) binding dissociation constant = 1-3 nM. Our data collectively support the classical VDR being the VDR(mem) in caveolae: 1) VDR antibody immunoreactivity was detected in CMF of all tissues tested; 2) competitive binding of [(3)H]-1,25D by eight analogs of 1,25D was significantly correlated between nuclei and CMF (r(2) = 0.95) but not between vitamin D binding protein (has a different ligand binding specificity) and CMF; 3) confocal immunofluorescence microscopy of ROS 17/2.8 cells showed VDR in close association with the caveolae marker protein, caveolin-1, in the plasma membrane region; 4) in vivo 1,25D pretreatment reduced in vitro [(3)H]-1,25D binding by 30% in chick and rat intestinal CMF demonstrating in vivo occupancy of the CMF receptor by 1,25D; and 5) comparison of [(3)H]-1,25D binding in VDR KO and WT mouse kidney tissue showed 85% reduction in VDR KO CMF and 95% reduction in VDR KO nuclear fraction. This study supports the presence of VDR as the 1,25D-binding protein associated with plasma membrane caveolae.
 ...
PMID:The vitamin D receptor is present in caveolae-enriched plasma membranes and binds 1 alpha,25(OH)2-vitamin D3 in vivo and in vitro. 1527 54


<< Previous 1 2 3 4 5 6 Next >>