Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: KEGG:D02003 (NBT)
 1,323 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which resistance to 1,25 dihydroxyvitamin D3 (1,25-(OH)2D3) occurs in patients with chronic renal failure was studied. This agent induces differentiation and 1,25-(OH)2D3-24-hydroxylase activity in the mitochondria of the human promyelocytic leukemia cell line, HL-60, via a steroid-hormone receptor mechanism. HL-60 cells were cultured in RPMI 1640 medium supplemented with 10% normal or uremic serum. Treatment of these cells with 10(-8)M 1,25-(OH)2D3 for 5 days in a medium containing 10% uremic serum from 4 patients with chronic renal failure resulted in a maturation of the cells amounting to 30.3 +/- 18.7% (mean +/- SD) and 32.5 +/- 11.2%, as obtained by NBT reduction assay and NSE assay, respectively. These values were significantly lower than those obtained with 10% serum from 3 normal controls (66.6 +/- 12.8%, 58.3 +/- 10.9%, p less than 0.02). The treatment of HL-60 cells with 1,25-(OH)2D3 in a mixture of 5% normal plus 5% uremic serum caused cell differentiation to an extent similar to that in 10% uremic serum, which suggests the presence of a substance(s) having 1,25-(OH)2D3-inhibitory activity in the uremic serum. Exposure of HL-60 cells to uremic serum significantly impaired their responsiveness to 1,25-(OH)2D3 as assessed by the induction of the cell's ability to hydroxylate the C-24 position of 1,25-(OH)2[3H]D3. The mechanism by which uremic serum confers an impaired cellular response to 1,25-(OH)2D3 seemed to be due, in part, to a decrease in 1,25-(OH)2D3 receptor levels. A significant positive correlation was observed between intracellular cAMP levels and 1,25-(OH)2D3-induced HL-60 cell maturation. In summary, the mechanism by which uremic serum confers 1,25-(OH)2D3 resistance upon HL-60 cells seemed to be due to the presence of 1,25-(OH)2D3-inhibitory activity in uremic serum, which may modulate cellular responsiveness to 1,25-(OH)2D3 by such mechanisms as reducing 1,25-(OH)2D3 receptor levels in the cells, in part through alteration in cAMP metabolism.
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PMID:Effects of uremic serum on 1,25-dihydroxyvitamin D3-induced differentiation of a human promyelocytic leukemia cell line, HL-60. 166 75

Influence of sera of 15 patients with acute lymphoblastic leukaemia (ALL) and 28 with acute myeloblastic leukaemia (AML) on proliferation and differentiation of human leukaemic cell lines K-562 and HL-60 in a 3 days liquid culture was examined. Differentiation of K-562 cells was measured by the percentage of cells synthesizing Hb, and HL-60 cells by the percentage of cells with positive NBT test and positive NSE activity. Additionally the influence of differentiation inducers such as hemin for K-562 and DMSO and TPA for HL-60 was examined. It has been found that sera of patients with ALL and AML inhibit the proliferation of K-562 and HL-60 cells, induce the differentiation of K-562 cells, but inhibit the induction of differentiation by hemin. The sera of the examined patients inhibit the differentiation of HL-60 into granulocytes and monocytes, but do not affect the differentiation induced with DMSO and TPA.
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PMID:[Influence of patients' sera in acute leukemia on proliferation and differentiation of K-562 and HL-60 cells in liquid culture]. 806 89

In acute myeloid leukemia (AML), cell proliferation and differentiation are uncoupled, causing a maturation block. Induction of terminal differentiation is a potential therapeutic strategy. 1alpha, 25(OH)2 Vitamin D3 regulates differentiation and is immunomodulatory at concentrations causing severe hypercalcemia, thus limiting its use. We investigated 1alpha, 25(OH)2 Vitamin D3 and 5 of its more potent analogs with reduced calcium resorbing activity for differentiation of blast cells from AML (FAB M1) patients, compared to TPA. Blast phenotype, p-glycoprotein expression, cytokine production, and lineage specificity were examined. The Vitamin D3 analogs had no effect on cell viability and proliferation. They induced incomplete differentiation, with increase in AP, NSE and NBT positivity of cells, but no cell sticking and spreading as observed with TPA. The analogs were more effective than the parent compound. They also inhibited the production of IL-6 and IL-8. Vitamin D3 and its analogs can induce differentiation of primary cells from AML patients in vitro, but may need to be combined with other agents for terminal differentiation of blasts and effective therapy in vivo.
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PMID:Effect of 1,25(OH)2 Vitamin D3 analogs on differentiation induction and cytokine modulation in blasts from acute myeloid leukemia patients. 1537 Feb 59

Pycnogenol, rich of many phytochemicals of medical value, is a commercialized nutrient supplement extracted from the bark of European coastal pine. In this study, we investigated the anti-tumor effects of Pycnogenol on HL-60, U937 and K562 human leukemia cell lines. We found that Pycnogenol inhibited cell proliferation dose- and time-dependently, and the IC(50)s of Pycnogenol on HL-60, U937 and K562 cells were 150, 40 and 100 microg/ml, respectively. When HL-60 cells were incubated with low concentrations of Pycnogenol (50, 100 and 125 microg/ml) for 24 h, a prominent G0/G1 arrest was observed, followed by gradual accumulation of sub-G0/G1 nuclei. At 48 h of treatment, 50-70% of HL-60 cells differentiated, as evidenced by morphological changes, NBT reduction, induction of NSE activity, and increases of cell surface expression of CD11b. However, results from Annexin V/PI staining, DAPI staining and DNA fragmentation assay indicated that Pycnogenol induced HL-60, U937 and K562 cell apoptosis at their respective IC(50)s after 24 h of treatments. Pretreatment of z-DEVD-fmk, a caspase-3 specific inhibitor, not only decreased caspase-3 activity but also reduced the percentage of apoptotic cells induced by Pycnogenol. This indicated that caspase-3 activation was involved in Pycnogenol induced-apoptosis. In conclusion, Pycnogenol induced differentiation and apoptosis in leukemia cells. Our data suggest that Pycnogenol could serve as a potent cancer chemopreventive or chemotherapeutic agent for human leukemia.
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PMID:Pycnogenol induces differentiation and apoptosis in human promyeloid leukemia HL-60 cells. 1586 10