Cholesterol as a Bioregulator in the Development and Inhibition of Leukemia

Inbar, Michael; Shinitzky, Meir

doi:10.1073/pnas.71.10.4229

Cited by 115 publications

(29 citation statements)

References 29 publications

(22 reference statements)

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“…High membrane fluidity in CLL lymphocytes due to low membrane cholesterol levels, which are reflected in reduced serum cholesterol concentrations, have been reported by a number of groups. [63][64][65] In addition, leukaemic leukocytes display substantial increases in sterol synthesis compared with cells isolated from healthy controls. 66,67 Malignant transformation of lymphocytes to highly proliferative CLL cells surely involves major usage and reorganisation of critical membrane components, such as cholesterol, a molecule transported from the liver through the blood stream primarily in VLDL and LDL.…”

Section: Classification Methodsmentioning

confidence: 99%

Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

et al. 2010

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Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease exhibiting variable clinical course and survival rates. Mutational status of the immunoglobulin heavy chain variable regions (IGHVs) of CLL cells offers useful prognostic information for high-risk patients, but time and economical costs originally prevented it from being routinely used in a clinical setting. Instead, alternative markers of IGHV status, such as zeta-associated protein (ZAP70) or messenger RNA levels are often used. We report a 1 H-NMR-based metabolomics approach to examine serum metabolic profiles of early stage, untreated CLL patients (Binet stage A) classified on the basis of IGHV mutational status or ZAP70. Metabolic profiles of CLL patients (n ¼ 29) exhibited higher concentrations of pyruvate and glutamate and decreased concentrations of isoleucine compared with controls (n ¼ 9). Differences in metabolic profiles between unmutated (UM-IGHV; n ¼ 10) and mutated IGHV (M-IGHV; n ¼ 19) patients were determined using partial least square discriminatory analysis (PLS-DA; R 2 ¼ 0.74, Q 2 ¼ 0.36). The UM-IGHV patients had elevated levels of cholesterol, lactate, uridine and fumarate, and decreased levels of pyridoxine, glycerol, 3-hydroxybutyrate and methionine concentrations. The PLS-DA models derived from ZAP70 classifications showed comparatively poor goodness-of-fit values, suggesting that IGHV mutational status correlates better with diseaserelated metabolic profiles. Our results highlight the usefulness of 1 H-NMR-based metabolomics as a potential non-invasive prognostic tool for identifying CLL disease-state biomarkers.

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Section: Classification Methodsmentioning

confidence: 99%

Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

et al. 2010

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“…Using this technique it was reported that the "microviscosity" of mouse lymphoma cells and liposomes prepared from them is markedly lower than that of normal mouse lymphocytes and the corresponding liposomes . The same authors have also reported that the "microviscosity" of isolated surface membranes from human chronic lymphocytic leukaemia (CLL) cells was also considerably less than that of normal human lymphocytes (Inbar and Shinitzky, 1974b). These differences in apparent "microviscosity" appear to reflect mainly the lower cholesterol/phospholipid ratio in the leukaemic and lymphoma cell when compared with normal lymphocytes (Shinitzky and Inbar, 1976 …”

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confidence: 97%

Mononuclear cell-membrane “fluidity”: a study in some haematological malignancies

Blecher¹,

Bisby²

1977

Br J Cancer

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Summary.-The polarization of fluorescence from diphenyl hexatriene embedded in the membranes of intact peripheral-blood mononuclear cells has been measured and used to assess the "microviscosity" or fluidity of the membrane. Cell preparations were examined from patients with various types of leukaemia and related conditions in which circulating primitive cells may occur. Significantly lower fluorescence polarization values were obtained in all samples from patients with chronic lymphocytic leukaemia, but normal results were obtained in cases of chronic granulocytic leukaemia, myelosclerosis, solid lymphomas and in acute leukaemias in remission. In relapsed acute leukaemia, fluorescence polarization indicated reduced "microviscosity" of the cell membrane when large numbers (>109/1) of primitive cells were present; normal "microviscosity" was indicated when <109/1 primitive cells were present. However, exceptions occurred in both cases, and the technique failed to give warning of imminent relapse in one case.Our findings suggest that a reduction in "microviscosity" as indicated by this technique is not a general property of the blood leucocytes in all types of leukaemia, and that the technique cannot, at present, be regarded as an alternative method for detecting circulating primitive cells.

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“…Free cholesterol incorporated into the cytoplasmic membrane suppresses membrane fluidity (13,24) and nuclear DNA synthesis (1,12). As reported in a previous paper cholesterol oleate is also incorporated into the cell membrane, but much faster than is free cholesterol, and it has similar biological activities (19).…”

mentioning

confidence: 58%

Effects of Cholesterol and Cholesterol Esters on Cell FunctionII. The Effects of Various Cholesterol Esters on the Cell Membrane and Related Functions

Naito

1978

Cell Struct. Funct.

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ABSTRACT. Effects of different cholesterol-fatty acid esters and free cholesterol were observed in vitro on membrane-related functions in human red blood cells (RBC) and Ehrlich ascites tumor cells (EATC). The esters used were acetate, oleate, linoleate, linolenate, palmitate and stearate. All these cholesterol esters were superior to free cholesterol in suppression of osmotic red cell fragility and of EATC cap formation and its DNA synthesis or 3H-thymidine incorporation. Of these esters cholesterol linoleate, linolenate and palmitate weremoreeffective.In long term incubation, however, free cholesterol showed nearly the same biological activity as cholesterol esters. The possible mechanism controlling the outstanding effects of cholesterol ester on cell functions was discussed.Free cholesterol incorporated into the cytoplasmic membrane suppresses membrane fluidity (13, 24) and nuclear DNA synthesis (1, 12). As reported in a previous paper cholesterol oleate is also incorporated into the cell membrane, but much faster than is free cholesterol, and it has similar biological activities (19). In a short incubation period (20 min), free cholesterol had no specific cytological effect, but cholesterol oleate made RBC resistant to hypotonic shock, and it made EATC low in membrane fluidity and less active in DNA synthesis (19). Cholesterol oleate should be more effective than free cholesterol in the control of membrane-related cell functions.The characteristics of cholesterol oleate may be common to various cholesterol-fatty acid esters. I attempted to determine this with six selected cholesterol-fatty acid esters (saturated and unsaturated), by observing their effects on the fragility of RBC, on the Con A-induced cap formation of EATC, and on membrane fluidity and DNA synthesis. I here report that cholesterol-fatty acid esters are taken up rapidly by the cells and that they have cytological activities similar to free cholesterol which requires a fairly long time (8 hours) to produce the same effect. Some differences in biological effect were found for these cholesterol-fatty acid esters, according to differences in fatty acid moieties. MATERIALS AND METHODSEhrlich ascites tumor cells (EATC) and human red blood cells (RBC) were used. Cell suspensions of both were prepared in phosphate buffered saline solution as described in a previous paper (19).

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Cholesterol as a Bioregulator in the Development and Inhibition of Leukemia

Cited by 115 publications

References 29 publications

Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

Mononuclear cell-membrane “fluidity”: a study in some haematological malignancies

Effects of Cholesterol and Cholesterol Esters on Cell FunctionII. The Effects of Various Cholesterol Esters on the Cell Membrane and Related Functions

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