Inhibition of protein, glycoprotein, ribonucleic acid and deoxyribonucleic acid synthesis by d-glucosamine and other sugars in mouse leukemic cells L5178Y and selective inhibition in SV-3T3 compared with 3T3 cells

Hb, Bosmann

doi:10.1016/0005-2787(71)90515-6

Cited by 42 publications

(17 citation statements)

References 26 publications

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“…However, in combination with growth-inhibitory concentrations of glucosamine (3 or 10 mM), irreversible cell damage resulted. With each combination shown in Table 2, the reduction in culture protein content was greater than would be expected for summation of mutually exclusive inhibitors (31 (16,(34)(35)(36); the second postulates that it disrupts the structure and function of cellular membrane systems (19).…”

Section: Resultsmentioning

confidence: 99%

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Membrane-active drugs potentiate the killing of tumor cells by D-glucosamine

Friedman

Skehan

1980

Proc. Natl. Acad. Sci. U.S.A.

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D-Glucosamine is toxic to several malignant cell lines and in vivo tumors at concentrations that have little effect upon normal host tissues. Evidence is presented to support the hypothesis that cellular membranes may be the primary targets of glucosamine's tumoricidal activity. Treatment of rat C6 glioma cells with a cytotoxic concentration of glucosamine (20 mM) caused fragmentation of rough endoplasmic reticulum, proliferation of Golgi complexes, evagination of outer nuclear and mitochondrial membranes, and the accumulation of membranous vacuoles and lipid droplets in the cytoplasm. These changes were detected within the first 3 hr after treatment of cultures with glucosamine and became increasingly severe until cell lysis occurred between 24 and 48 hr of treatment. The cytotoxicity of glucosamine was potentiated by the local anesthetic lidocaine, and by other membrane-active drugs, at concentrations that were growth inhibitory but nonlytic. Most of these drugs possessed local anesthetic activity and inhibited glioma sterol synthesis. Within the same period of time required or ultrastructural changes in cellular membranes, glucosamine inhibited the incorporation of [2-14Clacetate into sterols and into an unidentified 400-dalton lipid that migrated close to sterols on thin-layer chromatograms. This inhibition was potentiated by lidocaine and increased over the same range of D-glucosamine concentrations that led to increased cell toxicity after a 48-hr treatment. These findings suggest that the effects of glucosamine upon cellular membranes may be central to its tumoricidal activity and that glucosamine, in combination with membrane-active drugs, may be useful in the treatment of certain types of tumors, particularly those of the central nervous system.

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Section: Resultsmentioning

confidence: 99%

“…It exhibits little toxicity toward normal host tissues, but is an effective lytic agent for several types of transplantable animal tumors and human tumor xenografts grown in athymic mice (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

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confidence: 99%

Membrane-active drugs potentiate the killing of tumor cells by D-glucosamine

Friedman

Skehan

1980

Proc. Natl. Acad. Sci. U.S.A.

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“…Substantial evidence has accumulated in the meantime demonstrating that the induction of UTP deficiency by uridylate trapping is the key mechanism by which these hexose analogs exert their cytotoxic and growth inhibitory effects [lo, 1 1 , [34][35][36][37]. Glucosone, first synthesized in 1888 by E. Fischer [38], has been known for a long time for its striking toxicity [39] (for review see [40]) that could be explained only in part by hexokinase inhibition and interference with glucose uptake [I 5,17,40].…”

Section: Discussionmentioning

confidence: 99%

“…Most tumor cells are more sensitive to the glucose analogs [5,37] and recent work has demonstrated that glucosamine-induced UTP deficiency is much more pronounced in polyoma virus-transfromed than in untransformed fibroblasts [SO]. By contrast, liver and hepatoma cells are more sensitive to the galactose analogs [34,36].…”

Section: Discussionmentioning

confidence: 99%

Uridylate Trapping Induced by the C‐2‐Modified d‐Glucose Analogs Glucosone, Fluoroglucose, and Glucosamine

Holstege

Schulz-Holstege

Henninger

et al. 1982

European Journal of Biochemistry

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The interference of nucleotide metabolism induced by ~-arabino-hexos-2-u~ose (glucosone), 2-deoxy-2-fluoro-D-glucose (fluoroglucose) and, for comparison, 2-amino-2-deoxy-~-glucose (glucosamine) was studied in suspension cultures of TA3 mammary tumor cells. High-performance liquid chromatography, [I4C]uridine labeling and enzymatic analyses revealed that glucosone is metabolized to the U D P derivative leading to a diversion of [I4C]uridylate from UTP into UDP-glucosone. The accumulation of UDP-glucosone, that was measured in TA3 as well as AS-30D hepatoma cells, was associated with a depletion of UTP pools to less than 15'%; of control and a reduction of CTP contents to one third. UTP and CTP deficiency could be rapidly rcversed by addition of uridine to the cell suspension.Fluoroglucose acted both as a uridylate-trapping and as a guanylate-trapping hexose analog lowering the cellular contcnts of UTP and GTP to 5 % and 27 of control, respectively. The lowering of GTP was accompanied by an increase in total acid-soluble guanine nucleotides and a diversion of 84% of the [14C]guanylate into GDP-fluoroglucose. As compared to fluoroglucose and glucosone, glucosamine was less effective in TA3 cells in decreasing the content of UTP. The uridylate-trapping effect of glucosamine was in part compensated by the most active expansion of the acid-soluble uridylate pool; this reflects an enhanced rate of dc m v o pyrimidine synthesis that could be suppressed by the inhibitor 6-azauridine.As a side effect probably resulting from phosphate trapping, glucosone, fluoroglucose, and glucosamine depressed the levels of ATP and of total adenine 5'-nucleotides to a similar though moderate extent.The depletion of UTP, induced by these C-2-modified D-glucose analogs, and additionally of GTP in the case of fluoroglucose, represent a metabolic lesion that may explain their growth inhibitory and cytotoxic effects.Several C-2-modified D-glucose analogs are phosphorylated by hexokinase [l-31; some of them are metabolized further to U D P and/or GDP derivatives [4-61. Tntracellular formation and accumulation of the respective sugar 6-phosphate can result in a fall of inorganic phosphate triggering adenine nucleotide catabolism as one of its consequences [7 -91. Diversion of uridylate for the synthesis of UDP-sugar analogs leads to a lowering of cellular UTP levels and to a consecutive enhancement of the rate of de novo pyrimidine synthesis [lo]. The UTP depletion is followed by an inhibition of RNA synthesis [I I], while some of the C-2-modified UDPDedicated to Professor H. Holzer on the occasion of his 60th birthday. Abhreviutions. Glucosone, ~-arahino-hexos-2-ulose ; FGlc, fluoroglucose, 2-deoxy-2-fluoro-~-g~ucose; GlcN, glucosamine, 2-amino-2-deoxy-D-glucose; 6-AzaUrd, 6-azauridine; CAMP, CGMP, CUMP, sum of total acid-soluble adenine, guanine, and uracil 5'-nucleotides, respectively ; GDPMan, GDP-mannose; UDPGlc, UDP-glucose; UDPHexNAc, UDP-N-acetylhexosamines.Enzymes. Alkalinc phosphatase (EC 3.1.3.1): glucose-6-phosphate deliydrogenase (...

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“…Indirect immunofluorescence staining with antitubulin antiserum has revealed that MT disassembly occurs within 1 hr of treatment of quiescent 3T3 cells with 0.4 ,M colchicine (22). Thus, MT disassembly, whether caused by colchicine or vinblastine, eventually results in "cell activation" as indicated by an enhanced (5-fold) DNA synthesis that is accompanied by a dramatic imbalance in total cellular acid-soluble nucleotide pools-i.e., an increase in UTP pools coupled with a decrease in ATP pools such that the ratio of UTP/ATP pools increases by approximately 5-fold in colchicine-or vinblastine-treated cells ( (20,(24)(25)(26). As shown in Table 3, incubation for 24 hr of colchicine-treated cells with 2.5 mM D-glucosamine (an opti mal dose) resulted in diminution of total cellular UTP pools by 55% (see treatments 3 and 4).…”

Section: Resultsmentioning

confidence: 99%

Imbalance of total cellular nucleotide pools and mechanism of the colchicine-induced cell activation.

Chou¹,

Zeiger²,

Rapaport³

1984

Proc. Natl. Acad. Sci. U.S.A.

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Treatment with colchicine or vinblastine, both inhibitors of microtubule assembly, renders quiescent 3T3 cells in an "activated state" as evidenced by induction of DNA synthesis and other criteria. Microtubule disassembly caused by colchicine or vinblastine brings about a dramatic expansion of total cellular UTP pools with a concomitant diminution in total cellular ATP pools, thus resulting in a marked imbalance in total cellular nucleotide pools. Colchicine and vinblastine also stimulate total cellular RNA synthesis without enhancing uridine phosphorylation, suggesting that these drugs affect the G, phase of the cell cycle at a point beyond the enhancement of uridine phosphorylation that usually accompanies mitogenic stimulation of quiescent mammalian cells.The markedly expanded cellular UTP pools appear to be necessary for initiation of the colchicine-stimulated DNA synthesis because decreasing cellular UTP pools by addition of D-glucosamine results in a selective inhibition of DNA synthesis in the colchicine-stimulated, but not control, cells. Furthermore, Dglucosamine exerts its inhibitory effect only when it is present in the cultures within the first 14 hr after colchicine treatment. When added at 21 hr, D-glucosamine still decreases cellular UTP pools, but it is no longer inhibitory for DNA synthesis, which commences 14-16 hr after colchicine stimulation. Taxol, an antitumor drug, prevents microtubule disassembly and also blocks such events as expansion of total cellular UTP pools and stimulation of RNA and DNA synthesis, indicating that microtubule depolymerization acts as a primary event initiating the process of cell activation induced by colchicine.suggest that MT depolymerization is involved in modulating the initiation of DNA replication after mitogenic stimulation, although the underlying mechanism is not known.Since MT assembly in vitro is accompanied by GTP hydrolysis (12, 13), we have studied the effect of the colchicine-stimulated GO/G1 to S phase transition of 3T3 cells on the levels of cellular acid-soluble nucleotide pools, which have been shown to possess a regulatory role in the progression of mammalian cells along their cycle (14-17). We report here that MT disassembly induced by colchicine or vinblastine results in a sharp expansion of total cellular UTP pools with a concomitant diminution in total ATP pools and thus creates an imbalance in the cellular nucleotide pools as evidenced by large increases in the UTP/ATP ratio. In addition, we report that total cellular RNA synthesis, but not uridine phosphorylation, is stimulated following colchicine treatment. Furthermore, we also report that D-glucosamine effectively decreases the expanded cellular UTP pools and causes a selective inhibition of DNA synthesis in colchicinetreated, but not control, cells. Finally, we also report that taxol treatment effectively blocks events that normally occur following MT disassembly induced by colchicine or vinblastine. Taken together, our results suggest that the markedly increased cellular UTP p...

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Inhibition of protein, glycoprotein, ribonucleic acid and deoxyribonucleic acid synthesis by d-glucosamine and other sugars in mouse leukemic cells L5178Y and selective inhibition in SV-3T3 compared with 3T3 cells

Cited by 42 publications

References 26 publications

Membrane-active drugs potentiate the killing of tumor cells by D-glucosamine

Membrane-active drugs potentiate the killing of tumor cells by D-glucosamine

Uridylate Trapping Induced by the C‐2‐Modified d‐Glucose Analogs Glucosone, Fluoroglucose, and Glucosamine

Imbalance of total cellular nucleotide pools and mechanism of the colchicine-induced cell activation.

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