Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.1.1 (hexokinase)
 5,274 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The blood serum hexokinase (HK) level was studied in 122 patients suffering from thyroid diseases. Relatively low level of HK activity (3.96 +/- 0.78 ME) was seen in the blood of patients with thyroid malignant tumor and its rise was observed in all the patients with non-tumor injuries of this organ: in nodular euthyroid goitre 1.38 +/- 0.25 ME; in diffuse-toxic goitre 0.83 +/- 0.67 ME. The blood serum HK activity (3.43 +/- 0.73 ME) of patients with autoimmune thyroiditis did not statistically differ from that of the patients suffering from thyroid cancer.
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PMID:[Diagnostic value of the determination of serum hexokinase activity in thyroid cancer and autoimmune thyroiditis]. 729 Nov 36

The action of Lonidamine [1-(2,4-dichlorobenzyl)-1-H-indazol-3-carboxylic acid] on oxygen consumption and the rate of aerobic and anaerobic lactate production by Ehrlich ascites tumor cells has been investigated. The rate of oxygen consumption decreases exponentially with the increase of Lonidamine concentration, with maximal inhibition occurring at 0.40 mM Lonidamine. The rate of aerobic lactate production is inhibited to the same extent as is the oxygen consumption. However, the maximum effect is observed at 0.12 mM Lonidamine, and the decrease is linear with Lonidamine concentration. Anaerobic lactate production is more sensitive to Lonidamine, and complete inhibition can be observed by raising the concentration to 0.6 mM. The possibility that the decrease observed in lactate production was secondary to the inhibition of sodium- and potassium-containing adenosinetriphosphatase was excluded, because the drug has no effect on this enzyme. Mitochondrial adenosinetriphosphatase was not affected. Lonidamine was, however, shown to inhibit the activity of mitochondrially bound hexokinase to approximately the same extent as it inhibited aerobic glycolysis (approximately 70%). It is concluded that inhibition of the glycolysis of Ehrlich ascites tumor cells by Lonidamine results from an effect of the drug on the mitochondrially bound hexokinase.
Cancer Res 1981 Nov
PMID:Effect of lonidamine on the energy metabolism of Ehrlich ascites tumor cells. 730 82

Preliminary studies of 13 enzymes subserving various metabolic pathways were undertaken in tumor-free liver biopsy samples from cancer patients and control subjects. The observations indicate that as a result of nonhepatic neoplasms, with (7 cases) or without (6 cases) hepatic involvement, the biochemical composition of the liver becomes partially undifferentiated. Quantification of appropriate enzymes in histologically normal liver samples could thus distinguish clearly between cancer hosts and controls. The best discriminators include two hepatic enzymes whose concentrations were decreased to less than 30% of normal (soluble glutamate dehydrogenase and the cold stable pyrroline-5-carboxylate reductase) and three for which it was elevated two to four-fold (hexokinase, peptidyl proline hydroxylase and thymidine kinase) in response to distant neoplasms. The same alterations in hepatic enzyme pattern were not seen in any cancer-free patients with or without morphologic liver damage.
Cancer 1980 May 01
PMID:Enzyme pathology of the liver in patients with and without nonhepatic cancer. 737 35

We recently reported that tyrphostin 23 (3,4-dihydroxybenzylidene malononitrile) is unstable in solution and that some of the degradation products are better inhibitors of the tyrosine kinase activity of Src and the EGF-receptor kinase than the parent compound itself (Ramdas et al., Cancer Res. 54, 867-868, 1994). In this study, the tyrphostin 23-derived compound designated P3, which is a more stable and potent protein tyrosine kinase inhibitor, was isolated. P3 was purified from oxidized tyrphostin 23 by solvent extraction, silica-gel flash chromatography, and reverse-phase high-pressure liquid chromatography. The physical characteristics of the isolated compound were determined and its chemical structure elucidated by 1H and 13C NMR spectroscopy. The proposed structure of this new inhibitor is that of a tyrphostin 23 dimer joined at the benzylidene carbon. P3 was evaluated in vitro as an inhibitor of four different protein tyrosine kinases (Src, Csk, EGF-receptor, and FGF-receptor) and two protein serine kinases (PK-A and PK-C). This compound exhibited the most inhibitory activity against Src with a Ki value of 6 microM and was less inhibitory toward the other protein kinases with Ki values ranging from 35 to 300 microM. P3 did not inhibit other nucleotide-utilizing enzymes such as lactate dehydrogenase and hexokinase. The growth and colony formation of HT-29 colon adenocarcinoma cells that contain activated Src was inhibited by P3 with an IC50 value of approximately 10 microM.
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PMID:A tyrphostin-derived inhibitor of protein tyrosine kinases: isolation and characterization. 748 83

The steady state transcript levels of two hexokinase isozymes and type 1 glucose transporter in human tumor cell lines were analyzed. In HepG2 cells, both type II hexokinase and type 1 glucose transporter were highly expressed. However, in cell lines A431 and HeLa, in which the expression level of type 1 glucose transporter was lower than that in HepG2 cells, the amount of type II hexokinase transcript was almost negligible.
Cancer Lett 1994 Jul 15
PMID:Steady state transcript levels of the type II hexokinase and type 1 glucose transporter in human tumor cell lines. 751 42

Differences in modes of control of glycolysis in tumor cells, compared with normal cells, have suggested that phosphofructokinase may not catalyse the rate-controlling step. Instead, hexokinase activity may assume a more important regulatory role. Hexokinase activities are consistently lower than those of phosphofructokinase in tumor cells, and the former enzyme may be saturated with its substrate (M. Board et al., Biochem. J. 265: 503-509, 1990). The present work has focused on the glucose-phosphorylation step in tumor cell glycolysis. A range of eight human tumor cell-lines, one human tumor tissue, and four rat tumor cell lines were found to have an additional glucose-phosphorylating activity, with properties similar to hepatic glucokinase. Maximal activities range from 1.1-20 nmol/min/mg cell protein, and the activity is consistently absent from any untransformed cell line or tissue tested, except rat liver tissue (18 nmol/min/mg cell protein). Tumor cell glucokinase activity has been characterized by its high Km for glucose (8-11.8 mM); inhibition by the specific glucokinase inhibitor, mannoheptulose (I50, 12.5 mM); and lack of inhibition by 10 mM glucose-6-phosphate. Mannoheptulose also causes inhibition of glucose uptake by tumor cells (25-75% at 30 mM mannoheptulose) and inhibition of rates of growth of cultured tumor cell lines (I50, 21.4 mM). Rates of growth of human tumors in experimental animals are dramatically reduced (by 65-79%) by a dose of 1.7 mg/g mannoheptulose daily for 5 days. The potential of the naturally occurring sugar, mannoheptulose (which is purified from avocados and is assumed to be of low toxicity), as a cancer treatment is discussed.
Cancer Res 1995 Aug 01
PMID:High Km glucose-phosphorylating (glucokinase) activities in a range of tumor cell lines and inhibition of rates of tumor growth by the specific enzyme inhibitor mannoheptulose. 761 62

Hexokinase plays an important role in glucose-utilizing tissues like normal brain and cancers. In these tissues, hexokinase (HK) is mainly bound to mitochondria (mHK). Our objectives were to evaluate total HK (tHK) activity and mHK fraction in gliomas and to determine whether mHK binding could be targeted for therapy. Tumors were obtained from 26 patients and 13 were xenografted. HK, lactate and ATP were measured in cytosol and mitochondria extracts. The tHK expressed in mU/mg protein were 147 +/- 19 and 78 +/- 12, in fresh gliomas and xenografts, respectively, and of 489 in the normal brain. The mHK fraction was 76% in normal brain, 74 +/- 4% in fresh tumors and 53 +/- 6% in xenografts. Lactate/mHK ratios were higher in gliomas than in normal brain. The ATP was 10, 52 +/- 31 and 19 +/- 8 nmol/mg protein in normal brain, xenografts and fresh gliomas respectively. Loss of one copy of chromosome 10 which carries the HK1 gene, was evidenced in 11 of the 13 xenografted gliomas. The anti-tumor effect of lonidamine (LND), which affects glycolysis in interfering with mHK activity, was tested in nude mice bearing 4 gliomas. LND (125 mg/kg, given i.p., twice daily for 5 days) led to a growth inhibition of TG-7-RO of 72%, with 2-fold growth retardation, and had no effect for TG-8-OZ. Intermediate LND-sensitivities for TG-11-DU and TG-10-PY were noted. The LND-sensitivity was correlated with the mHK activity (R2 = 0.73) and mHK fraction (R2 = 0.88). HK binding to mitochondria is a key of glycolysis in malignant gliomas, and targetting this binding with appropriate agents could be an effective therapeutic approach.
Int J Cancer 1995 Jul 17
PMID:Mitochondria-bound hexokinase as target for therapy of malignant gliomas. 762 99

One of the most characteristic phenotypes of rapidly growing cancer cells is their propensity to catabolize glucose at high rates. Type II hexokinase, which is expressed at high levels in such cells and bound to the outer mitochondrial membrane, has been implicated as a major player in this aberrant metabolism. Here we report the isolation and sequence of a 4.3-kilobase pair proximal promoter region of the Type II hexokinase gene from a rapidly growing, highly glycolytic hepatoma cell line (AS-30D). Analysis of the sequence enabled the identification of putative promoter elements, including a TATA box, a CAAT element, several Sp-1 sites, and response elements for glucose, insulin, cAMP, Ap-1, and a number of other factors. Transfection experiments with AS-30D cells showed that promoter activity was enhanced 3.4-, 3.3-, 2.4-, 2.1-, and 1.3-fold, respectively, by glucose, phorbol 12-myristate 13-acetate (a phorbol ester), insulin, cAMP, and glucagon. In transfected hepatocytes, these same agents produced little or no effect. The results emphasize normal versus tumor cell differences in the regulation of Type II hexokinase and indicate that transcription of the Type II tumor gene may occur independent of metabolic state, thus, providing the cancer cell with a selective advantage over its cell of origin.
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PMID:Glucose catabolism in cancer cells. Isolation, sequence, and activity of the promoter for type II hexokinase. 762 9

The glycolytic enzyme hexokinase plays a key role in regulating cell energy metabolism. Its activity has been associated with cell growth rate and, notably, with neoplastic transformation. NIH-3T3 cells were transfected with a tumor hexokinase cDNA. The transfected cells showed increased hexokinase amount and activity, mainly located in the particulate cellular fraction, increased glycolytic rate evaluated as lactate production, and, finally, enhanced growth rate. These data may suggest that high hexokinase activity might be not merely the consequence of peculiar metabolic demands by actively replicating normal or cancer cells, but also a modification able per se to drive, at least partially, a more intense mitotic activity.
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PMID:Glycolysis and growth rate in normal and in hexokinase-transfected NIH-3T3 cells. 770 26

The mechanism of action of the antineoplastic drug lonidamine (LND) on MCF-7 human breast cancer cells was studied with the use of 31P and 13C nuclear magnetic resonance (NMR) spectroscopy. The cells were embedded in alginate microcapsules, perfused with growth media and LND at physiological conditions in the NMR tube, and continuously monitored in vivo for the effects of LND. 31P NMR demonstrated intracellular acidification after LND perfusion concomitant with ATP depletion and changes in phospholipid metabolites. 13C NMR showed marked LND-induced accumulation of lactate, and spectra of the perfusate disclosed that LND inhibited lactate transport. Kinetic 13C NMR also furnished information on LND effects on glucose metabolism; LND decreased initial glucose uptake and lactate formation, although the final intracellular glucose levels were higher compared with those in controls. Combined administration of LND and the metabolic inhibitor 2-deoxyglucose yielded additive but not synergistic cytotoxicity and enabled assessment of hexokinase activity. Overall, the results indicate that the major metabolic changes induced by LND are inhibition of lactate transport and its accumulation, which lead to intracellular acidification.
Cancer Res 1995 Jul 01
PMID:Mechanism of action of the antineoplastic drug lonidamine: 31P and 13C nuclear magnetic resonance studies. 779 8


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