Cardiac troponins in congestive heart failure.

BACKGROUND: We sought to assess the release of cardiac troponins in congestive heart failure (CHF). METHODS AND RESULTS: We performed a computer-assisted search of the English language literature (MEDLINE database) followed by a manual search of the reference list of pertinent articles retrieved. Studies evaluating the release of cardiac troponins (T and I) in patients with CHF were screened for review. Studies investigating cardiac troponins in patients with ischemic coronary syndromes that reported the rate of CHF were also selected. Available data on the release of cardiac troponins in ischemic and nonischemic CHF were summarized. Possible mechanisms of cell death in the progression to end-stage CHF were discussed. CONCLUSIONS: Cardiac troponins were detected in patients with advanced CHF. These markers correlated with the severity of CHF and suggest an association with worse prognosis. Possible mechanisms for the release of cardiac troponins T and I in advanced CHF may include the following: ventricular remodeling, presence of coronary artery disease in CHF, abnormalities of coronary microcirculation, and reduced coronary reserve. Further studies will be necessary to elucidate the actual mechanism and determine the clinical significance of cardiac troponins in CHF.

Glycolysis and growth rate in normal and in hexokinase-transfected NIH-3T3 cells.

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.

Rhein inhibits glucose uptake in Ehrlich ascites tumor cells by alteration of membrane-associated functions.

Rhein (RH), 4,5 dihydroxyanthraquinone-2-carboxylic acid, is known to inhibit the glycolysis of neoplastic cells by impairing glucose uptake. In order to establish whether this might be due to a selective interaction of the carrier with the drug or to functional modifications of the cell membrane, the effect of RH on glucose uptake in Ehrlich ascites tumor cells has been investigated. RH strongly inhibits the uptake of both 2-deoxyglucose and 3-O-methylglucose, so the reduced influx therefore cannot be ascribed to an effect on glucose phosphorylation. The inhibition of glucose transport does not depend on a reduction of the number of the carriers as indicated by the inability of the drug to interfere with the synthesis of the transporter. Moreover, the extent of total binding of cytochalasin B, as well as the fact that glucose specificity is not altered, indicate that the intrinsic activity of the glucose carrier is not affected. We therefore conclude that the inhibition of glucose uptake must be ascribed to an interaction of the drug with cell membranes that results in an alteration of membrane-associated functions.

Glucose metabolism in adriamycin-sensitive and -resistant LoVo human colon carcinoma cells.

The utilization of carbon from 14C-labeled glucose by adriamycin (ADM)-sensitive and -resistant LoVo human colon carcinoma cells has been investigated. The following summarizes the results: 1. Aerobic glycolysis is the main energy-yielding process in both cell lines, whereas only a small proportion of glucose carbon atoms are incorporated into CO2, lipids, nucleic acids, and supporting structures. 2. Basic alterations in glucose metabolism are associated with drug resistance in tumor cells. In fact, ADM-resistant LoVo cells show a significant increase in the oxidative pathway of glucose metabolism as well as in acetyl-CoA production. 3. In adriamycin-resistant LoVo cells, the amount of glucose carbon atoms metabolized through the pentose phosphate pathway is significantly higher than in adriamycin-sensitive cells. These findings confirm a modified glucose metabolism in cells with a resistant phenotype.

Glucose utilization by tumor cells: a post-translational modification of mitochondrial hexokinase may play a regulatory role.

In Northern blot analysis of a series of tumor cell lines a single hexokinase mRNA species of 4.3 Kb was detected. Detailed examination of one such line, the rat AS-30D hepatoma, revealed that two mitochondrial species of hexokinase are present with a molecular mass of 115 and 107 KDa. The smaller of the two species is 4-fold more active than the larger. Only the larger, less active species is detected in the well differentiated H-35 rat hepatoma cell line which exhibits a lower glucose catabolic rate. These results suggest that a post-translational proteolytic event may play a central role in regulating the glucose utilization capacity of tumor cells by modulating the relative levels of high and low activity forms of hexokinase.

The membrane-bound hexokinase as a potential marker for malignancy in human gliomas.

Hexokinase is a key enzyme in carbohydrate metabolism. Its activity has been shown elevated in cells with high mitotic index. In particular, experimental cancer cells, due to their peculiar energy metabolism, display a hexokinase activity proportional to the degree of malignancy. This is the case also for human gliomas in which glucose metabolism, evaluated via positron emission tomography, has been shown to be predictive for patient prognosis. In order to better correlate these findings, specific reagents for tumor hexokinase (a polyclonal antibody and a full-length cDNA probe both specific for murine tumor hexokinase) have been successfully employed to quantitate the protein and its messenger in cultured cell lines; the antibody was also tested in four specimens obtained from human astrocytomas.

rp-120: a common endogenous substrate for insulin and IGF-1 receptor-associated tyrosine kinase activity in the highly malignant AS-30D rat hepatoma cells.

Receptors for Insulin, Epidermal Growth Factor, Platelet-Derived Growth Factor and Insulin-like Growth Factor type 1 are tyrosine-specific protein kinases. This enzymatic activity may play a role in mediating the biological actions of these peptides. It has recently been identified a Mr 120 KDa glycoprotein in rat liver plasma membranes which can be phosphorylated by the insulin receptor and by the EGF receptor in a cell-free system and by the insulin receptor in intact cultured H-35 hepatoma cells. In the present report it is shown that the solubilized Insulin-like Growth Factor type 1 receptor can phosphorylate tyrosine residues in the same 120 KDa glycoprotein from the AS-30D rat hepatoma cells.

Effect of lonidamine on human malignant gliomas: biochemical studies.

Lonidamine (LND) has been shown to inhibit tumor aerobic glycolysis. Its effect was evaluated on several human astrocytomas at different degrees of malignancy; a correlation was found between LDN effect on lactate production and tumor malignancy: in grade I and II astrocytomas LND stimulates lactate production, while in grade III, IV and glioblastoma multiforme lactate production is inhibited. In an attempt to explain this different behaviour, hexokinase content and compartmentation was evaluated in astrocytomas from fresh operatory specimens and from cultured cells as well, observing a significative correlation between malignancy, hexokinase activity, percent of mitochondrially-bound hexokinase and LND effect. The results justify from a biochemical point of view the role of LND as a 'non-conventional' agent in multimodality combined treatment for malignant gliomas.

Effect of lonidamine on the utilization of 14C-labeled glucose by human astrocytoma cells.

The effect of lonidamine (LND), 1-(2,4-dichlorobenzyl)-1H-indazol-3 carboxylic acid, on the utilization of carbon from 14C-labeled glucose by cell cultures of the permanent strain LI derived from a human glioblastoma multiforme (astrocytoma) has been investigated. The results may be summarized as follows. Aerobic glycolysis is the main energy-yielding process as shown by the fact that the greatest part of glucose carbon atoms is incorporated into lactate. Nevertheless, the amount of glucose converted accounts for only 63% of the lactate produced, indicating the presence of an elevated endogenous aerobic glycolysis. The amount of glucose carbon atoms incorporated into CO2, lipids, nucleic acid, and supporting structures is low. LND decreased the incorporation of 14C activity in all the above mentioned isolated compounds because of its ability to inhibit glucose phosphorylation. Consequently, there is a lower concentration of glucose-6-phosphate which, in turn, affects the rate of formation of several metabolites in glycolytic and pentose phosphate pathways. Experiments with [1-14C]-2-deoxy-D-glucose further substantiate the idea of glucose phosphorylation as a main target of LND and strongly suggest the presence of a mitochondrially bound hexokinase. The higher inhibition of glucose phosphorylation in exponentially growing cells indicates a further shift of the enzyme toward mitochondria-bound form and confirms the importance of the energy status of the cell in eliciting the response to LND. The reduced capacity of LND-treated cells to synthetize ATP and glucose-6-phosphate reflects the decreased synthesis of proteins and nucleic acids, which affects cell growth and duplication.