Glycolysis

About: Glycolysis is a research topic. Over the lifetime, 10593 publications have been published within this topic receiving 507460 citations. The topic is also known as: GO:0006096 & glycolysis.

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Abstract: The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling — the continuing reduction of oxygen without ATP synthesis — has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells — cultured alone or on bone marrow stromal cells — to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737, which supports the notion that fatty acids promote cell survival. Mechanistically, we generated evidence suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Importantly, etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human acute myeloid leukemia samples and, when combined with either ABT-737 or cytosine arabinoside, provided substantial therapeutic benefit in a murine model of leukemia. The results support the concept of FAO inhibitors as a therapeutic strategy in hematological malignancies.

Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions

Abstract: Time for primary review 28 days. The regulation of mammalian myocardial carbohydrate metabolism is complex in that it is linked to arterial substrate and hormone levels, coronary flow, inotropic state and the nutritional status of the tissue. Optimal cardiac function under normal and pathological conditions is dependent upon glycolysis and pyruvate oxidation. The purpose of this review is to examine the regulation of myocardial carbohydrate metabolism under physiological conditions, and during myocardial ischaemia and reperfusion. The therapeutic potential of a variety of pharmacological interventions affecting myocardial carbohydrate metabolism will then be discussed. The tricarboxylic acid cycle (TCA cycle) provides reducing equivalents for mitochondrial oxidative phosphorylation, resulting in the condensation of ADP and inorganic phosphate to regenerate ATP, and is fueled by acetyl-CoA formed primarily from oxidation of pyruvate and fatty acids (Fig. 1). Cardiomyocytes oxidise fatty acids derived from both the plasma and the breakdown of intracellular triacylglycerol stores, while pyruvate is derived from either lactate dehydrogenase or glycolysis. The rates of these metabolic pathways are tightly coupled to the rate of contractile work, and conversely, contractile work is coupled to the supply of oxygen and the rate of oxidative phosphorylation (Fig. 1). Early studies in animals [1] and human [2, 3] showed that after an overnight fast the heart extracts free fatty acids (FFA), lactate and glucose from the blood, and that if one assumes complete oxidation of extracted substrates, fatty acids are the major oxidative fuel for the heart (60–100% of the oxygen consumption), with a lesser contribution from lactate and glucose (0–20% from each) [2, 3]. Subsequent studies by others using a variety of experimental approaches have confirmed these early results (see [4–7] for reviews). Fig. 1 Schematic depiction of myocardial substrate metabolism. Abbreviations: G 6-P, glucose 6-phosphate; TCA, tricarboxylic acid; GT, GLUT 1 and GLUT 4 glucose …

Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis.

Abstract: The “Warburg effect,” an elevation in aerobic glycolysis, may be a fundamental property of cancer cells. For cancer diagnosis and treatment, it would be valuable if elevated glycolytic metabolism could be quantified in an image in animals and humans. The pyruvate molecule is at the metabolic crossroad for energy delivery inside the cell, and with a noninvasive measurement of the relative transformation of pyruvate into lactate and alanine within a biologically relevant time frame (seconds), it may be possible to quantify the glycolytic status of the cells. We have examined the metabolism after i.v. injection of hyperpolarized 13 C-pyruvate in rats with implanted P22 tumors. The strongly enhanced nuclear magnetic resonance signal generated by the hyperpolarization techniques allows mapping of pyruvate, lactate, and alanine in a 5 × 5 × 10 mm 3 imaging voxel using a 1.5 T magnetic resonance scanner. The magnetic resonance scanning (chemical shift imaging) was initiated 24 seconds after the pyruvate injection and had a duration of 14 seconds. All implanted tumors showed significantly higher lactate content than the normal tissue. The results indicate that noninvasive quantification of localized Warburg effect may be possible. (Cancer Res 2006; 66(22): 10855-60)

Metabolic coupling factors in pancreatic beta-cell signal transduction.

Abstract: This chapter focuses on the biochemical mechanisms that mediate glucose-stimulated insulin secretion (GSIS) from beta-cells of the islets of Langerhans and the potentiating role played by fatty acids. We summarize evidence supporting the idea that glucose metabolism is required for GSIS and that the GLUT-2 facilitated glucose transporter and the glucose phosphorylating enzyme glucokinase play important roles in measuring changes in extracellular glucose concentration. The idea that glucose metabolism is linked to insulin secretion through a sequence of events involving changes in ATP:ADP ratio, inhibition of ATP-sensitive K+ channels, and activation of voltage-gated Ca2+ channels is critically reviewed, and the relative importance of ATP generated from glycolytic versus mitochondrial metabolism is evaluated. We also present the growing concept that an important signal for insulin secretion may reside at the linkage between glucose and lipid metabolism, specifically the generation of the regulatory molecule malonyl CoA that promotes fatty acid esterification and inhibits oxidation. Finally, we show that in contrast to its short term potentiating effect on GSIS, long-term exposure of islets to high levels of fatty acids results in beta-cell dysfunction, suggesting that hyperlipidemia associated with obesity may play a causal role in the diminished GSIS characteristic of non insulin-dependent diabetes mellitus (NIDDM).