BAPST. A Combo of Common use drugs as metabolic therapy of cancer—a theoretical proposal.

2021 ◽  
Vol 14 ◽  
Author(s):  
Adriana Romo-Perez ◽  
Guadalupe Dominguez-Gomez ◽  
Alma Chavez-Blanco ◽  
Lucia Taja-Chayeb ◽  
Aurora Gonzalez-Fierro ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Mevalonate Pathway ◽  
Classical Model ◽  
Plasma Concentrations ◽  
Metabolic Phenotype ◽  
Cancer Drug ◽  
Acid Oxidation ◽  
Ulcer Disease ◽  
Primary Indication ◽  
Drug Affordability

: Advances in cancer therapy have yet to impact worldwide cancer mortality. Poor cancer drug affordability is one of the factors limiting mortality burden strikes. Up to now, cancer drug repurposing had no meet expectations concerning drug affordability. The three FDA-approved cancer drugs developed under repurposing -all-trans-retinoic acid, arsenic trioxide, and thalidomide- do not differ in price from other drugs developed under the classical model. Though additional factors affect the whole process from inception to commercialization, the repurposing of widely used, commercially available, and cheap drugs may help. This work reviews the concept of the malignant metabolic phenotype and its exploitation by simultaneously blocking key metabolic processes altered in cancer. We elaborate on a combination called BAPST, which stands for the following drugs and pathways they inhibit: Benserazide (glycolysis), Apomorphine (glutaminolysis), Pantoprazole (Fatty-acid synthesis), Simvastatin (mevalonate pathway), and Trimetazidine (Fatty-acid oxidation). Their respective primary indications are: • Parkinson's disease (benserazide and apomorphine). • Peptic ulcer disease (pantoprazole). • Hypercholesterolemia (simvastatin). • Ischemic heart disease (trimetazidine). When used for their primary indication, the literature review on each of these drugs shows they have a good safety profile and lack predicted pharmacokinetic interaction among them. Most importantly, the inhibitory enzymatic concentrations required for inhibiting their cancer targets enzymes are below the plasma concentrations observed when these drugs are used for their primary indication. Based on that, we propose that the regimen BAPTS merits preclinical testing.

Effect of short-term fasting on the lipolytic response to theophylline

1991 ◽  
Vol 261 (4) ◽  
pp. E500-E504 ◽  
Author(s):  
E. J. Peters ◽  
S. Klein ◽  
R. R. Wolfe
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Indirect Calorimetry ◽  
Adenosine Receptors ◽  
Plasma Concentrations ◽  
Inhibitory Effect ◽  
Acid Oxidation ◽  
Inhibitory Influence ◽  
Receptor Blockade ◽  
Short Term

We investigated the hypothesis that the increase in lipolysis that occurs in short-term (86-h) fasting is due to a decreased inhibitory influence of adenosine. In normal volunteers who fasted for 14 and 86 h, the response to adenosine receptor blockade was assessed by the infusion of theophylline at a rate sufficient to produce plasma concentrations (30 microM) that blocked adenosine receptors but that were well below the threshold for inhibition of phosphodiesterase. Lipolysis was assessed by determining the rate of appearance of glycerol using D-5-glycerol infusion. Fatty acid flux was also determined by means of [1-13C]palmitate infusion, and total fatty acid oxidation was determined by indirect calorimetry. There was a mild stimulatory effect of theophylline on lipolysis at 14 h. After the subjects fasted for 86 h, theophylline infusion caused a much greater increase in both lipolysis and fatty acid oxidation. These results suggest that the inhibitory effect of adenosine on lipolysis is increased during short-term fasting.

scholarly journals Blockade of fatty acid oxidation mimics phase II-phase III transition in a fasting bird, the king penguin

2002 ◽  
Vol 283 (1) ◽  
pp. R144-R152 ◽  
Author(s):  
Servane F. Bernard ◽  
Eliane Mioskowski ◽  
René Groscolas
Keyword(s):  
Fatty Acid ◽  
Phase Ii ◽  
Plasma Concentrations ◽  
Fold Increase ◽  
Phase Iii ◽  
Acid Oxidation ◽  
Body Protein ◽  
Nonesterified Fatty Acids ◽  
Protein Sparing

This study tests the hypothesis that the metabolic and endocrine shift characterizing the phase II-phase III transition during prolonged fasting is related to a decrease in fatty acid (FA) oxidation. Changes in plasma concentrations of various metabolites and hormones and in lipolytic fluxes, as determined by continuous infusion of [2-3H]glycerol and [1-14C]palmitate, were examined in vivo in spontaneously fasting king penguins in the phase II status (large fat stores, protein sparing) before, during, and after treatment with mercaptoacetate (MA), an inhibitor of FA oxidation. MA induced a 7-fold decrease in plasma β-hydroxybutyrate and a 2- to 2.5-fold increase in plasma nonesterified fatty acids (NEFA), glycerol, and triacylglycerols. MA also stimulated lipolytic fluxes, increasing the rate of appearance of NEFA and glycerol by 60–90%. This stimulation might be partly mediated by a doubling of circulating glucagon, with plasma insulin remaining unchanged. Plasma glucose level was unaffected by MA treatment. Plasma uric acid increased 4-fold, indicating a marked acceleration of body protein breakdown, possibly mediated by a 2.5-fold increase in circulating corticosterone. Strong similarities between these changes and those observed at the phase II-phase III transition in fasting penguins support the view that entrance into phase III, and especially the end of protein sparing, is related to decreased FA oxidation, rather than reduced NEFA availability. MA could be therefore a useful tool for understanding mechanisms underlying the phase II-phase III transition in spontaneously fasting birds and the associated stimulation of feeding behavior.

scholarly journals Metabolic re-patterning in COPD airway smooth muscle cells

2017 ◽  
Vol 50 (5) ◽  
pp. 1700202 ◽  
Author(s):  
Charalambos Michaeloudes ◽  
Chih-Hsi Kuo ◽  
Gulam Haji ◽  
Donna K. Finch ◽  
Andrew J. Halayko ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Airway Smooth Muscle ◽  
Redox Balance ◽  
Growth Conditions ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Acid Oxidation ◽  
Oxidation Capacity

Chronic obstructive pulmonary disease (COPD) airways are characterised by thickening of airway smooth muscle, partly due to airway smooth muscle cell (ASMC) hyperplasia. Metabolic reprogramming involving increased glycolysis and glutamine catabolism supports the biosynthetic and redox balance required for cellular growth. We examined whether COPD ASMCs show a distinct metabolic phenotype that may contribute to increased growth.We performed an exploratory intracellular metabolic profile analysis of ASMCs from healthy nonsmokers, healthy smokers and COPD patients, under unstimulated or growth conditions of transforming growth factor (TGF)-β and fetal bovine serum (FBS).COPD ASMCs showed impaired energy balance and accumulation of the glycolytic product lactate, glutamine, fatty acids and amino acids compared to controls in unstimulated and growth conditions. Fatty acid oxidation capacity was reduced under unstimulated conditions. TGF-β/FBS-stimulated COPD ASMCs showed restoration of fatty acid oxidation capacity, upregulation of the pentose phosphate pathway product ribose-5-phosphate and of nucleotide biosynthesis intermediates, and increased levels of the glutamine catabolite glutamate. In addition, TGF-β/FBS-stimulated COPD ASMCs showed a higher reduced-to-oxidised glutathione ratio and lower mitochondrial oxidant levels. Inhibition of glycolysis and glutamine depletion attenuated TGF-β/FBS-stimulated growth of COPD ASMCs.Changes in glycolysis, glutamine and fatty acid metabolism may lead to increased biosynthesis and redox balance, supporting COPD ASMC growth.

Strenuous endurance training increases lipolysis and triglyceride-fatty acid cycling at rest

1993 ◽  
Vol 75 (1) ◽  
pp. 108-113 ◽  
Author(s):  
J. A. Romijn ◽  
S. Klein ◽  
E. F. Coyle ◽  
L. S. Sidossis ◽  
R. R. Wolfe
Keyword(s):  
Fatty Acid ◽  
Endurance Training ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Acid Oxidation ◽  
Body Lipid ◽  
Control Subjects ◽  
Triglyceride Fatty Acid ◽  
Fatty Acid Release ◽  
Acid Release

Basal whole body lipid kinetics were evaluated in nine endurance-trained cyclists and 10 untrained healthy controls. The rate of appearance (Ra) of glycerol (an index of whole body lipolysis), the Ra of palmitate (an index of fatty acid release), and the rate of triglyceride-fatty acid cycling (reesterification of fatty acids released during lipolysis) were determined by infusing [2H5]glycerol and [2H2]palmitate in conjunction with indirect calorimetry. All subjects were studied while they were at rest after fasting overnight. Glycerol Ra and free fatty acid Ra in the athletes (7.33 +/- 0.68 and 14.88 +/- 1.35 mumol.kg-1 x min-1, respectively) were two- to threefold higher than the values in untrained control subjects (2.53 +/- 0.15 and 7.64 +/- 0.92 mumol.kg-1 x min-1, respectively; P < 0.02). The total rate of triglyceride-fatty acid cycling was approximately four-fold higher in the athletes (16.86 +/- 2.07 mumol.kg-1 x min-1) than in the control subjects (3.91 +/- 0.36 mumol.kg-1 x min-1). Plasma concentrations of insulin and catecholamines, hormones that regulate whole body lipid kinetics, were the same in both groups. We conclude that resting basal lipid kinetics are markedly increased in athletes involved in strenuous endurance training and that this enhances the potential for increasing fatty acid oxidation rapidly at the onset of exercise.

Abstract 649: Does Chronic Increase of Glucose Uptake Cause Cardiac “glycotoxicity”?

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jie Yan ◽  
Ivan Luptak ◽  
Lei Cui ◽  
Mohit Jain ◽  
Ronglih Liao ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Functional Recovery ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
High Energy ◽  
Atp Depletion ◽  
Metabolic Phenotype ◽  
Acid Oxidation

A shift of substrate preference toward glucose in the heart is considered a reversion to fetal metabolic profile but its role in the pathogenesis of cardiac diseases is incompletely understood. We performed a 2-year follow-up study in transgenic mice with sustained high glucose uptake and utilization in the heart by cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (GLUT1-TG). Compared to wildtype (WT) littermates, the GLUT1-TG mice showed normal survival rate and unaltered contractile function of the heart monitored by serial echocardiography and by pressure-volume studies in isolated perfused hearts in the 2-year period. When the hearts were subjected to ischemia-reperfusion, an age-related impairment in functional recovery was observed in WT; cardiac function recovered to 35% vs. 52% of the preischemic level in old (22 months) vs. young (3 months) WT hearts respectively (p<0.05). Ischemic tolerance was markedly enhanced in GLUT1-TG hearts, and importantly, the greater functional recovery in GLUT1-TG hearts was sustained at older age (83% vs. 86% for old and young GLUT1-TG, respectively, p=ns). 31 P NMR spectroscopic measurement showed delayed ATP depletion, reduced acidosis during ischemia and improved recovery of high energy phosphate content in old GLUT1-TG hearts (p<0.05 vs. old WT). These differences were found to be independent of alterations in the activations of Akt and AMPK by ischemia. During reperfusion, glucose oxidation was 3-fold higher while fatty acid oxidation was 45% lower in old GLUT1-TG hearts compared to old WT (p<0.05) suggesting that the deleterious effects of excessive fatty acid oxidation during reperfusion was prevented in old GLUT1-TG hearts. Thus, these results suggest that a normal heart is capable of adapting to chronic increases in basal glucose entry into cardiomyocytes without developing “glucotoxicity”, and furthermore, life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against aging-associated increase of susceptibility to ischemic injury.

Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation

2004 ◽  
Vol 287 (4) ◽  
pp. H1538-H1543 ◽  
Author(s):  
Margaret P. Chandler ◽  
Janos Kerner ◽  
Hazel Huang ◽  
Edwin Vazquez ◽  
Aneta Reszko ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Metabolic Phenotype ◽  
Acid Oxidation ◽  
Malonyl Coa ◽  
Myocardial Substrate ◽  
Cpt I ◽  
End Stage

Recent human and animal studies have demonstrated that in severe end-stage heart failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype, characterized by downregulation of free fatty acid (FFA) oxidation and an enhancement of glucose oxidation. The goal of this study was to examine myocardial substrate metabolism in a model of moderate coronary microembolization-induced HF. We hypothesized that during well-compensated HF, FFA oxidation would predominate as opposed to a more fetal metabolic phenotype of greater glucose oxidation. Cardiac substrate uptake and oxidation were measured in normal dogs ( n = 8) and in dogs with microembolization-induced HF ( n = 18, ejection fraction = 28%) by infusing three isotopic tracers ([9,10-3H]oleate, [U-14C]glucose, and [1-13C]lactate) in anesthetized open-chest animals. There were no differences in myocardial substrate metabolism between the two groups. The total activity of pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation (and hence glucose and lactate oxidation) was not affected by HF. We did not observe any difference in the activity of carnitine palmitoyl transferase I (CPT-I) and its sensitivity to inhibition by malonyl-CoA between groups; however, malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be explained by changes in the Michaelis-Menten constant and maximal velocity for malonyl-CoA decarboxylase because neither were affected by HF. These results support the concept that there is no decrease in fatty acid oxidation during compensated HF and that the downregulation of fatty acid oxidation enzymes and the switch to carbohydrate oxidation observed in end-stage HF is only a late-stage phenomemon.

Metabolic response to a high-fat diet in neonatal and adult rat muscle

1992 ◽  
Vol 262 (2) ◽  
pp. C282-C286 ◽  
Author(s):  
P. M. Nemeth ◽  
B. W. Rosser ◽  
R. M. Choksi ◽  
B. J. Norris ◽  
K. M. Baker
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
High Fat Diet ◽  
Metabolic Response ◽  
Dietary Factors ◽  
Metabolic Phenotype ◽  
Acid Oxidation ◽  
Neonatal Rats ◽  
High Fat ◽  
Low Carbohydrate Diet

Neonatal rats were exposed to a high-fat low-carbohydrate diet to determine how substrate availability might affect the metabolic phenotype of muscle. Mixed-fiber homogenates of extensor digitorum longus, soleus, and diaphragm muscles were assayed for beta-hydroxyacyl-CoA dehydrogenase (beta-OAC), succinate dehydrogenase, malate dehydrogenase, lactate dehydrogenase, phosphofructokinase (PFK), adenylokinase, and creatine kinase. The three muscles showed significant increases in enzyme activity for fatty acid oxidation (beta-OAC) in weaned neonatal rats maintained on the high-fat diet compared with normal weaned controls. This effect persisted for 6 wk of the diet. The other consistent metabolic change was a decrease in PFK. Adult animals subjected to the same diet had similar increases in fatty acid oxidation and a fall in PFK after 1 wk, with most of these changes persisting for the 4 wk of the diet. Examination of individual fibers revealed enzyme changes in fibers of all types, but with the largest effect in type IIb fibers. The data indicate that both adult and neonatal muscles are similarly capable of adjusting their energy metabolism in response to dietary factors.

Transforming growth factor-β in the brain regulates fat metabolism during endurance exercise

2006 ◽  
Vol 291 (6) ◽  
pp. E1151-E1159 ◽  
Author(s):  
Toma Ishikawa ◽  
Wataru Mizunoya ◽  
Tetsuro Shibakusa ◽  
Kazuo Inoue ◽  
Tohru Fushiki
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Transforming Growth Factor ◽  
Plasma Concentrations ◽  
Transforming Growth Factor Β ◽  
Gas Analysis ◽  
Treadmill Running ◽  
Control Group ◽  
Acid Oxidation ◽  
The Brain

We have previously reported that the concentration of transforming growth factor-β (TGF-β) increases in the cerebrospinal fluid of rats during exercise and that there is an increase in whole body fat oxidation following the intracisternal administration of TGF-β. These results led us to postulate that TGF-β in the brain regulates the enhancement of fatty acid oxidation during exercise. To test this hypothesis, we carried out respiratory gas analysis during treadmill running following the inhibition of TGF-β activity in rat brain by intracisternal administration of anti-TGF-β antibody or SB-431542, an inhibitor of the type 1 TGF-β receptor. We found that each reagent partially blocked the increase in the fatty acid oxidation. We also compared the plasma concentrations of energy substrates in the group administered anti-TGF-β antibody and the control group during running. We found that the plasma concentrations of nonesterified fatty acids and ketone bodies in the group administered anti-TGF-β antibody were lower than in the control group at the end of running. In the same way, we carried out respiratory gas analysis during treadmill running after depressing corticotropin-releasing factor activity in the brain using intracisternal administration of astressin, an inhibitor of the corticotropin-releasing factor receptor. However, there were no significant differences in respiratory exchange ratio or oxygen consumption in moderate running (60% maximum oxygen consumption). These results suggest that brain TGF-β has a role in enhancing fatty acid oxidation during endurance exercise and that this regulation is executed at least partly via the type 1 TGF-β receptor signal transduction system.

scholarly journals Very long chain fatty acid metabolism is required in acute myeloid leukemia

Blood ◽  
2021 ◽  
Author(s):  
Matthew Tcheng ◽  
Alessia Roma ◽  
Nawaz Ahmed ◽  
Richard William Smith ◽  
Preethi Jayanth ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Fatty Acid ◽  
Cell Biology ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Tca Cycle ◽  
Atp Depletion ◽  
Metabolic Phenotype ◽  
Acid Oxidation ◽  
Acute Myeloid

Acute myeloid leukemia (AML) cells have an atypical metabolic phenotype characterized by increased mitochondrial mass as well as a greater reliance on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) for survival. To exploit this altered metabolism, we assessed publicly available databases to identify FAO enzyme overexpression. VLCAD (ACADVL) was found to be overexpressed and critical to leukemia cell mitochondrial metabolism. Genetic attenuation or pharmacological inhibition of VLCAD hindered mitochondrial respiration and FAO contribution to the TCA cycle, resulting in decreased viability, proliferation, clonogenic growth and AML cell engraftment. Suppression of FAO at VLCAD triggered an increase in PDH activity insufficient to increase glycolysis but resulted in ATP depletion and AML cell death with no effect in normal hematopoietic cells. Together, these results demonstrate the importance of VLCAD in AML cell biology and highlight a novel metabolic vulnerability for this devastating disease.

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