scholarly journals The Pentose Phosphate Pathway in Cancer: Regulation and Therapeutic Opportunities

Chemotherapy ◽  
2021 ◽  
pp. 1-13
Author(s):  
Noorhan Ghanem ◽  
Chirine El-Baba ◽  
Khaled Araji ◽  
Riyad El-Khoury ◽  
Julnar Usta ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pentose Phosphate Pathway ◽  
Aerobic Glycolysis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Pentose Phosphate ◽  
Nucleotide Synthesis ◽  
Intermediary Metabolites ◽  
Dividing Cells ◽  
Metabolites Production ◽  
Reductive Metabolism

<b><i>Background:</i></b> Tumorigenesis is associated with deregulation of nutritional requirements, intermediary metabolites production, and microenvironment interactions. Unlike their normal cell counterparts, tumor cells rely on aerobic glycolysis, through the Warburg effect. <b><i>Summary:</i></b> The pentose phosphate pathway (PPP) is a major glucose metabolic shunt that is upregulated in cancer cells. The PPP comprises an oxidative and a nonoxidative phase and is essential for nucleotide synthesis of rapidly dividing cells. The PPP also generates nicotinamide adenine dinucleotide phosphate, which is required for reductive metabolism and to counteract oxidative stress in tumor cells. This article reviews the regulation of the PPP and discusses inhibitors that target its main pathways. <b><i>Key Message:</i></b> Exploiting the metabolic vulnerability of the PPP offers potential novel therapeutic opportunities and improves patients’ response to cancer therapy.

scholarly journals Annurca Apple Polyphenols Ignite Keratin Production in Hair Follicles by Inhibiting the Pentose Phosphate Pathway and Amino Acid Oxidation

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1406 ◽  
Author(s):  
Nadia Badolati ◽  
Eduardo Sommella ◽  
Gennaro Riccio ◽  
Emanuela Salviati ◽  
Dimitri Heintz ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Hair Growth ◽  
High Resolution Mass Spectrometry ◽  
Negative Impact ◽  
Adult Population ◽  
Pentose Phosphate ◽  
Hair Follicles ◽  
Acid Oxidation ◽  
Healthy Human ◽  
Nucleotide Synthesis

Patterned hair loss (PHL) affects around 50% of the adult population worldwide. The negative impact that this condition exerts on people’s life quality has boosted the appearance of over-the-counter products endowed with hair-promoting activity. Nutraceuticals enriched in polyphenols have been recently shown to promote hair growth and counteract PHL. Malus pumila Miller cv. Annurca is an apple native to Southern Italy presenting one of the highest contents of Procyanidin B2. We have recently shown that oral consumption of Annurca polyphenolic extracts (AAE) stimulates hair growth, hair number, hair weight and keratin content in healthy human subjects. Despite its activity, the analysis of the molecular mechanism behind its hair promoting effect is still partially unclear. In this work we performed an unprecedented metabolite analysis of hair follicles (HFs) in mice topically treated with AAE. The metabolomic profile, based on a high-resolution mass spectrometry approach, revealed that AAE re-programs murine HF metabolism. AAE acts by inhibiting several NADPH dependent reactions. Glutaminolysis, pentose phosphate pathway, glutathione, citrulline and nucleotide synthesis are all halted in vivo by the treatment of HFs with AAE. On the contrary, mitochondrial respiration, β-oxidation and keratin production are stimulated by the treatment with AAE. The metabolic shift induced by AAE spares amino acids from being oxidized, ultimately keeping them available for keratin biosynthesis.

scholarly journals Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation

Oncotarget ◽  
2015 ◽  
Vol 7 (3) ◽  
pp. 2910-2920 ◽  
Author(s):  
Géraldine De Preter ◽  
Marie-Aline Neveu ◽  
Pierre Danhier ◽  
Lucie Brisson ◽  
Valéry L. Payen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
Pentose Phosphate Pathway ◽  
Aerobic Glycolysis ◽  
Pentose Phosphate ◽  
Cancer Cell Proliferation ◽  
Missing Link

344 PENTOSE PHOSPHATE PATHWAY ACTIVITY CONTROLS NUCLEAR MATURATION OF PORCINE OOCYTES

2006 ◽  
Vol 18 (2) ◽  
pp. 279 ◽  
Author(s):  
L. Tubman ◽  
A. Peter ◽  
R. Krisher
Keyword(s):  
Pentose Phosphate Pathway ◽  
Control Level ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Germinal Vesicle ◽  
Pentose Phosphate ◽  
Meiotic Stage ◽  
Germinal Vesicle Breakdown ◽  
Pathway Activity ◽  
Nuclear Maturation

Diphenyleneiodonium (DPI), an inhibitor of the pentose phosphate pathway (PPP), arrests nuclear maturation of porcine oocytes. This inhibition is reversed using products or cofactors of PPP such as nicotinamide adenine dinucleotide phosphate (NADP), phosphoribose diphosphate (PRPP), and ribose-5-phosphate (R5P). The objective of this study was to determine the relationship between DPI-mediated meiotic inhibition, reversal of this inhibition, and metabolism of in vitro-matured (IVM) porcine oocytes. Oocytes were aspirated, searched, and selected in the presence of DPI, with the exception of control oocytes. Oocytes were then matured in one of five treatments for 40 h in 7% CO2 in air at 39°C in defined Purdue Porcine Medium for maturation (PPMmat). Treatments included control, 50 nM DPI (DPI), DPI + 5 mM NADP (NADP), DPI + 12.5 mM PRPP (PRPP), and DPI + 10 mM R5P (R5P). Following IVM, oocytes were denuded by vortexing. Glycolysis and PPP activities were measured in 4 μL hanging drops containing labeled glucose (0.0125 mM 5-3H glucose and 0.482 mM 1-14C glucose, respectively) for 3 h in 6% CO2. Oocytes were then individually fixed in a 3:2:1 solution of ethanol:acetic acid:chloroform and stained with aceto-orcein for determination of meiotic stage (germinal vesicle = 1 through metaphase II = 7). Data were analyzed using one-way ANOVA. The use of DPI inhibited PPP and nuclear maturation; additionally glycolysis was decreased by DPI compared to control. Addition of NADP and PRPP increased both metabolic pathways and nuclear maturation compared to DPI. R5P restored glycolysis and nuclear maturation to control levels, and PPP to above the control level. There were no significant differences among meiotic stages relative to glycolytic activity. PPP activity was significantly different (values with different superscripts; P < 0.05) among oocytes of different meiotic stages (germinal vesicle = 0.24 ± 0.03ad, germinal vesicle breakdown = 0.40 ± 0.05bcde, condensed chromatin = 0.44 ± 0.05bcd, metaphase I = 0.45 ± 0.12abcd, anaphase = 0.76 ± 0.50abcde, telophase = 0.92 ± 0.17be, metaphase II = 0.74 ± 0.08be). Percentages of oocytes reaching MII were 43.48 (control), 2.08 (DPI), 28.30 (NADP), 18.18 (PRPP), and 46.94 (R5P). These results demonstrate that the PPP is a critical control mechanism for nuclear maturation of porcine oocytes, as inhibition of this metabolic pathway resulted in arrest of nuclear maturation. Addition of PPP cofactors or end products to the arresting medium led to reversal of inhibition as demonstrated by restoration of PPP activity resulting in nuclear maturation. Table 1. Meiotic stage, glycolysis, and pentose phosphate pathway activity after in vitro maturation of porcine oocytes

scholarly journals 287 INHIBITION OF THE PENTOSE PHOSPHATE PATHWAY RESULTS IN MEIOTIC ARREST IN PORCINE OOCYTES THAT CAN BE OVERCOME BY THE ADDITION OF PATHWAY COFACTORS AND END PRODUCTS

2005 ◽  
Vol 17 (2) ◽  
pp. 293 ◽  
Author(s):  
R. Krisher
Keyword(s):  
Glucose Metabolism ◽  
Pentose Phosphate Pathway ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Pentose Phosphate ◽  
Meiotic Maturation ◽  
Dependent Manner ◽  
Meiotic Arrest ◽  
Immature Oocytes ◽  
Maturation Medium ◽  
End Products

Glucose metabolism is an indicator of oocyte developmental competence, and is also correlated with meiotic maturation. In vitro maturation of porcine oocytes with the pentose phosphate pathway (PPP) inhibitor diphenyleneiodonium (DPI) blocks meiotic progression to metaphase II. The objectives of this study were (1) to examine the reversibility of meiotic arrest induced by DPI; and (2) to overcome metabolically induced meiotic arrest by the addition of PPP end products and cofactors downstream of DPI inhibition. Oocytes were matured for 40 h in standard (defined) maturation media containing 0, 25, 50, or 100 nM DPI. At that time half the oocytes in each treatment (TRT) were fixed, and half were moved into standard maturation medium with no DPI for an additional 40 h, at which time all remaining oocytes were fixed. Two oocytes were matured for 40 h in one of 11 media: standard (defined) maturation medium (STND), standard with 50 nM DPI (DPI), standard with 50 nM DPI and 0.25, 2.5, or 5 mM phosphoribose diphosphate (PRPP), nicotinamide adenine dinucleotide phosphate (NADP), or ribose-5-phosphate (R5P). Additionally, 10 mM R5P and 12.5 mM PRPP were examined. All oocytes were fixed. Oocytes were assigned a meiotic score; germinal vesicle (GV) = 1, GV breakdown (GVBD) = 2, condensed chromatin (CC) = 3, metaphase I (MI) = 4, anaphase (A) = 5, telophase (T) = 6, and metaphase II (MII) = 7. Immature oocytes were classified as those at GV or GVBD stages, and mature oocytes as those at A, T or MII stages. Data were analyzed by ANOVA and are presented as mean ± SEM. After 40 h of arrest (n = 79–87/TRT), increasing concentrations of DPI significantly increased the % of immature oocytes (0, 7.2 ± 2.9; 25, 26.4 ± 4.8; 50, 53.2 ± 5.7; 100, 75.9 ± 4.8) and decreased the % of mature oocytes (0, 73.5 ± 4.9; 25, 52.9 ± 5.4; 50, 20.3 ± 4.6; 100, 0). After an additional 40 hours in standard maturation medium (n = 89–93/TRT), there was no difference in the % of immature oocytes between treatments (0, 7.5 ± 2.8; 25, 14.4 ± 3.7; 50, 13.0 ± 3.5; 100, 9.0 ± 3.0) although the % of mature oocytes significantly decreased with increasing DPI concentration (0, 90.3 ± 3.1; 25, 68.9 ± 4.9; 50, 35.9 ± 5.0; 100, 10.1 ± 3.2). Data from experiment 2 are presented below. Meiotic maturation is significantly inhibited by DPI in a dose-dependent manner. Ability of the oocyte to reach MII following 40 h of arrest is also concentration-dependent, although all treatments resulted in GVBD following removal from DPI. Metabolic arrest can be overcome, resulting in numbers of mature oocytes equal to standard controls, by NADP and PRPP but only moderately by R5P. These data demonstrate that glucose metabolism via the PPP is a critical control mechanism of meiotic maturation in porcine oocytes. Table 1. Effect of PPP cofactors and end products on overcoming metabolically induced meiotic arrest in porcine oocytes

scholarly journals Theoretical Analysis of the Built-in Metabolic Pathway Effect on the Metabolism of Erythrocyte-Bioreactors That Neutralize Ammonium

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 36
Author(s):  
Evgeniy Protasov ◽  
Larisa Koleva ◽  
Elizaveta Bovt ◽  
Fazoil I. Ataullakhanov ◽  
Elena Sinauridze
Keyword(s):  
Steady State ◽  
Glutamate Dehydrogenase ◽  
Pentose Phosphate Pathway ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Pentose Phosphate ◽  
Nicotinamide Adenine ◽  
Limiting Factor ◽  
Glutamate Dehydrogenase Activity ◽  
Reduced Nicotinamide Adenine Dinucleotide

The limitations of the efficiency of ammonium-neutralizing erythrocyte-bioreactors based on glutamate dehydrogenase and alanine aminotransferase reactions were analyzed using a mathematical model. At low pyruvate concentrations in the external medium (below about 0.3 mM), the main limiting factor is the rate of pyruvate influx into the erythrocyte from the outside, and at higher concentrations, it is the disappearance of a steady state in glycolysis if the rate of ammonium processing is higher than the critical value (about 12 mM/h). This rate corresponds to different values of glutamate dehydrogenase activity at different concentrations of pyruvate in plasma. Oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) by glutamate dehydrogenase decreases the fraction of NADPH in the constant pool of nicotinamide adenine dinucleotide phosphates (NADP + NADPH). This, in turn, activates the pentose phosphate pathway, where NADP reduces to NADPH. Due to the increase in flux through the pentose phosphate pathway, stabilization of the ATP concentration becomes impossible; its value increases until almost the entire pool of adenylates transforms into the ATP form. As the pool of adenylates is constant, the ADP concentration decreases dramatically. This slows the pyruvate kinase reaction, leading to the disappearance of the steady state in glycolysis.

scholarly journals The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH

Metabolites ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 285 ◽  
Author(s):  
Khalid O. Alfarouk ◽  
Samrein B. M. Ahmed ◽  
Robert L. Elliott ◽  
Amanda Benoit ◽  
Saad S. Alqahtani ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Cancer Cells ◽  
Intracellular Ph ◽  
Pentose Phosphate Pathway ◽  
Cellular Proliferation ◽  
Defense Mechanism ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Pentose Phosphate ◽  
Reduced Form ◽  
The Warburg Effect

The Pentose Phosphate Pathway (PPP) is one of the key metabolic pathways occurring in living cells to produce energy and maintain cellular homeostasis. Cancer cells have higher cytoplasmic utilization of glucose (glycolysis), even in the presence of oxygen; this is known as the “Warburg Effect”. However, cytoplasmic glucose utilization can also occur in cancer through the PPP. This pathway contributes to cancer cells by operating in many different ways: (i) as a defense mechanism via the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) to prevent apoptosis, (ii) as a provision for the maintenance of energy by intermediate glycolysis, (iii) by increasing genomic material to the cellular pool of nucleic acid bases, (iv) by promoting survival through increasing glycolysis, and so increasing acid production, and (v) by inducing cellular proliferation by the synthesis of nucleic acid, fatty acid, and amino acid. Each step of the PPP can be upregulated in some types of cancer but not in others. An interesting aspect of this metabolic pathway is the shared regulation of the glycolytic and PPP pathways by intracellular pH (pHi). Indeed, as with glycolysis, the optimum activity of the enzymes driving the PPP occurs at an alkaline pHi, which is compatible with the cytoplasmic pH of cancer cells. Here, we outline each step of the PPP and discuss its possible correlation with cancer.

scholarly journals p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Derek A. Franklin ◽  
Yizhou He ◽  
Patrick L. Leslie ◽  
Andrey P. Tikunov ◽  
Nick Fenger ◽  
...  
Keyword(s):  
Dna Repair ◽  
Pentose Phosphate Pathway ◽  
Pentose Phosphate ◽  
Nucleotide Synthesis
Sign in / Sign up

Export Citation Format

Share Document