scholarly journals Energy-modulating vitamins – a new combinatorial therapy prevents cancer cachexia in rat mammary carcinoma

2005 ◽  
Vol 93 (6) ◽  
pp. 901-909 ◽  
Author(s):  
Selvanathan Saravana Perumal ◽  
Palanivelu Shanthi ◽  
Panchanadham Sachdanandam
Keyword(s):  
Body Weight ◽  
Energy Metabolism ◽  
Oxidative Phosphorylation ◽  
Oral Administration ◽  
Cancer Cells ◽  
Mammary Carcinoma ◽  
Cancer Cachexia ◽  
Krebs Cycle ◽  
Mitochondrial Enzymes ◽  
Atp Production

Mitochondria are the major intracellular organelles producing ATP molecules via the electron transport chain. Cancer cells have a deviant energy metabolism, and a high rate of glycolysis is related to a high degree of dedifferentiation and proliferation. The overall net ATP production is diminished with cancer, which ultimately leads to cancer cachexia. The present study was designed to investigate the altered energy metabolism in cancer cells and to enhance ATP production in the normal host cell metabolism by enhancing the activities of mitochondrial enzymes, using energy-modulating vitamins, and thus prevent cancer cachexia. Female Sprague–Dawley rats were selected for the experimental study. Mammary carcinoma was induced by the oral administration of 7,12-dimethylbenz[a]anthracene (25 mg/kg body weight), and treatment was started by the oral administration of the energy-modulating vitamins riboflavin (45 mg/kg body weight per d), niacin (100 mg/kg body weight per d) and coenzyme Q10(40 mg/kg body weight per d) for 28 d. Mitochondria were isolated from the mammary gland and liver of all four groups, and the Krebs cycle and oxidative phosphorylation enzymes were assayed. In mammary carcinoma-bearing animals, the activities of the Krebs cycle and oxidative phosphorylation enzymes were significantly decreased. These activities were restored to a greater extent in animals treated with energy-modulating vitamins. From these experimental results, one may hypothesize that the combination therapy of energy-modulating vitamins could be of major therapeutic value in breast cancer.

scholarly journals Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes

2020 ◽  
Vol 295 (24) ◽  
pp. 8331-8347 ◽  
Author(s):  
Martin Zoltner ◽  
Gustavo D. Campagnaro ◽  
Gergana Taleva ◽  
Alana Burrell ◽  
Michela Cerone ◽  
...  
Keyword(s):  
Early Stage ◽  
Krebs Cycle ◽  
Protozoan Parasite ◽  
Surface Glycoprotein ◽  
Mitochondrial Enzymes ◽  
East African ◽  
Compensatory Mechanisms ◽  
Invariant Surface ◽  
African Trypanosomes ◽  
Atp Production

Introduced about a century ago, suramin remains a frontline drug for the management of early-stage East African trypanosomiasis (sleeping sickness). Cellular entry into the causative agent, the protozoan parasite Trypanosoma brucei, occurs through receptor-mediated endocytosis involving the parasite's invariant surface glycoprotein 75 (ISG75), followed by transport into the cytosol via a lysosomal transporter. The molecular basis of the trypanocidal activity of suramin remains unclear, but some evidence suggests broad, but specific, impacts on trypanosome metabolism (i.e. polypharmacology). Here we observed that suramin is rapidly accumulated in trypanosome cells proportionally to ISG75 abundance. Although we found little evidence that suramin disrupts glycolytic or glycosomal pathways, we noted increased mitochondrial ATP production, but a net decrease in cellular ATP levels. Metabolomics highlighted additional impacts on mitochondrial metabolism, including partial Krebs' cycle activation and significant accumulation of pyruvate, corroborated by increased expression of mitochondrial enzymes and transporters. Significantly, the vast majority of suramin-induced proteins were normally more abundant in the insect forms compared with the blood stage of the parasite, including several proteins associated with differentiation. We conclude that suramin has multiple and complex effects on trypanosomes, but unexpectedly partially activates mitochondrial ATP-generating activity. We propose that despite apparent compensatory mechanisms in drug-challenged cells, the suramin-induced collapse of cellular ATP ultimately leads to trypanosome cell death.

scholarly journals p53-inducible DPYSL4 associates with mitochondrial supercomplexes and regulates energy metabolism in adipocytes and cancer cells

2018 ◽  
Vol 115 (33) ◽  
pp. 8370-8375 ◽  
Author(s):  
Hidekazu Nagano ◽  
Naoko Hashimoto ◽  
Akitoshi Nakayama ◽  
Sawako Suzuki ◽  
Yui Miyabayashi ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Immunohistochemical Analysis ◽  
Cellular Functions ◽  
Atp Production ◽  
Chip Sequencing ◽  
Metastasis Models ◽  
Tumor Growth And Metastasis

The tumor suppressor p53 regulates multiple cellular functions, including energy metabolism. Metabolic deregulation is implicated in the pathogenesis of some cancers and in metabolic disorders and may result from the inactivation of p53 functions. Using RNA sequencing and ChIP sequencing of cancer cells and preadipocytes, we demonstrate that p53 modulates several metabolic processes via the transactivation of energy metabolism genes including dihydropyrimidinase-like 4 (DPYSL4). DPYSL4 is a member of the collapsin response mediator protein family, which is involved in cancer invasion and progression. Intriguingly, DPYSL4 overexpression in cancer cells and preadipocytes up-regulated ATP production and oxygen consumption, while DPYSL4 knockdown using siRNA or CRISPR/Cas9 down-regulated energy production. Furthermore, DPYSL4 was associated with mitochondrial supercomplexes, and deletion of its dihydropyrimidinase-like domain abolished its association and its ability to stimulate ATP production and suppress the cancer cell invasion. Mouse-xenograft and lung-metastasis models indicated that DPYSL4 expression compromised tumor growth and metastasis in vivo. Consistently, database analyses demonstrated that low DPYSL4 expression was significantly associated with poor survival of breast and ovarian cancers in accordance with its reduced expression in certain types of cancer tissues. Moreover, immunohistochemical analysis using the adipose tissue of obese patients revealed that DPYSL4 expression was positively correlated with INFg and body mass index in accordance with p53 activation. Together, these results suggest that DPYSL4 plays a key role in the tumor-suppressor function of p53 by regulating oxidative phosphorylation and the cellular energy supply via its association with mitochondrial supercomplexes, possibly linking to the pathophysiology of both cancer and obesity.

scholarly journals Potent Anticancer Effect of the Natural Steroidal Saponin Gracillin Is Produced by Inhibiting Glycolysis and Oxidative Phosphorylation-Mediated Bioenergetics

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 913 ◽  
Author(s):  
Hye-Young Min ◽  
Honglan Pei ◽  
Seung Yeob Hyun ◽  
Hye-Jin Boo ◽  
Hyun-Ji Jang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Anticancer Agent ◽  
Aerobic Glycolysis ◽  
Cancer Cell Line ◽  
Steroidal Saponin ◽  
Antitumor Effects ◽  
Metabolic Switch ◽  
Atp Production

Metabolic rewiring to utilize aerobic glycolysis is a hallmark of cancer. However, recent findings suggest the role of mitochondria in energy generation in cancer cells and the metabolic switch to oxidative phosphorylation (OXPHOS) in response to the blockade of glycolysis. We previously demonstrated that the antitumor effect of gracillin occurs through the inhibition of mitochondrial complex II-mediated energy production. Here, we investigated the potential of gracillin as an anticancer agent targeting both glycolysis and OXPHOS in breast and lung cancer cells. Along with the reduction in adenosine triphosphate (ATP) production, gracillin markedly suppresses the production of several glycolysis-associated metabolites. A docking analysis and enzyme assay suggested phosphoglycerate kinase 1 (PGK1) is a potential target for the antiglycolytic effect of gracillin. Gracillin reduced the viability and colony formation ability of breast cancer cells by inducing apoptosis. Gracillin displayed efficacious antitumor effects in mice bearing breast cancer cell line or breast cancer patient-derived tumor xenografts with no overt changes in body weight. An analysis of publicly available datasets further suggested that PGK1 expression is associated with metastasis status and poor prognosis in patients with breast cancer. These results suggest that gracillin is a natural anticancer agent that inhibits both glycolysis and mitochondria-mediated bioenergetics.

scholarly journals Extracellular citrate and metabolic adaptations of cancer cells

2021 ◽  
Author(s):  
E. Kenneth Parkinson ◽  
Jerzy Adamski ◽  
Grit Zahn ◽  
Andreas Gaumann ◽  
Fabian Flores-Borja ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Immune Cells ◽  
Warburg Effect ◽  
Cancer Metabolism ◽  
Krebs Cycle ◽  
Therapy Resistance ◽  
Tumour Microenvironment ◽  
The Warburg Effect

Abstract It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.

Glutamine and glucose metabolism in thymocytes from normal and spontaneously diabetic BB rats

1991 ◽  
Vol 69 (12) ◽  
pp. 801-808 ◽  
Author(s):  
Guoyao Wu ◽  
Catherine J. Field ◽  
Errol B. Marliss
Keyword(s):  
Energy Metabolism ◽  
Krebs Cycle ◽  
Major Product ◽  
Lymphoid Organs ◽  
Glutamine Metabolism ◽  
Potential Production ◽  
Atp Production ◽  
Bb Rats ◽  
Oxidation Of Glucose ◽  
Diabetic Syndrome

Metabolism of glutamine and glucose was studied in thymocytes from normal rats and BB rats with the spontaneous autoimmune diabetic syndrome to assess their potential roles as fuels. The major measured products from glucose were lactate and, to a lesser extent, CO2, and pyruvate. Glutamine had no effect on the rates of their production from glucose. Glutamine was metabolized to ammonia, aspartate, glutamate, and CO2, with aspartate being the major product of carbons from glutamine in the absence of glucose. Glucose markedly decreased the formation of ammonia, aspartate, and CO2 from glutamine, but increased that of glutamate, with an overall decrease in glutamine utilization by 55%. More glutamate than aspartate was produced from glutamine in the presence of glucose. The potential production of ATP from glucose was similar to that when glutamine was present alone. However, glucose markedly decreased production of ATP from glutamine, but not vice versa. This resulted in ATP production from glucose being 2.5 times that from glutamine when both substrates were present. The oxidation of glucose to CO2 via the Krebs cycle accounts for 75–80% of glucose-derived ATP production. Cellular ATP levels markedly decreased in the absence of exogenous substrates, but were constant throughout a 2-h incubation in the presence of glutamine, glucose, or both. There were no differences in thymocyte glucose or glutamine metabolism between normal and diabetic BB rats, in contrast to previous findings in peripheral lymphoid organs. Our results suggest that glucose is a more important fuel than glutamine for "resting" thymocytes, again in contrast to the cells of peripheral lymphoid organs in which glutamine is as important as glucose as a fuel. The enhanced energy metabolism found in the cells from peripheral lymphoid organs of diabetic BB rats, if due to T-lymphocytes, must occur after their migration out of the thymus.Key words: glutaminolysis, glycolysis, thymocytes, ATP, BB rats.

scholarly journals Disruption of Glycolysis, TCA Cycle, Respiratory Chain, Calcium and Iron Homeostasis in Doxorubicin Induced Cardiomyopathy-An In-silico Approach

2021 ◽  
Vol 12 (6) ◽  
pp. 8527-8542
Keyword(s):  
Energy Metabolism ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Krebs Cycle ◽  
Atp Depletion ◽  
Critical Function ◽  
Free Iron ◽  
Atp Production ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

Doxorubicin is a well-known anthracycline antibiotic that is frequently used to treat a variety of malignancies. However, its clinical use is limited due to its adverse consequences, most notably cardiomyopathy. In the present work, we evaluated the molecular mechanisms behind the impairment of cardiac energetics in doxorubicin-induced cardiomyopathy. According to molecular docking, the interaction of doxorubicin with phosphofructokinase (PKF) and α-enolase is likely to negatively affect glycolysis. The interaction between doxorubicin with HMOX1 results in the accumulation of free iron. The free iron contributes to the heme-driven toxicity and the oxidizing environment that results in reactive oxygen species (ROS) production resulting from cell death. Additionally, the interaction of doxorubicin with HMOX1 impairs the availability of iron required for the Krebs cycle and ETC function. The interaction between doxorubicin and PINK1 results in a reduced membrane potential, which results in calcium accumulation. On the other hand, a lack of iron and calcium in the mitochondrial matrix results in ATP depletion, impairing the Krebs cycle activity. At the same time, the primary cause of doxorubicin-induced cardiomyopathy is cardiac energy metabolism. Thus, our work shows that doxorubicin impairs the activity of PFK, α-enolase, HMOX1, and PINK1, resulting in ATP production failure. As a result of changes in the heart energy metabolism, this ultimately leads to dilated cardiomyopathy caused by doxorubicin. Understanding the critical function of cardiac energy metabolism in doxorubicin-induced cardiomyopathy is critical for overcoming the obstacles that effectively limit the clinical effectiveness of this life-saving anti-cancer treatment.

scholarly journals Energy Metabolism Decline in the Aging Brain; Pathogenesis of Neurodegenerative Disorders

2020 ◽  
Author(s):  
Janusz Błaszczyk
Keyword(s):  
Energy Metabolism ◽  
Neurodegenerative Diseases ◽  
Krebs Cycle ◽  
Brain Structures ◽  
The Elderly ◽  
Review Article ◽  
Aging Brain ◽  
Salvage Pathway ◽  
Atp Production ◽  
The Brain

A growing body of evidence indicates that aging of the brain is strictly related to the decline of energy metabolism. In particular, in older adults, the neuronal metabolism of glucose declines steadily resulting in a growing deficit of ATP production. The decline is evoked by deficient NAD recovery in the salvage pathway and subsequent impairment of the Krebs cycle. NAD deficit impairs also the activity of NAD-dependent enzymes. All these open vicious circles of neurodegeneration and neuronal death. Some brain structures are particularly prone to aging and neurodegeneration. These are pathological foci of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. This review article summarizes the impacts and mutual relationships between metabolic processes both on neuronal and brain levels. It also provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases.

scholarly journals Laboratory Yeast Strains Rely On Oxidative Phosphorylation For Efficient ATP Production

2021 ◽  
Author(s):  
Akshay Moharir ◽  
Lincoln Gay ◽  
Markus Babst
Keyword(s):  
Plasma Membrane ◽  
Oxygen Consumption ◽  
Energy Metabolism ◽  
Oxidative Phosphorylation ◽  
Atp Synthase ◽  
High Glucose ◽  
Anaerobic Conditions ◽  
Atp Production ◽  
Yeast Strains ◽  
Biological Studies

AbstractEven though it is a well-accepted fact that the energy metabolism of yeast is likely to impact all cellular activities, surprising little is known about the ATP homeostasis of particular yeast strains that are commonly used in cell biological studies. Therefore, we determined key parameters such as oxygen consumption and fermentation rates of the lab strain SEY6210. Our data indicated that even at high glucose concentrations, SEY6210 produces 30-50% of cellular ATP from oxidative phosphorylation. Loss of respiration, either by disrupting ATP synthase function or by growth in anaerobic conditions, was not fully compensated by fermentation and as a result affected energy intensive processes such as the maintenance of the plasma membrane proton gradient and the associated import of nutrients.

scholarly journals Gibbs Free Energy of Protein-Protein Interactions Correlates with ATP Production in Cancer Cells

2018 ◽  
Author(s):  
Stefan M. Golas ◽  
Amber N. Nguyen ◽  
Edward A. Rietman ◽  
Jack A. Tuszynski
Keyword(s):  
Free Energy ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Gibbs Free Energy ◽  
Protein Interaction ◽  
Interaction Network ◽  
Inverse Correlation ◽  
Metabolic Shift ◽  
Atp Production ◽  
Protein Protein Interaction

In this paper we analyze several cancer cell types from two seemingly independent angles: (a) the over-expression of various proteins participating in protein-protein interaction networks and (b) a metabolic shift from oxidative phosphorylation to glycolysis. We use large data sets to obtain a thermodynamic measure of the protein-protein interaction network, namely the associated Gibbs free energy. We find a reasonably strong inverse correlation between the percentage of energy production via oxidative phosphorylation and the Gibbs free energy of the protein networks. The latter is a measure of functional dysregulation within the cell. Our findings corroborate earlier indications that signaling pathway upregulation in cancer cells are linked to the metabolic shift known as the Warburg effect, hence these two seemingly independent characteristics of cancer phenotype may be interconnected.

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