RECOMMENDED CANCER, STARVING DIET, MACROPHAGES

Highlites of Seyfried 2014 Plus 2 more articles

Highlites of Seyfried 2014, at /id4, previous page

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3941741/

Cancer as a metabolic disease: implications for novel therapeutics
Seyfried & D’Agostino 2014

Experiment showing that mDNA is the essential transformation leading to cancer. The tumorigenic phenotype is suppressed when normal mitochondria are transferred to the tumor cell cytoplasm. On the other hand, the tumorigenic phenotype is enhanced when tumor mitochondria are transferred to a normal cell cytoplasm. These findings further suggest that tumorigenesis is dependent more on mitochondrial function than on the types of mutations in the nucleus.

Unique process of lactic acid fermentation in presence of oxygen It is important to recognize that pyruvate is produced through aerobic glycolysis in most normal cells of the body that use glucose for energy. The reduction of pyruvate to lactate distinguishes the tumor cells from most normal cells, which fully oxidize pyruvate to CO₂ and water for adenosine triphosphate (ATP) production through the tricarboxylic acid (TCA) cycle and the electron transport chain chain (56). Aerobic glycolysis with lactate production can occur in normal retina though more ATP is produced through respiration than through glycolysis, as is the case in most respiring tissues (72). On the other hand, enhanced aerobic glycolysis without significant lactate production or energy through fermentation can occur in normal cardiac and brain tissues under conditions of increased activity (73–75). The slight transient increase in lactate production under these conditions is not associated with a significant increase in total energy production. As enhanced aerobic glycolysis does not produce significant lactate in normal cells under well-oxygenated conditions, a phenotype of enhanced aerobic glycolysis is therefore not synonymous with a Warburg effect.

ROS causes the mDNA mutations causing anaerobic metabolism Evidence indicates that a persistent retrograde response or mitochondrial stress response leads to abnormalities in DNA repair mechanisms and to the upregulation of fermentation pathways

Both function and structures are caused by those mutations Tumor cells can have abnormalities in both the content and composition of their mitochondria… Tumor cells can have abnormalities in both the content and composition of their mitochondriam. The high glycolytic activity and lactate production seen in the most malignant tumors were also linked to the mitochondrial structural abnormalities seen in the tumors.

Restriction to mainly relying on lactic acid fermentation is a target for therapy As glucose is the major fuel for tumor energy metabolism through lactate fermentation, the restriction of glucose becomes a prime target for management. However, most normal cells of the body also need glycolytic pathway products, such as pyruvate, for energy production through OxPhos.….. Hence, metabolic stress will be greater in tumor cells than in normal cells when the whole body is transitioned away from glucose and to ketone bodies for energy.

Hyperbolic oxygen as adjunct therapy Poff et al. also recently showed a synergistic interaction between the KD and hyperbaric oxygen therapy (HBO₂T) (Figure 6).

Three reasons why if cancer used ketone bodies, they wouldn’t be cancer The metabolic shift from glucose metabolism to ketone body metabolism creates an anti-angiogenic, anti-inflammatory and pro-apoptotic environment within the tumor mass (192,195–199).

Oncogenes upregulation (being turned on) promotes fermentation Oncogene upregulation becomes essential for increased glucose and glutamine metabolism following respiratory impairment.

The metabolic waste products of fermentation can destabilize the morphogenetic field of the tumor microenvironment thus contributing to inflammation, angiogenesis and progression; the somatic mutations arise as effects rather than as causes of tumorigenesis

Figure 5 shows that with the production of ketone bodies on day 3 of fast is there a decline in tumor growth

Don’t need drugs which target metabolic pathways when fasting. Dietary energy reduction will simultaneously target multiple metabolic signaling pathways without causing adverse effects or toxicity (208)

Insulin (IGF( stimulates cancer growth. Dietary energy reduction will simultaneously target multiple metabolic signaling pathways without causing adverse effects or toxicity (208).

A dependency on glucose and an inability to use ketones for energy makes tumor cells selectively vulnerable to this therapy. A dependency on glucose and an inability to use ketones for energy makes tumor cells selectively vulnerable to this therapy.

Treated animals showed less bioluminescence than controls with KD + HBO₂T mice exhibiting a profound decrease in tumor bioluminescence compared with all groups.

Many metastatic cancers express multiple characteristics of macrophages (146,218). Glutamine is a major fuel of macrophages and other cells of the immune system (146,219). targeting glutamine without toxicity might be more difficult than targeting glucose (220,221)

Some of the cancer metabolic drugs could include 2-deoxyglucose, 3-bromopyruvate and dichloroacetate (56,120,225–227)

Products of the virus can damage mitochondria in the infected tumor cells, thus contributing to a further dependence on glucose and glutamine for energy metabolism (18,229–231). The virus often infects cells of monocyte/macrophage origin, which are considered the origin of many metastatic cancers (145,146,232,233). We predict that the KD-R used together with anti-viral therapy will also be an effective Press-Pulse strategy for reducing progression of those cancers infected with human cytomegalovirus (234).

The administration of ketone esters could conceivably enable patients to circumvent the dietary restriction generally required for sustained nutritional ketosis. Ketone ester-induced ketosis would make sustained hypoglycemia more tolerable and thus assist in metabolic management of cancer (235,236). We would therefore consider personalized molecular therapy as a final strategy rather than as an initial strategy for cancer management

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http://www.hopkinsmedicine.org/news/media/releases/cancer_cells_feed_on_sugar_free_diet

Cancer Cells Feed on Sugar-Free Diet

Study highlights role of glutamine in absence of glucose in growth of B cell tumors

Release Date: January 10, 2012

Cancer cells have been long known to have a “sweet tooth,” using vast amounts of glucose for energy and for building blocks for cell replication.

Now, a study by a team of researchers at Johns Hopkins and elsewhere shows that lymph gland cancer cells called B cells can use glutamine in the absence of glucose for cell replication and survival, particularly under low-oxygen conditions, which are common in tumors.

Writing in the Jan. 4, 2012, edition of Cell Metabolism, Anne Le, M.D., and a team of investigators collaborating with the Johns Hopkins Brain Science Institute, say the finding is critical for developing innovative cancer therapies because it offers “proof of concept” evidence that curbing the growth of B cell cancers can be accomplished by inhibiting a glutamine enzyme called glutaminase.

Le notes that although little is known about glutamine’s role in the growth of B cell cancer, the amino acid circulates in the blood at the highest level among the 20 amino acids that do so.

The tricarboxylic acid cycle (TCA or Krebs cycle) is classically regarded as a pathway for glucose oxidation. However, the experiments by Le and the team show that B cells oxidize glutamine when glucose is absent.

The study also found that when oxygen is scarce, there is enhanced conversion of glutamine to glutathione, an important agent for controlling the accumulation of oxygen-containing chemically reactive molecules that cause damage to normal cells.

When the investigators used a glutaminase inhibitor, cancerous growth of B cells was stopped in petri dishes.

“The flexibility of the TCA cycle in using both glutamine and glucose pathways may be important for cancer cells to proliferate and survive, especially under the low-oxygen and nutrient-deprived conditions often encountered in the tumor microenvironment,” says Le.

Now, perhaps, scientists can exploit that survival strategy to stop cancer, according to former Johns Hopkins scientist Chi Dang, M.D., now at the Abramson Cancer Center at the University of Pennsylvania. “A broader and deeper understanding of cancer cell metabolism and cancer cells’ability to reprogram biochemical pathways under metabolic stress can be a rich ground for therapeutic approaches targeting tumor metabolism,” he says.

In addition to Le, an assistant professor in the Department of Pathology at the Johns Hopkins University School of Medicine, other researchers from Johns Hopkins who participated in this study include Sminu Bose, Arvin Gouw, Joseph Barbi, Takashi Tsukamoto, Camilo J. Rojas and Barbara Slusher. The Johns Hopkins Brain Science Institute, where Tsukamoto, Rojas and Slusher are faculty, is pursuing the development of new glutaminase inhibitor drugs.

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http://www.sciencedirect.com/science/article/pii/S0005272810006857?np=y&npKey=310746908b7a234502102baaa6e227fe10024331cca44217e01857b2efa59baf

Metabolic management of brain cancer

· Thomas N. Seyfried^,,

· Michael A. Kiebish ¹,

· Jeremy Marsh ²,

· Laura M. Shelton,

· Leanne C. Huysentruyt ³,
· Purna Mukherjee

Abstract

Malignant brain tumors are a significant health problem in children and adults. Conventional therapeutic approaches have been largely unsuccessful in providing long-term management. As primarily a metabolic disease, malignant brain cancer can be managed through changes in metabolic environment. In contrast to normal neurons and glia, which readily transition to ketone bodies (β-hydroxybutyrate) for energy under reduced glucose, malignant brain tumors are strongly dependent on glycolysis for energy. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome and normal mitochondria can effectively transition from one energy state to another. Mutations restrict genomic and metabolic flexibility thus making tumor cells more vulnerable to energy stress than normal cells. We propose an alternative approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and metabolically challenged tumor cells. This approach to brain cancer management is supported from recent studies in mice and humans treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are presented for the metabolic management of brain cancer. This article is part of a Special Issue entitled: Bioenergetics of Cancer.

Research Highlights

► Most cancer, including brain cancer, is primarily a disease of energy metabolism. ► Current standards of care for brain cancer management can provoke brain cancer growth and recurrence. ► Brain tumors use glucose and glutamine as major metabolic fuels, but do not use ketone bodies. ► Non-toxic calorie restricted ketogenic diets target glucose and glutamine and are anti-angiogenic, anti-invasive, and pro-apoptotic. ► Brain cancer can be managed based on principles of evolutionary biology, metabolic control analysis, and the Warburg theory of cancer.

Abbreviations

DR, dietary restriction;
CR, caloric restriction;
KD, ketogenic diet;
RKD, calorically restricted ketogenic diet

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As required by law, I am not recommending that the public do as I do. I am only setting out why some scientist subscribe to a different theory of cancer and its treatment, and what I would do based on their theory. See your physician for medical advice.