targeting cancer metabolism: glutamin and glucose

new_direction

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845135/

Besides glucose, glutamine can also serve as a major energy metabolite for some cancers.

Numerous studies show that tumor mitochondria are structurally and functionally abnormal and incapable of generating normal levels of energy .

Cancer cells contain abnormalities in cardiolipin content or composition, which are associated with electron transport abnormalities [73]. Cardiolipin is the only lipid synthesized almost exclusively in the mitochondria.

Cardiolipin abnormalities in cancer cells can arise from any number of unspecific influences to include damage from mutagens and carcinogens, radiation, low level hypoxia, inflammation, ROS, or from inherited mutations that alter mitochondrial energy homeostasis

Hence, mitochondrial dysfunction will cause cancer cells to rely more heavily than non-cancer cells on substrate level phosphorylation for energy production.

The gene theory of cancer would argue that mitochondrial dysfunction is an effect rather than a cause of cancer, whereas the metabolic impairment theory would argue the reverse.

If, on the other hand, impaired energy metabolism is primarily responsible for cancer, then most cancers can be considered a type of metabolic disease requiring fewer and less complicated solutions.

While numerous genetic abnormalities have been described in most human cancers, no specific mutation is reliably diagnostic for any specific type of tumor [7,17,105]. On the other hand, few if any tumors are known, which express normal respiration.

Impairment of mitochondrial function can occur following prolonged injury or irritation to tissues including disruption of morphogenetic fields

The accumulation of mitochondrial damage over time is what ultimately leads to malignant tumor formation. Acquired abnormalities in mitochondrial function would produce a type of vicious cycle where impaired mitochondrial energy production initiates genome instability and mutability

In other words, the well-documented tumor-associated abnormalities in oncogenes, tumor suppressor genes, and chromosomal imbalances can arise as a consequence of the progressive impairment of mitochondrial function.

Although viral disruption of mitochondrial function will kill most cells through apoptosis following an acute infection, those infected cells that can up-regulate substrate level phosphorylation will survive and potentially produce a neoplasm following chronic infection.

It is well documented that tumorigenicity can be suppressed when cytoplasm from enucleated normal cells is fused with tumor cells to form cybrids, suggesting that normal mitochondria can suppress the tumorigenic phenotype

A persistent impairment in respiratory function will trigger the RTG response, which is necessary for up-regulating the pathways of glycolysis and glutaminolysis

Tumor cells will continue to evade apoptosis as long as they have access to glucose and glutamine

Tumor progression is linked to a greater dependence on substrate level phosphorylation, which eventually becomes irreversible.

Dietary energy restriction specifically targets the IGF-1/PI3K/Akt/HIF-1α signaling pathway, which underlies several cancer hallmarks to include cell proliferation, evasion of apoptosis, and angiogenesis [168,175,176,250,251,254,258-265]. Calorie restriction also causes a simultaneous down-regulation of multiple genes and metabolic pathways regulating glycolysis

By targeting the glycolytically active tumor cells that produce pro-cachexia molecules, restricted diet therapies can potentially reduce tumor cachexia [278,287]. These therapies could be supplemented with omega-3 fatty acids, which can also reduce the cachexia phenotype [285]. Omega-3 fatty acids from fish oil also have the benefit of maintaining low glucose while elevating ketone levels. Once the tumor becomes managed, individuals can increase caloric consumption to achieve weight gain.

Although dietary energy restriction and anti-glycolytic cancer drugs will have therapeutic efficacy against many tumors that depend largely on glycolysis and glucose for growth, these therapeutic approaches could be less effective against those tumor cells that depend more heavily on glutamine than on glucose for energy

Glutamine is a major energy metabolite for many tumor cells and especially for cells of hematopoietic or myeloid lineage [47,49,294,295]. This is important as cells of myeloid lineage are considered the origin of many metastatic cancers

Glutamine metabolism can be targeted in humans using the glutamine binding drug, phenylacetate, or the glutamine analogue DON (6-Diazo-5-oxo-L-norleucine)

Recent studies suggest that the green tea polyphenol (EGCG) could target glutamine metabolism by inhibiting glutamate dehydrogenase activity under low glucose conditions [67]. This and other glutamine-targeting strategies could be even more effective when combined with energy restricting diets, which lower glucose levels while elevating ketone bodies. Hence, effective non-toxic targeting of both glucose and glutamine metabolism should be a simple therapeutic approach for the global management of most localized and metastatic cancers.

Hence, simply reducing exposure to cancer risk factors, which produce chronic inflammation and mitochondrial damage, will reduce the incidence of at least 80% of all cancers

In addition to avoiding exposure to established cancer risk factors, the metabolism of ketone bodies protects the mitochondria

Coenzyme Q is a hydrophobic molecule that resides in the inner mitochondrial membrane and is essential for electron transfer.

It is important to emphasize adequate nutrition, as calorie restriction associated with malnutrition can potentially increase cancer incidence [301-303]. Consequently, consumption of foods containing the active groups of respiratory enzymes (iron salts, riboflavin, nicotinamide, and pantothenic acid) could be effective in maintaining health when combined with dietary energy restriction

it remains to be determined if members of our species are willing or motivated enough to adopt the life style changes necessary to prevent cancer.

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Conclusions, way of living:
Avoiding risk factors
Calorie restriction plus consuming foods of respiratory enzymes + omega 3
Green tea to target glutamin
aspirin to target glutamin
Coenzyme Q

Wikipedia:
Phenyl acetate is the ester of phenol and acetic acid. One way that it can be produced by decarboxylation of aspirin

Falconer

I read the whole piece, as I am thinking always of nutrition and health. I don't know- 7 years ago I stopped eating refined sugar. I still have fruit but limited amounts of carbs and had meats and whole grains. I'm a certified yoga teacher and have had a stable weight; except for my three pregnancies where I gained normal amounts of weight. Perhaps this bc began long before 7 years ago when I still had sugar in my diet? Ketogenic diets seem reasonable but I wish we knew if it was the true panacea for bc.