Glutamate and Cancer

January 27, 2011, Featured in Cancer and Natural Medicines, 0 Comments

We have already discussed the issues in other blogs about glutamine, and we already know that glutamine, converted to glutamate in the body, can stimulate growth of tumors.

Glutamine may actually stimulate growth of tumors.

High concentrations of oral glutamine also produce high amounts of glutamate in the blood, a breakdown product of glutamine. Glutamate is a key molecule in cellular metabolism and is the most common neurotransmitter in the brain. It is particularly abundant in the nervous system. The most common excitatory neurotransmitters are glutamate and aspartate while the primary inhibitory neurotransmitter is GABA. It is necessary for excitatory and inhibitory neurotransmitters to be in balance for proper brain function to occur. Glutamate receptors are responsible for the glutamate-mediated post-synaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

Glutamate is also elevated in cancer patients, and several authors have shown that elevated extracellular glutamate levels inhibit competitively the membrane transport of cystine and cause a decrease of intracellular cysteine. A study shows that patients with lung cancer with the lowest glutamate levels had the highest survival rates. They also had the highest cysteine levels. Cysteine – a sulfur containing amino acid – is used to make glutathione as well as taurine – the body’s natural water soluble anti-oxidant. This finding suggests that glutamate may interfere with cysteine and glutathione production in the body.

Glutamate regulates proliferation and migration of neurons during development. Also, glutamate appears to play a central role in the malignant phenotype of glioma via multiple mechanisms. By binding to peritumoral neuronal glutamate receptors, glutamate is responsible for seizure induction and similarly causes excitotoxicity, which aids the expansion of tumor cells into the space vacated by destroyed tissue. Glutamate also activates ionotropic and metabotropic glutamate receptors on glioma cells in a paracrine and autocrine manner.

Glutamate also influences proliferation, migration and invasion of tumor cells. A study demonstrated that glutamate antagonists inhibit tumor growth. Glutamate antagonists apparently also inhibit cancer cell migration and so may be useful in preventing cells from proliferating throughout the body. One has to ask the nagging question, then – If blocking glutamate can cause cancer cells to die and stop migrating, shouldn’t cancer patients stop eating MSG (monosodium glutamate) and aspartame? Unfortunately, patients suffering from cancer are rarely, if ever told this information.

MSG is adding flavor to your food, but if you’re consuming a diet with glutamate in it, particularly high levels, you’re making your cancer grow very rapidly. We refer to it as cancer fertilizer. The cancers of this type include several brain cancers, colon cancer, breast cancer, pancreatic cancer and others as well. When you increase the glutamate level, cancer just grows like wildfire, and then when you block glutamate, it dramatically slows the growth of the cancer. Aspartame is the second most widely used artificial sweetener in the world ans is a multipotential carcinogenic compound. In fact, when cancer cells were exposed to aspartame, they became more mobile, and you see the same effect with MSG.

Glutamine and glutamate–their central role in cell metabolism and function. 

Targeting glutamine metabolism sensitizes melanoma cells to TRAIL-induced death. 

T4+ cell numbers are correlated with plasma glutamate and cystine levels: association of hyperglutamataemia with immunodeficiency in diseases with different aetiologies. 

Glutamate and the biology of gliomas. 

A role for glutamate in growth and invasion of primary brain tumors. 

Glutamate increases pancreatic cancer cell invasion and migration via AMPA receptor activation and Kras-MAPK signaling.

Glutamate receptor-mediated effects on growth and morphology of human histiocytic lymphoma cells. 

Glutamate antagonists limit tumor growth. 

Aspartame administered in feed, beginning prenatally through life span, induces cancers of the liver and lung in male Swiss mice. 

First experimental demonstration of the multipotential carcinogenic effects of aspartame administered in the feed to Sprague-Dawley rats.

In addition to its extracellular roles as a neurotransmitter, glutamate serves important intracellular signaling functions via its metabolism through glutamate dehydrogenase (GDH). GDH is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate. Glutamate, which already induces insulin release from the pancreas, is turned into GABA in the body. GABA causes the pituitary to release growth hormone – not a good thing if you have cancer. Also, insulin can stimulate the growth of cancer cells as well. Cancer cells actually manufacture and secrete their own insulin. Related to this insulin secretion is the even more interesting fact that cancer cells have ten times more insulin receptors per cell than any of the normal cells in the body. The metabolic modifications by insulin results from the fact that not only can it join up with its own specific receptors on cell membranes, but insulin is also able to join up with the receptors for insulin-like growth-factor, and to communicate messages about growth to these cells.

The growth of blood vessels is the trouble when there is tumor growth. Angiogenesis, the formation of new blood vessels, is a multi-step process regulated by pro- and anti-angiogenic factors. In order to grow and metastasize, tumors need a constant supply of oxygen and nutrients. For their growth beyond the size of 1-2 mm tumors are dependent on angiogenesis. Well – elevated levels of GABA and glutamate are present in people with diabetic retinopathy (damage to the eyes). Vascular endothelial growth factor (VEGF) is at work here too.

Glutaminolysis and insulin secretion: from bedside to bench and back. 

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets. 

Overexpression of constitutively activated glutamate dehydrogenase induces insulin secretion through enhanced glutamate oxidation. 

Expression of the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs) in human gastric cancer cells. 

Elevated gamma-aminobutyric acid, glutamate, and vascular endothelial growth factor levels in the vitreous of patients with proliferative diabetic retinopathy.

Theanine is an amino acid found in green tea. Theanine is a glutamate receptor antagonist and has been shown to decrease brain norepinephrine (NE) levels secondarily to increasing GABA levels. It is capable of blocking the uptake of the amino acid glutamate into cells. This inhibits something called the glutamate/cystine antiporter (xCT) resulting in a reduction in the reducing agent glutathione in the cancer cells. This makes the cancer cells very sensitive to the waste products they generate. Wolfberries (Lycium barbarum) are also believed to be quite potent as a glutamate antagonist. Wolfberry (Lycium barbarum) is a common ingredient in oriental cuisines.

The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. 

L-theanine protects the APP (Swedish mutation) transgenic SH-SY5Y cell against glutamate-induced excitotoxicity via inhibition of the NMDA receptor pathway. 

Theanine, gamma-glutamylethylamide, a unique amino acid in tea leaves, modulates neurotransmitter concentrations in the brain striatum interstitium in conscious rats. 

Theanine, an ingredient of green tea, inhibits [3H]glutamine transport in neurons and astroglia in rat brain. 

l-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. 

Polysaccharides from wolfberry antagonizes glutamate excitotoxicity in rat cortical neurons.

Radix Stephaniae tetrandrae, generally known as “Fangji”in Chinese, is the dry root of Stephaniae tetrandra S. Moore (Menispermaceae). This plant is often used in Chinese traditional medicine because its main components fangchinoline and tetrandrine show a lot of pharmacological activities including anti-allergic, anti-inflammatory, anti-hyperglycemic and anti-cancer activities. Fangchinoline has been shown to possess neuroprotective properties. Findings from an animal study suggest that fangchinoline inhibits glutamate release from the cortical synaptosomes through the suppression of voltage-dependent Ca(2+) channel activity and subsequent reduces Ca(2+) entry into nerve terminals, rather than any upstream effect on nerve terminal excitability.

Fangchinoline inhibits glutamate release from rat cerebral cortex nerve terminals (synaptosomes). 

Anti-inflammatory effects of the partially purified extract of radix Stephaniae tetrandrae: comparative studies of its active principles tetrandrine and fangchinoline on human polymorphonuclear leukocyte functions. 

Anti-inflammatory effects of fangchinoline and tetrandrine.

Inhibitory effects of bisbenzylisoquinoline alkaloids on induction of proinflammatory cytokines, interleukin-1 and tumor necrosis factor-alpha. 

Anti-hyperglycemic effect of fangchinoline isolated from Stephania tetrandra Radix in streptozotocin-diabetic mice.

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