Methionine dependency of cancer cells and dietary methionine restriction

January 5, 2013, Featured in Cancer and Natural Medicines, 0 Comments

Metabolic abnormalities of tumor cells offer opportunities of therapeutic targeting. Tumor cells are more sensitive to methionine restriction than normal tissues, a phenomenon known as methionine auxotrophy. Methionine is one of the essential amino acids with many key roles in mammalian metabolism such as protein synthesis, methylation of DNA and polyamine synthesis but cannot be produced in the body, and so must be provided through our diet.

Many cancer cells and primary tumors have absolute requirements for methionine. Methionine-dependent increase in tumor cells is a specific metabolic defect. The biochemical mechanism for methionine dependency has been studied extensively, but the fundamental mechanism remains unclear. Methionine starvation can powerfully modulate DNA methylation, cell cycle transition, polyamines and antioxidant synthesis of tumor cells. Therefore, low methionine in the diet may be an important strategy in cancer growth control particularly in breast, colon, prostate, lung and a host of other cancers that exhibit dependence on methionine for survival and proliferation. In contrast, normal cells are relatively resistant to exogenous methionine restriction.

A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension.

Targeting methionine auxotrophy in cancer: discovery & exploration.

Methionine dependency and cancer treatment.

Methionine restriction selectively targets thymidylate synthase in prostate cancer cells.

Induction of caspase-dependent and -independent apoptosis in response to methionine restriction.

Nutrient intake and nutritional indexes in adults with metastatic cancer on a phase I clinical trial of dietary methionine restriction.

Can dietary methionine restriction increase the effectiveness of chemotherapy in treatment of advanced cancer?

Antisense inhibition of methylenetetrahydrofolate reductase reduces cancer cell survival in vitro and tumor growth in vivo.

The vegan diet (which includes no animal products) is low in methionine. The methionine content of plant proteins tends to be lower than those of animal proteins. For instance, wheat and potatoes have about four times less methionine than eggs and chicken respectively. Furthermore, low-fat vegan diets, coupled with exercise training, can be expected to improve cancer treatment efficacy by decreasing systemic levels of insulin and free insulin growth factor-1 (IGF-I). The association between IGF-I and cancer risk is well established. IGF-I’s normal function is to stimulate cell division, especially during childhood development.

Furthermore, plants have a high source of glycine, an essential amino acid that serves as functional antagonist to methionine. Whole-food vegan diets that moderate bean and soy intake, while including ample amounts of fruit, can be quite low in methionine, while supplying abundant nutrition for health. Methionine is an intermediate precursor of cysteine, L-carnitine, taurine and cancer patients undergoing methionine restriction may have to supplement these nutrients through other sources.

Top 10 Methionine Rich Foods: Eggs, Fish, Poultry, Meat, Shellfish, Cottage cheese, Peanuts, Whole lentils, Yoghurt

The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy.

The associations of diet with serum insulin-like growth factor I and its main binding proteins in 292 women meat-eaters, vegetarians, and vegans.

Association between Circulating Levels of IGF-1 and IGFBP-3 and Lung Cancer Risk: A Meta-Analysis.

Associations of insulin-like growth factor and insulin-like growth factor binding protein-3 with mortality in women with breast cancer.

Insulin-like growth factor-1 and childhood cancer risk.

Prostate cancer risk in relation to insulin-like growth factor (IGF)-I and IGF-binding protein-3: a prospective multiethnic study.

Homocysteine, a demethylated form of methionine, is a metabolite of methionine. It exists at a critical biochemical juncture between methionine metabolism and the biosynthesis of the amino acids cysteine and taurine. Homocysteine is normally metabolized via two biochemical pathways; re-methylation, which converts homocysteine back to methionine, and trans-sulfuration, which converts homocysteine to cysteine and taurine.

Re-methylation primarily occurs when a methyl group is transferred from methyltetrahydrofolate (MTHF), the active form of the folate (folic acid) cycle, by a methyltransferase enzyme requiring cobalamin (vitamin B12) as a necessary cofactor. If this recycling doesn’t occur, due to a folate deficiency, for example, homocysteine builds up. A secondary remethylation pathway, active primarily in liver and kidney cells, uses betaine (also called trimethylglycine: TMG) as the methyl donor. The transsulfuration pathway requires two enzymatic reactions, both of which require the cofactor pyridoxal-5-phospate- the active form of vitamin B6.

Homocysteine is a sulfur amino acid. When excess homocysteine is made and not readily converted into methionine or cysteine, it is excreted out of the tightly regulated cell environment into the blood. It is the role of the liver and kidney to remove excess homocysteine from the blood. Homocysteine is known to damage blood vessels and other cells. The link between homocysteine and cardiovascular disease is well established. This would make homocysteine a great anti-angiogenesis agent.

Recent study shows that homocysteine inhibits angiogenesis through VEGF/VEGFR, Akt, and ERK1/2 inhibition. VEGF (vascular endothelial grrowth factor) is a glycoprotein that acts as a growth factor specific to endothelial cells. VEGF, released by cancer and other cells, stimulates the growth of blood vessels into tumors, thereby allowing them to grow larger and most metastatic. VEGF also activates proliferation and survival pathways in endothelial cells. VEGF is also a major growth factor for many leukemia cells.

VEGF ligands mediate their angiogenic effects by binding to specific VEGF receptors (VEGFRs), leading to receptor dimerization and subsequent signal transduction. While VEGF receptors are well known to be present on the surface of endothelial cells, research suggests that they may also be expressed by tumor cells. AKT is the master switch for the development of all cancers and leukemias and activation of ERK1/2 generally promotes cancer cell survival. If we can inhibit the activation of these enzymes, cancer/ leukemia will cease to exist. Homocysteine is not just bad for the heart and arteries. It is clearly toxic to cancer cells.

The methionine-homocysteine cycle and its effects on cognitive diseases.

Homocysteine-impaired angiogenesis is associated with VEGF/VEGFR inhibition.

The effects of homocysteine and folic acid on angiogenesis and VEGF expression during chicken vascular development.

The blood vessels in tumors are not normal. They are in fact quite unstable. Therefore, we need both a reduction in methionine and an increase in homocysteine in order for this type of cancer diet to be effective. Homocysteine is simply a metabolic product that causes damage to tumor blood vessels over a prolonged period of time.

  • In adults elevated homocysteine levels are usually related to the inadequate intake of B vitamins, particularly folate (folic acid), B6, B12, and betaine (trimethylglycine: TMG). They all act as cofactors in the metabolism of homocysteine.
  • Several studies have indicated that coffee consumption appears to cause a dose-related increase in homocysteine. A large study (4,754 participants) found that the more coffee one consumes the higher ones’ homocysteine levels
  • Niacin (vitamin B3) is one of the most economical and effective ways to lower total cholesterol, triglycerides, and lipoprotein, and to raise HDL (the “good” cholesterol). However, doses of niacin in excess of 1,000 mg have been shown to cause an increase in homocysteine. Naturally folate (folic acid) and vitamin B-6 antagonize this affect. Niacin is safe at 2,000 mg a day.
  • Metformin (Glucophage), a drug widely used to treat type2 diabetes, has been shown in several studies to cause an increase in homocysteine. As we discussed in previous articles, Metformin is an anti-cancer drug by virtue of its ability to increase AMPK activity. AMPK is a matabolic tumor suppressor.  

Unfortunately, curcumin has been found to prevent the dysfunction of the endothelial cells, caused by the elevated homocysteine. Curcumin may block homocysteine’s toxic effects. So we do not recommend the use of curcumin on methionine deficient cancer diets.  

Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population.

Niacin treatment increases plasma homocyst(e)ine levels.

Vitamin B-6 normalizes the altered sulfur amino acid status of rats fed diets containing pharmacological levels of niacin without reducing niacin’s hypolipidemic effects.

Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease.

Does metformin increase the serum total homocysteine level in non-insulin-dependent diabetes mellitus?

Curcumin blocks homocysteine-induced endothelial dysfunction in porcine coronary arteries.

Studies found that the methioninase (also called methionine gamma-lyase, L-methionine gamma-lyase) can specificly split the methionine of extracellular and intracellular, so it can strongly inhibit the growth of tumor cells and induce apoptosis of tumor cells. However, no effect on normal cells has been found. Therefore, its major function is to stop or slow down the tumor cell division. The development of methioninase which depletes circulating levels of methionine may be another useful strategy in limiting cancer growth.

Serum methionine depletion without side effects by methioninase in metastatic breast cancer patients.

Anticancer efficacy of methioninase in vivo.

Recombinant methioninase infusion reduces the biochemical endpoint of serum methionine with minimal toxicity in high-stage cancer patients.

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