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.
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.
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
Association between Circulating Levels of IGF-1 and IGFBP-3 and Lung Cancer Risk: A Meta-Analysis.
Insulin-like growth factor-1 and childhood cancer risk.
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 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.
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.
Niacin treatment increases plasma homocyst(e)ine levels.
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.
