This is a follow-on from something that came up in the "Cysteine depletion sensitizes prostate cancer cells to agents that enhance DNA damage and to immune checkpoint inhibition" post.
Some here may be unfamiliar with the idea of selective amino acid restriction.
I have never been tempted to adopt a vegan diet. I admire those who have done so and avoided the pitfalls. It's easy to become unintentionally deficient in one of a number of nutrients, but it is also easy to intentionally restrict an essential nutrient. Is it possible to do this safely so that only cancer cells are targeted?
We need 20 amino acids to make protein. Some must be obtained from the diet - essential AAs [EAA] while others can be made by the body - non-essential AAs [NEAA]. {Others are provisionally essential - when the body demands more than can be made.}
When we consume American portions (lol) of fully-formed protein, we give the cancer all of the AAs it needs to proliferate. If we restrict fully-formed protein and foods that contain EAAs, an important change occurs in the body - the level of insulin-like growth factor I [IGF-I] drops. The body cannot commit to growth if the building blocks are not available. [1] The study notes that "IGFBP-1 concentrations were significantly increased in adults (from 40 +/- 6 to 62 +/- 4 ng/mL)". The "BP" stands for "binding protein". There are a number of IGFBPs and each binds to IGF-I, making it less available.
The next paper is a good introduction to selective amino acid restriction [2]. It is not PCa-specific.
The author offers this counter-intuitive thought:
"Restricting NEAAs may be more effective than restricting EAAs. Neither normal cells nor cancer cells can synthesize EAAs. However, normal cells can synthesize NEAAs while cancer cells are probably unable to obtain all of them. This difference may confer selectivity." (my emphasis). But which NEAAs would we choose?
What does he have to say about cysteine & methionine?
"Because the presence of some AAs can compensate for the deficit of others, it may be important to restrict complementary AAs simultaneously. For example, serine is required for the synthesis of cysteine, and serine and glycine are interconvertible through the enzymes serine hydroxymethyltransferases SHMT1 and SHMT2 (Figure (Figure1).1). Restricting these three NEAAs together may force cells to activate a variety of genetic programs, some of which may be inactivated in cancer cells. In fact, TP53 gene (which encodes p53 protein) is the most frequently mutated gene in cancer, and evidence suggests that p53- defficient tumors are vulnerable to serine starvation [46]. Rapidly proliferating cancer cells from a variety of tissues, but not rapidly proliferating normal cells, are also vulnerable to glycine deprivation [47]. Restricting cysteine may also be important to reduce the synthesis of the tripeptide glutathione (γ-L-glutamyl-L-cysteinylglycine); cancer cells may need high levels of the antioxidant glutathione to cope with the oxidative stress resulting from serine deprivation [46]. Reducing the levels of the EAA methionine (a precursor of cysteine) may increase the toxicity of this combination to cancer cells, but perhaps to normal cells too. Alternatively, if the restriction of serine, glycine and cysteine is enough to kill the cancer cells, increasing the levels of methionine may reduce the toxicity of this combination towards normal cells and make it more selective. Again, the key is not to find the most toxic combination for cancer cells, but to find a combination able to eliminate the cancer cells without significantly affecting our normal body cells."
...
"SAART may also be combined with standard anticancer treatments. For example, high levels of the tripeptide glutathione (GSH) confer resistance to a wide range of anticancer drugs [57–59], including the commonly used anticancer agent cisplatin [60]. Inhibitors of GSH synthesis and of GSH-dependent detoxifying enzymes have been developed [58,59]. These inhibitors increase the toxicity of many anticancer agents to cancer cells. However, these combinations induce toxicity to normal cells too. The reason is that normal cells also need GSH and GSH-dependent enzymes to protect themselves against these drugs and against the reactive oxygen species (e.g., hydrogen peroxide) produced during normal cell metabolism. As discussed before, restriction of the NEAAs cysteine, glycine and serine may compromise the synthesis of GSH in cancer cells, but not in normal cells. Normal cells would use GSH to detoxify the anticancer drugs and would survive. Cancer cells may be unable to do so and would die."
To keep this short (lol), I'll end with:
"Methionine Restriction: Ready for Prime Time in the Cancer Clinic?" [3].
"Attempts to selectively starve cancers in the clinic have been made at least since the time of Warburg beginning 100 years ago. Calorie-restriction or low-carbohydrate diets have had limited success with cancer patients. Methionine restriction is another strategy to selectively starve cancer cells, since cancers are addicted to methionine, unlike normal cells. Methionine addiction of cancer is termed the Hoffman effect. Numerous preclinical studies over the past half century have shown methionine restriction to be highly effective against all major cancer types and synergistic with chemotherapy. Low-methionine medical diets can be effective in lowering methionine and have shown some clinical promise, but they are not palatable and thereby not sustainable. However, selectively choosing among plant-based foods allows a variety of low-methionine diets that are sustainable. Our laboratory has developed a methioninase that can be administered orally as a supplement and has resulted in anecdotal positive results in patients with advanced cancer, including hormone-independent prostate cancer, and other recalcitrant cancers. The question is whether methionine restriction through a low-methionine diet, or even greater methionine restriction with methioninase in combination with a low-methionine diet, is ready for prime time in the clinic, especially in combination with other synergistic therapy. The question will hopefully be answered in the near future, especially for advanced cancer patients who have failed all standard therapy."
But, as I mentioned in the other post, much of our methionine needs are met by recycling homocysteine back to methionine. This requires a methyl donor - often folate or folic acid - and cofactors that include vitamin B12.
-Patrick
[1] academic.oup.com/jcem/artic...
