This review is prompted by a new paper:
"Methionine Restriction: Ready for Prime Time in the Cancer Clinic?" [1]
"Methionine ... is an essential amino acid in humans. As the substrate for other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical role in the metabolism and health of many species, including humans." [2]
There was a "Methionine Restriction" thread 3 years ago [3].
PubMed has 303 hits for <""Methionine Restriction"">, beginning 1972. 165 with the term in the title, but only 3 with "prostate" in the title (2000, 2002 & 2003) - not exactly a hot topic in the PCa world. Why?
Many of you will recall that methionine is the starting point in the SAM cycle:
Methionine --> SAM --> Homocysteine (+ methyl donor, Folate) ---> Methionine
I'm going to steal most of what follows, from a 2020 paper [4]:
You might like to skip to the PCa section [4.2].
"Methionine Restriction and Cancer Biology"
"2. Methionine Restriction
"Methionine is an essential amino acid, and as such it must be consumed in the diet to sustain life. Despite consumption of methionine being essential for survival, studies have shown that limiting methionine in the diet of animals or in cell culture media provides metabolic benefits such as decreasing adiposity , increasing insulin sensitivity, decreasing inflammation, and oxidative stress, and extending lifespan. In fact, rats fed a diet with 80% less methionine lived 40% longer than rats fed a control diet. Subsequent studies found that dietary MR was also effective at extending lifespan in outbred mice and several rat strains with different age-related pathologies. The lifespan-extending effects of MR have been attributed to a number of different mechanisms, including MR-induced reductions in oxidative stress and inflammation, alterations in autophagy, and increases in cardioprotective hormones. Another mechanism by which MR may extend lifespan is by providing a reduction in cancer incidence and overall reduction in cancer mortality.
"The ability of MR to improve insulin sensitivity and reduce adiposity may be directly related to its anti-cancer potential as there are several types of cancer that are closely linked to obesity and insulin resistance and the anti-cancer effects of MR may be secondary to its ability to reduce adiposity and increase insulin sensitivity. In mice, eight weeks of dietary MR produced a 3.1-fold increase in whole-body insulin sensitivity and an increase in tissue-specific glucose uptake measured during a hyperinsulinemic-euglycemic clamp. Additionally, MR enhanced insulin-stimulated Akt phosphorylation in liver, muscle, and brown and white adipocytes in mice. At least part of the insulin-sensitizing effect of MR can be attributed to its ability to reduce body weight and adiposity. However, limiting media methionine concentrations also enhances insulin signaling in HepG2 cells, indicating cell-autonomous effects of MR. Of note, methionine restriction is effective when the non-essential amino acid, cysteine, is absent from the diet or media. Inclusion of cysteine reverses the effects of MR on metabolism and antioxidant status"
"3. Methionine Metabolism
"While methionine is involved in many biological processes, this review will highlight three major functions of methionine with relevance to cancer biology: (1) glutathione formation, (2) polyamine synthesis, and (3) methyl group donation)."
"3.1. Glutathione Formation
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"3.2. Polyamine Synthesis
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Polyamine metabolism is a potential target for treatment of several types of cancers. Given that polyamine synthesis is dependent upon methionine, MR may be a novel approach to inhibit cancer cell growth by downregulating polyamine formation."
"3.3. DNA Methylation
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"4. Methionine Restriction and Cancer
"4.1. Overview
"In 1959, one of the early studies conducted in methionine restriction evaluated several outcomes produced from diets lacking specific amino acids. The study was conducted on rats fed isocaloric diets that were complete in all amino acids or devoid of one essential amino acid. After transplantation of the Walker tumor, and 10-day preparative diet, rats were divided into different groups. Each group was fed a specific diet with different amino acid compositions for 5 days. While the initial aim of this study was to distinguish between two opposing views on nitrogen balance and amino acid restriction, the results showed a significant reduction in tumor growth in the rats fed diets lacking either methionine, valine, or isoleucine [70].
"A subsequent study published in 1974 focused on methionine specifically. This study was conducted on tissue cultures including W-256 (a rat breast cancer cell line), L1210 (a mouse lymphatic leukemia cell line), J111 (a human leukemia cell line), liver epithelial and liver fibroblasts of rats, skin fibroblasts of mice, and human breast and prostate cells that were normal or malignant. The cells were cultured in folic acid- and cyanocobalamin-rich medium that either contained methionine or was methionine-free with a homocysteine supplement. Despite the media containing other methyl donors, the growth of the malignant cells was significantly impaired in the methionine-depleted media, while the normal cell growth was unchanged. These effects were attributed to the ability of normal cells to recycle homocysteine through methionine synthase to supply methionine endogenously. While this is true for normal cells, malignant cells lack the enzyme required to recycle homocysteine therefore giving methionine restriction the capacity to alter cancer cells while maintaining normal, healthy cells. This enables the possibility that methionine restriction, as a therapeutic, may be able to specifically target cancer cells, preventing off-target effects on normal cellular processes. The following sections of this review provide an overview of the literature regarding methionine restriction and specific cancer types, including prostate, breast, and colorectal cancers."
"4.2. Methionine Restriction and Prostate Cancer
"Prostate cancer is the second leading cause of cancer death among adult men in the US and current treatment options include hormonal therapy to reduce testosterone levels, radiation therapy, or surgical procedures [90]. While there are treatment options available for prostate cancer, there are no known interventions to prevent the development of prostate cancer. Using a well-characterized mouse model for prostate cancer (Transgenic Adenocarcinoma of the Mouse Prostate; TRAMP), it was shown that dietary MR inhibits prostate cancer development especially in the anterior and dorsal lobes of the prostate, where the most severe lesions are found [82]. While the mechanism by which MR inhibits prostate cancer development is not known, evidence suggests that MR may work by inhibiting prostate cancer cell proliferation, inhibiting the insulin/IGF-1 axis, or by reducing polyamine synthesis [82]. The cells of the prostate produce high levels of polyamines and inhibition of polyamine synthesis is effective at suppressing tumor growth in prostate cancer [91]. Given the dependence of polyamine synthesis on methionine, the polyamine biosynthetic pathway may be a primary target of MR in prevention and/or treatment of prostate cancer.
"Another target of MR in prostate cancer cells is thymidylate synthase (TS). Thymidylate synthase is the enzyme that catalyzes the methylation of deoxyuridylic acid during nucleotide biosynthesis and is thus an important target for cancer treatment. The chemotherapy drug, 5-fluorouracil (5-fu), inhibits TS activity by disrupting action of TS, causing DNA and RNA damage, making 5-fu an effective and commonly used cancer treatment [74]. However, 5-fu has also been reported to increase TS protein expression, resulting in 5-fu drug resistance [92]. Interestingly, several studies have shown that MR and 5-fu have synergistic anti-cancer effects [12,83,84,87]. MR selectively reduces TS activity in prostate cancer cells by ~80% within 48 h, but does not affect TS activity in normal prostate epithelial cells [74]. Importantly, MR also reduces TS protein expression, potentially explaining the synergy between MR and 5-fu [74]. That MR also reduces TS protein expression may make MR an attractive treatment alongside 5-fu to help combat resistance to 5-fluoruracil.
"Methionine restriction has been shown to induce apoptosis in the human prostate cancer cell lines, PC3 and DU145 [75,76,77]. MR inhibits Raf and Akt oncogenic pathways, while increasing caspase-9 and the mitochondrial pro-apoptotic protein, Bak [75,76]. Restricting media methionine concentrations damages mitochondrial integrity, leading to apoptosis in both prostate cancer cell lines [75,76]. Additionally, energy production was impaired and ROS production was decreased. Caspase-dependent and -independent apoptosis was observed in response to MR [75,76]. Other studies have identified that c-Jun N-terminal kinases (JNK1) is a critical regulator of MR-induced apoptosis in prostate cancer cells [78].
"In another study, PC-3, DU-145, and LNCaP human prostate cancer cell lines were cultured in complete- or methionine-free media and methionine dependency was evaluated [77]. The results showed that PC-3 is completely methionine-dependent, while DU-145 cells were mildly dependent, and LNCaP cells were almost completely methionine-independent. These data indicate that the responses to methionine restriction vary across different cancers, although MR inhibited growth of all three cancer cell lines [77]. The mechanisms by which MR reduced cancer growth also differed between the cell lines, with MR upregulating p21 and p27 (cell cycle inhibitors that halt cell cycle progression) in LNCaP cells, but only increasing p27 in PC-3 cells [77]. Further, the PC-3 cells began to undergo apoptosis within six days of MR, whereas the LNCaP cells were relatively resistant to MR-induced apoptosis [77]. Together, these data indicate a precision diet such as MR may benefit a subpopulation of patients with prostate cancer."
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It has often seemed to me that evolution has given us the SAM cycle because methionine (an essential amino acid which must supposedly come from the diet), rarely comes from the diet in sufficient amounts. Therefore, homocysteine must be recycled to make up for the shortfall.
And therefore, a folate restriction might be a good way to limit methionine levels.
Or, if B12 uptake is a problem, that could be a useful tool to control methionine.
In terms of methionine in the diet, egg whites are an excellent source. {My idea of hell might include a daily breakfast of an egg-white omelet.}
Here is the Abstract from the new paper [1]:
"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."
-Patrick
[1] pubmed.ncbi.nlm.nih.gov/350...
[2] en.wikipedia.org/wiki/Methi...
