Blocking Cystine, And Thus Glutathione (GSH) Synthesis, Kills Cancer Stem Cells

movebetter

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a quote from the linked article:
"Thiamine supplementation may contribute to a high rate of tumor cell survival, proliferation and chemotherapy resistance. Thiamine has also been implicated in cancer through its effects on matrix metalloproteinases, prostaglandins, cyclooxygenase-2, reactive oxygen species, and nitric oxide synthase. However, some studies have suggested that thiamine may exhibit some antitumor effects. The role of thiamine in cancer is controversial. However, thiamine deficiency may occur in patients with cancer and cause serious disorders, including Wernicke’s encephalopathy, that require parenteral thiamine supplementation. A very high dose of thiamine produces a growth-inhibitory effect in cancer. Therefore, further investigations of thiamine in cancer are needed to clarify this relationship."

The title of the article is:

The Role of Thiamine in Cancer: Possible Genetic and Cellular Signaling Mechanisms​

It is posted in this publication: Cancer Genomics & Proteomics.

I'm a Ray Peat fan. This puts me in the camp that believes most illness is caused by environmental factors. "Modern" medicine got hijacked by the Genetics devotees sometime after WWII and around Nixon's time as President. Peat discusses this quite a bit. The perspective that blames EVERYTHING on genetics also holds the idea that cancer cells are evil and must be destroyed. Another way to look at it is that the cancer cells are sick because their environment is damaging to them.

The oncologists who practice slash and burn don't like things that get in the way of their slash and burn. Improving the quality of the patient's internal environment can do that. Many oncologists don't like thiamine because it will cancel out the devastating effects of chemotherapy drugs which are used to slash and burn cancer cells.

suggested reading:
The prior Ray Peat articles linked to earlier.
also:
bioenergetic search This is a search for "genetics" in Ray Peat interviews. Read through, find one you find of interest, listen to the program.
also:

I cannot make the decision to take thiamine for you. This is your body and your decision. I encourage you to learn about it and to also learn about the problems that are rampant with the current popular cancer "treatments" promoted by the Medical Industrial Complex.
Hi and thanks, i am in agreement with you and i have read everything i could find from Ray about cancer and also Georgi. I am doing low fat as per many of georgi's posts. I avoid mainstream medicine and even alternative. Everyone is trying to sell something. I just dont want to take anything that might make things worse but it looks pretty safe if i keep the b1 in the 1 to 3 gr per day range.
 

mostlylurking

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Hi and thanks, i am in agreement with you and i have read everything i could find from Ray about cancer and also Georgi. I am doing low fat as per many of georgi's posts. I avoid mainstream medicine and even alternative. Everyone is trying to sell something. I just dont want to take anything that might make things worse but it looks pretty safe if i keep the b1 in the 1 to 3 gr per day range.
I believe that providing things that your body needs to normalize its function are positive and helpful. Your body will heal itself if it has the materials and energy it needs to do the job.

There are multiple choices regarding the types of thiamine available. If you are referring to thiamine hcl, I agree that the higher dose you mention is needed. TTFD thiamine does not require that high a dose. However, if you are low in glutathione (which I was), TTFD can cause negative side effects because it uses glutathione to work (somehow, some way) so it will worsen a glutathione issue. TTFD gave me a 36 hour headache from a single 100mg capsule, so I personally prefer the hcl type and found Dr. Costantini's website the most helpful with practical hands on information. I found watching the patients' before and after videos extremely helpful. Even though these people suffered from Parkinson's Disease (instead of cancer), it is plain to see that they each are in real trouble before treatment and are vastly improved quickly from the treatment. The improvement in overall body energy is remarkable; it's like someone flipped an electrical switch.

You'll need to experiment with the dose of thiamine hcl. I didn't have a doctor helping me and I had not yet found Dr. Costantini's website so I spent 4 months titrating my dose of thiamine hcl from 300mg, 2Xday up to 750mg, 2Xday (with water, never juice). Then I found Dr. Costantini's site and learned my optimum dose based on my weight should be 1 gram, 2Xday so I increased it to that. Within 2 days, my entire digestive tract normalized for the first time in decades on that recommended dose. So although I did experience improvements on the lower doses, I did not get full benefit until I attained 2 grams/day dose level.

The only time that I had a negative experience from thiamine hcl was when I tried taking 2.5 grams in one day. That night, when I went to bed, I experienced shooting electrical pains in my thighs. So I went back to the 2 grams/day and am still taking that dose with no ill effects (3 years now).
 

movebetter

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I believe that providing things that your body needs to normalize its function are positive and helpful. Your body will heal itself if it has the materials and energy it needs to do the job.

There are multiple choices regarding the types of thiamine available. If you are referring to thiamine hcl, I agree that the higher dose you mention is needed. TTFD thiamine does not require that high a dose. However, if you are low in glutathione (which I was), TTFD can cause negative side effects because it uses glutathione to work (somehow, some way) so it will worsen a glutathione issue. TTFD gave me a 36 hour headache from a single 100mg capsule, so I personally prefer the hcl type and found Dr. Costantini's website the most helpful with practical hands on information. I found watching the patients' before and after videos extremely helpful. Even though these people suffered from Parkinson's Disease (instead of cancer), it is plain to see that they each are in real trouble before treatment and are vastly improved quickly from the treatment. The improvement in overall body energy is remarkable; it's like someone flipped an electrical switch.

You'll need to experiment with the dose of thiamine hcl. I didn't have a doctor helping me and I had not yet found Dr. Costantini's website so I spent 4 months titrating my dose of thiamine hcl from 300mg, 2Xday up to 750mg, 2Xday (with water, never juice). Then I found Dr. Costantini's site and learned my optimum dose based on my weight should be 1 gram, 2Xday so I increased it to that. Within 2 days, my entire digestive tract normalized for the first time in decades on that recommended dose. So although I did experience improvements on the lower doses, I did not get full benefit until I attained 2 grams/day dose level.

The only time that I had a negative experience from thiamine hcl was when I tried taking 2.5 grams in one day. That night, when I went to bed, I experienced shooting electrical pains in my thighs. So I went back to the 2 grams/day and am still taking that dose with no ill effects (3 years now).
Wow,! Thanks that is very helpful and I will check out Dr. Costantini's site
 

Alpha

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Sometimes whats good for healthy cells is also good for cancer cells, and whats bad for healthy cells is also bad for cancer cells
Ding-Ding-Ding

Ever wonder why cancer cells avoid the oxidative phosphorylation pathway? They have mitochondrial function, but it would slowdown the rapid growth, despite producing more ATP. Instead it makes up for it by 10 to 20 times higher utilization of glucose. The high turnover of cells still need NAD+ production to keep up the glycolysis, that's where tryptophan and niacin come in. The other way they do that is through rationing, by inhibiting DNA repair and amplifying the NAM-NAD+ pathway, they can maintain a stable balance to maintain rapid glycolysis.

Most importantly, it avoids its biggest enemy in the process, oxygen and oxidative stress.
 
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Yet another study that adds to the evidence that cancer is a metabolic disease, driven by excessive reductive stress. I posted a few other threads on the role of glutathione precursors in cancer, and specifically on the role of cysteine in melanoma. In the body, cysteine gets converted into cystine and the latter is used for glutathione synthesis. Glutathione depletion has been demonstrated to increase vulnerability of virtually all known cancer types to chemotherapy and radiation. Given that cancer cells rely primarily on glutathione (high GSH/GSSG ratio) to protect themselves from apoptosis and maintain a growth-promoting environment, the effects of glutathione depletion on mature cancer cells are quite expected. And now this new study demonstrated that blocking cystine uptake leads to quick death (ferroptosis) of cancer stem cells. The mechanism of action is again (reduced) glutathione depletion and increased vulnerability of cancer stem cells to ROS. While the study used various small molecules with toxic side effects, a number of other studies have shown that simply eating sucrose or administering aspirin also has a powerful effect on lowering GSH/GSSG and thus may potentially block the very "seed" of cancer.

Small-Molecule Ferroptotic Agents with Potential to Selectively Target Cancer Stem Cells

"...To further investigate the connection between ferroptosis in NCI-H522 cells and cystine availability, we deprived them of the amino acid. Cells died without cystine, but could be rescued by chelating iron (cyclopirox olamine), scavenging ROS (Trolox, ferrostatin), scavenging lipid ROS (liproxstatin) or providing reduced thiols (βME) (Fig. 5C,D). Maximal rescue occurred at 100 μM external cysteine (Fig. 5D). These results indicate that NCI-H522 can be induced to undergo ferroptosis simply by removing cystine. Next, we attempted to induce ferroptosis in NCI-H522 by elevating external glutamate to interfere with the xc−antiporter activity. Adding 5 mM glutamate for three days had no effect on viability (Fig. 5B)."

Killing the seeds of cancer: A new finding shows potential in destroying cancer stem cells

"...Cancer stem cells are an intriguing target for researchers because of their potential to re-seed tumors. When doctors remove a tumor surgically or target it with chemotherapy drugs or radiation therapy, the cancer may appear to be gone. However, evidence suggests that a tiny subpopulation of adaptable cancer cells can remain and circulate through the body to seed new metastasis in far-off locations. Those cancer stem cells, Taylor said, are similar to dandelions in a well-manicured lawn. "You could chop the plant off, but it will drop a seed. You know the seeds are there, but they're hiding," he said. "You pull one weed out and another comes up right after it. Cancers can be like this as well." The small molecule they have isolated appears to lock on to those stem cells and kill them by blocking their absorption of an amino acid called cystine. UToledo was awarded a patent for the discovery late last year. For Tillekeratne and Taylor, uncovering a new class of therapeutic molecules could prove to be an even larger contribution to cancer research than the project they initially envisioned. At present, there are no drugs that can kill cancer stem cells, but people are looking for them," Tillekeratne said. "A lot of drugs are discovered by serendipity. Sometimes in research if you get unexpected results, you welcome that because it opens up a new line of research. This also shows the beauty of collaboration. I wouldn't have been able to do this on my own, and [Taylor] wouldn't have been able to do it on his own."
How does gelatin/collagen powder factor in with cancer? Are there things that cancel out it’s cysteine content?
 

movebetter

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hi , chlorophyll A (not chlorophyllin) might be a good one (1 study where pancreas tumors were 1/3 the size in mice fed low dose 1.5mg/kg orally. and maybe even shrank. mechanism relating to reducing mitochondrial ros. unlike glutathione in the cell (helps prevent cancer but can promote survival for existing) increasing glutathione inside mitochondria might be anti-cancer). green peas are 1 source that give this amount
and vitamin e succinate maybe another one (effect is selective but not sure if fully long term)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051000/
View attachment 58992
Hi, can you tell me a source for chlorophyll A?
 

movebetter

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More information about the dosage of thiamine regarding cancer:
For thiamine (B1), "The RDA for adults is 1.2 mg/day for men and 1.1 mg/day for women." So 1.2mg/day for men X 2500=3000mg/day. That said, I remember that I did the math on this a year or so ago and was relieved to learn that my 2000mg/day of thiamine hcl regimen was considered safe regarding the effect that size dose has on cancer growth. I'll see if I can find the study.

"Self-supplementation vitamin preparations containing levels of thiamine greater than the RDI are readily accessible and considered to be safe and harmless for patients (Table 1). Although the use of thiamine to treat deficiency-related symptoms attributed to the disease or therapy is warranted, this is currently done with limited comprehension of the role thiamine may contribute towards malignant progression. In light of our knowledge regarding alterations of thiamine homeostasis in cancer, the impact of thiamine supplementation on cancer growth has received minimal research attention. In 2001, Comin-Anduix et al. evaluated the effect of increasing thiamine supplementation in multiples of the RDI on an Ehrlich ascites tumor-mouse model [58]. Their findings indicated a statistically significant stimulatory effect of thiamine supplementation on tumor growth compared to non-supplemented controls. Moderate doses of 12.5 to 37.5 times the RDI had the greatest stimulatory effect, peaking at approximately 250% greater tumor cell proliferation with 25 times the RDI. Interestingly, at values above 75 times the RDI, no change was found in tumor cell proliferation, and a slight decrease was found at 2,500 times the RDI. This observation suggests that there is a specific range in which thiamine supports proliferation. A recent study explored the relationship between a high-fat diet and thiamine levels on the tumor latency in the Tg(MMTVneu) spontaneous breast cancer-tumor mouse model [59]. In this study a normal-fat (NF) diet contained 10% of the calories from fat while the high-fat diet contained 60%. Low thiamine (LT) levels were defined as 2 mg of thiamine per 4,057 kcal and normal thiamine (NT) levels as 6 mg per 4,057 kcal. Tumor latency was significantly longer (295 days) in animals given a NF/LT diet compared with animals on NF/NT (225 days). Interestingly,the delay in tumor latency from LT was abolished when given a high-fat diet. This demonstrates an important interplay of dietary constituents on tumor progression that needs further characterization. Although more research is needed to confirm and evaluate the role of thiamine on disease progression, these studies have significant clinical implications. First, patients requiring thiamine to treat either chemotherapy or disease-associated deficiency should receive high-dose thiamine to avoid enhancing tumor growth. Second, self-supplementation of thiamine by cancer patients should be avoided as the low-to-moderate levels of thiamine may contribute to disease exacerbation."
-end paste-

Unfortunately, this study only names high-fat and not the saturation of the fat. Polyunsaturated fat (PUFA) is known to be carcinogenic. PUFA is known to deplete thiamine, (at least in the Salmon farming industry). Thiamine is required for oxidative metabolism. When oxidative metabolism is blocked, the result is what Otto Warburg called the Cancer Metabolism.

""Warburg Effect" refers to Otto Warburg's observation that cancer cells produce lactic acid even in the presence of adequate oxygen."
"From the 19th century until the second quarter of the 20th century, cancer was investigated mainly as a metabolic problem. This work, understanding the basic chemistry of metabolism, was culminating in the 1920s in the work of Otto Warburg and Albert Szent-Gyorgyi on respiration. Warburg demonstrated as early as 1920 that a respiratory defect, causing aerobic glycolysis, i.e., the production of lactic acid even in the presence of oxygen, was an essential feature of cancer. (The25 formation of lactic acid is normal and adaptive when the supply of oxygen isn't adequate to meet energy demands, for example when running.)"
Hi, do you know how the 2500 x RDA would translate into dosage of thiamine TTDF?
 

mostlylurking

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Hi, do you know how the 2500 x RDA would translate into dosage of thiamine TTDF?
Sorry, no I don't know how to translate that for high dose thiamine TTFD. Although there is a lot of discussion of TTFD at doses of 100-300mg/day, not a lot is available at higher doses, except anecdotally in a few videos. This one with Dr. Chandler Marrs goes into a patient with MS getting great benefit from doses of TTFD as high as 2000+mg of TTFD. This is the book referenced in the video at the link.

It is difficult to get thiamine hcl taken orally into the bloodstream via the intestinal wall. 2000mg of thiamine hcl, taken daily for 7 days equals to a single 100mg injection of thiamine hcl per week. TTFD does not have difficulty getting through the intestinal wall and into the bloodstream so it does not have this issue. TTFD also has no problems getting into the the cells; no "transporter" is required. However, there seems to be more problems of tolerance for TTFD; one reason is that it uses glutathione so if you are low in glutathione, you can have tolerance problems with TTFD. I couldn't tolerate it; it gave me a headache.
 

cs3000

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Hi, can you tell me a source for chlorophyll A?
hi 1/2 cup - 1 cup green peas gives a functional amount. i think its unstable as a supplement so they sell chlorophyllin instead. similar but not exactly the same compound so not sure on effects in this area. u get a lot of copper with that form too.
 

movebetter

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hi 1/2 cup - 1 cup green peas gives a functional amount. i think its unstable as a supplement so they sell chlorophyllin instead. similar but not exactly the same compound so not sure on effects in this area. u get a lot of copper with that form too.
thanks, it sounds like green peas are the best form.?
 

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