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

haidut

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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."
 

Philomath

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Thank you Haidut. I have three questions:
1. You've said Aspirin, methylene blue and sucrose can lower Glutathione levels (or the ratio) can you elaborate on their method of action?
2. Sounds like Glutathione is the cancer stem cells main antioxidant protector. Would high doses of other antioxidants be utilized by the cell if Glutathione is blocked?
3. Do ingested antioxidants even get to the intracellular level?
 

Cirion

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I always thought Glutathione was a beneficial thing. Can you expand more on this and why it is not? For example--doesn't gelatin/glycine increase glutathione levels? One of the supposed benefits of glutathione is gut health, for example.
 

haidut

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Thank you Haidut. I have three questions:
1. You've said Aspirin, methylene blue and sucrose can lower Glutathione levels (or the ratio) can you elaborate on their method of action?
2. Sounds like Glutathione is the cancer stem cells main antioxidant protector. Would high doses of other antioxidants be utilized by the cell if Glutathione is blocked?
3. Do ingested antioxidants even get to the intracellular level?

The mechanism of #1 has been discussed multiple times - increasing OXPHOS, which consumes GSH. MB can also oxidize GSH directly into GSSG so it has an extra pro-oxidant effect the other 2 do not.
Yes, other anti-oxidants would also be utilized but that does not seem to be enough to protect the cancer cell. If GSH drops all cells become much more vulnerable to ROS and thus to apoptosis.
Many antioxidants get to the intracellular level but that does not mean they all exert meaningful antioxidant effect. NAC has to be converted into GSH in order to have an effect and I don't think NAC does much directly except possibly suppress thyroid.
 

bdawg

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The mechanism of #1 has been discussed multiple times - increasing OXPHOS, which consumes GSH. MB can also oxidize GSH directly into GSSG so it has an extra pro-oxidant effect the other 2 do not.
Yes, other anti-oxidants would also be utilized but that does not seem to be enough to protect the cancer cell. If GSH drops all cells become much more vulnerable to ROS and thus to apoptosis.
Many antioxidants get to the intracellular level but that does not mean they all exert meaningful antioxidant effect. NAC has to be converted into GSH in order to have an effect and I don't think NAC does much directly except possibly suppress thyroid.

Haidut, im on your side here but could you please reference your NAC to lower thyroid relationship assertion?
 

Blue Jefe

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@haidut I noticed Gelatin has virtually no Cystine. If one with cancer was able to consume all protein through gelatin would this do the same thing as blocking Cysine absorption, theoretically?
 

haidut

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@haidut I noticed Gelatin has virtually no Cystine. If one with cancer was able to consume all protein through gelatin would this do the same thing as blocking Cysine absorption, theoretically?

You can't survive on gelatin alone as it does not have all the essential amino acids. But it can be up to say 75% of your daily protein intake. And yes, it should inhibit cysteine absorption as does aspirin and potentially BCAA.
 

haidut

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Haidut, im on your side here but could you please reference your NAC to lower thyroid relationship assertion?

Here is a pretty good one as it also shows the anti-thyroid effects of methionine, tryptophan, histidine, and even tyrosine/phenylalanine.
Thyroid peroxidase activity is inhibited by amino acids. - PubMed - NCBI
"...Normal in vitro thyroid peroxidase (TPO) iodide oxidation activity was completely inhibited by a hydrolyzed TPO preparation (0.15 mg/ml) or hydrolyzed bovine serum albumin (BSA, 0.2 mg/ml). A pancreatic hydrolysate of casein (trypticase peptone, 0.1 mg/ml) and some amino acids (cysteine, tryptophan and methionine, 50 microM each) also inhibited the TPO iodide oxidation reaction completely, whereas casamino acids (0.1 mg/ml), and tyrosine, phenylalanine and histidine (50 microM each) inhibited the TPO reaction by 54% or less. A pancreatic digest of gelatin (0.1 mg/ml) or any other amino acid (50 microM) tested did not significantly decrease TPO activity. The amino acids that impair iodide oxidation also inhibit the TPO albumin iodination activity. The inhibitory amino acids contain side chains with either sulfur atoms (cysteine and methionine) or aromatic rings (tyrosine, tryptophan, histidine and phenylalanine). Among the amino acids tested, only cysteine affected the TPO guaiacol oxidation reaction, producing a transient inhibition at 25 or 50 microM. The iodide oxidation inhibitory activity of cysteine, methionine and tryptophan was reversed by increasing iodide concentrations from 12 to 18 mM, while no such effect was observed when the cofactor (H2O2) concentration was increased. The inhibitory substances might interfere with the enzyme activity by competing with its normal substrates for their binding sites, binding to the free substrates or reducing their oxidized form."

And another one, with similar information. It not only adds GSH to the list of anti-thyroid agents but suggests that it is their reducing agent properties that are to blame for these effects.
https://lib.dr.iastate.edu/cgi/viewcontent.cgi?article=2651&context=rtd
"...It was snown by Calvo and Goemine (24) that the combination of iodine with casein is inhibited by thiourea, thiouracil, phenylthiourea, and by amino acids such as cysteine, reduced glutathione and methionine. This inhibiting effect was not snown by thiourea derivatives containing alkyl groups attached to tne sulfur atom. These results point up the possibility of a simple reduction as the basis for their antithyroid activity, since the iodination of casein and tyrosine are very similar reactions."
 

bdawg

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Here is a pretty good one as it also shows the anti-thyroid effects of methionine, tryptophan, histidine, and even tyrosine/phenylalanine.
Thyroid peroxidase activity is inhibited by amino acids. - PubMed - NCBI
"...Normal in vitro thyroid peroxidase (TPO) iodide oxidation activity was completely inhibited by a hydrolyzed TPO preparation (0.15 mg/ml) or hydrolyzed bovine serum albumin (BSA, 0.2 mg/ml). A pancreatic hydrolysate of casein (trypticase peptone, 0.1 mg/ml) and some amino acids (cysteine, tryptophan and methionine, 50 microM each) also inhibited the TPO iodide oxidation reaction completely, whereas casamino acids (0.1 mg/ml), and tyrosine, phenylalanine and histidine (50 microM each) inhibited the TPO reaction by 54% or less. A pancreatic digest of gelatin (0.1 mg/ml) or any other amino acid (50 microM) tested did not significantly decrease TPO activity. The amino acids that impair iodide oxidation also inhibit the TPO albumin iodination activity. The inhibitory amino acids contain side chains with either sulfur atoms (cysteine and methionine) or aromatic rings (tyrosine, tryptophan, histidine and phenylalanine). Among the amino acids tested, only cysteine affected the TPO guaiacol oxidation reaction, producing a transient inhibition at 25 or 50 microM. The iodide oxidation inhibitory activity of cysteine, methionine and tryptophan was reversed by increasing iodide concentrations from 12 to 18 mM, while no such effect was observed when the cofactor (H2O2) concentration was increased. The inhibitory substances might interfere with the enzyme activity by competing with its normal substrates for their binding sites, binding to the free substrates or reducing their oxidized form."

And another one, with similar information. It not only adds GSH to the list of anti-thyroid agents but suggests that it is their reducing agent properties that are to blame for these effects.
https://lib.dr.iastate.edu/cgi/viewcontent.cgi?article=2651&context=rtd
"...It was snown by Calvo and Goemine (24) that the combination of iodine with casein is inhibited by thiourea, thiouracil, phenylthiourea, and by amino acids such as cysteine, reduced glutathione and methionine. This inhibiting effect was not snown by thiourea derivatives containing alkyl groups attached to tne sulfur atom. These results point up the possibility of a simple reduction as the basis for their antithyroid activity, since the iodination of casein and tyrosine are very similar reactions."

captain coconut posted this study i while back as well

thanks for this, you're absolutely right, i did some further reading for mechanism, quite a few aminos do it though cysteine and tryptophan was by far the strongest competitor for iodide oxidation. Not sure how relevant in vivo and in what concentrations:

In theiodide oxidation reaction tryptophan andcysteine were the most potent inhibitors,with equivalent increases in K0.5 (Table 1);however, cysteine was more potent than tryp-tophan in inhibiting the iodination reaction(Figure 4). Tyrosine also inhibited the iodi-nation reaction, but to a lesser extent, while50 μM phenylalanine, histidine, proline orcystine did not inhibit the iodination activity

However, tryptophan andmethionine, like cysteine, seem to be com-petitive inhibitors of the iodide oxidationreaction, and therefore may react with theoxidized form of iodide, as we propose forcysteine, and/or compete reversibly with theiodide ion for its site on TPO
 

BigChad

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@haidut good info. What I'm wondering is isnt cysteine essential for several processes in the body.
I thought gluthathione is needed? One of the key things to make glutathione is selenium iirc so should selenium be avoided? Thats one of seleniums basic functions i thought.

Regarding the list of anti thyroid hormones, i thought tyrosine and phenylalanine were peaty amino acids? Tyrosine itself, is a part of thyroid hormone as well.
Should we not be supplementing any of those aminos, and minimizing their dietary intake?

Is NAC particularly extra harmful to the thyroid or is it just equivalent to taking the same amount of cysteine?

I was gonna supplement n acetyl tyrosine and maybe lysine and phenylalanine...not sure now
 

FredSonoma

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Jun 23, 2015
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Does anyone know what GSSG is? Online it seems to be the "oxidized" state of Glutathione, is that kind of like the "used up" state? I thought a high amount of "reduced" Glutathione is a good thing?
 
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