The Warburg "effect" Is, In Fact, A Direct Cause Of Cancer

[Inaut]

Another good post ^^^^^ @Obi-wan

Thanks

 

[Mito]

A cancer cell has many mitochondria. Many are defective but many are working overtime to meet the energy requirements of the cancer cell.

Are you saying that some of the mitochondria in a cancer cell are working correctly in other words all electron transport chain complex's are working including ATP synthase?

 

[Obi-wan]

Are you saying that some of the mitochondria in a cancer cell are working correctly in other words all electron transport chain complex's are working including ATP synthase?

Yes, cancer is way more complex than we invision it. Some mitochondria produce lactic acid others produce oxophos

 

[Mito]

Yes, cancer is way more complex than we invision it. Some mitochondria produce lactic acid others produce oxophos

It would make sense then that the more mitochondria that are not completing oxphos, the higher grade or more malignant the cancer cell. I wonder if that is the case?

 

[Obi-wan]

It would make sense then that the more mitochondria that are not completing oxphos, the higher grade or more malignant the cancer cell. I wonder if that is the case?

Depends on the phenotype of the cancer. Prostate cancer uses oxyphos to oxidize citrate for FAS it’s favorite source of fuel

 

[haidut]

Metabolic aids don't work on cancer.

So, how come now even Harvard is saying metabolic aids DO work on cancer? All they did was change diet and restrict/block glutamine.
(Brain) Cancer Is A Metabolic Disease, Can Be Treated By Glutamine Restriction

What about the baking soda approach, which is now apparently becoming all the rage? Those threads are also linked in the main post of the link above.
Anything that does not involve "cut, poison, burn" is in fact a metabolic aid therapy. It's either cytotoxic or metabolic. There is no third way. Apoptosis is also metabolism driven - lower intracellular alkalinity by raising CO2 and a stressed cell immediately goes into apoptosis. That's what acetazolamide does and that drug is now quietly being thrown into hundreds of cancer trials as an "adjuvant", simply to avoid ascribing a complete cure to something so purely metabolic.

 

[haidut]

Prostate cancer uses oxyphos to oxidize citrate for FAS it’s favorite source of fuel

Actually, technically it is not OXPHOS because it does not go through the last step - ETC. So, all cancer cells have some mitochondrial activity (Krebs cycle) because they depend on FAS and FAO and as such a portion of the Krebs cycle is working so they can synthesize the fat they need. But I know of no cancer that has a well-functioning ETC. Cytochrome C oxidase is always blocked in cancer, usually by NO. Hence, the trials with NO antagonists as treatment for cancer. It is precisely this blockade of cytochrome C oxidase that often starts the whole acidification and cancerization cascade.
Disruption of Cytochrome c Oxidase Function Induces Warburg Effect and Metabolic Reprogramming
Treatment with the nitric oxide synthase inhibitor L-NAME provides a survival advantage in a mouse model of Kras mutation-positive, non-small cell ... - PubMed - NCBI

 

[papaya]

You can achieve the same anti-lipid effects and blockade of FAS with much lower risk by using orlistat. No need to take CoQ10-depleting statins of acidosis-inducing metformin. And yes, orlistat was tested specifically on cancer so it is not something purely theoretical.
https://raypeatforum.com/community/threads/cancer-cells-addicted-to-fat-and-use-fat-oxidation-for-survival.7639/
https://raypeatforum.com/community/threads/achilles-heel-of-cancer-found-its-addiction-to-fat.10537/

should you take orlistat with every meal? also, would a combo of aspirin, niacinamide, orlistat be better? what dose of each?

 

[Obi-wan]

Actually, technically it is not OXPHOS because it does not go through the last step - ETC. So, all cancer cells have some mitochondrial activity (Krebs cycle) because they depend on FAS and FAO and as such a portion of the Krebs cycle is working so they can synthesize the fat they need. But I know of no cancer that has a well-functioning ETC. Cytochrome C oxidase is always blocked in cancer, usually by NO. Hence, the trials with NO antagonists as treatment for cancer. It is precisely this blockade of cytochrome C oxidase that often starts the whole acidification and cancerization cascade.
Disruption of Cytochrome c Oxidase Function Induces Warburg Effect and Metabolic Reprogramming
Treatment with the nitric oxide synthase inhibitor L-NAME provides a survival advantage in a mouse model of Kras mutation-positive, non-small cell ... - PubMed - NCBI

How does the Citrate become oxidized?

 

[haidut]

How does the Citrate become oxidized?

Most of it does not. A very small portion of it completes the full Krebs cycle. Most of it gets exported back to the cytosol and becomes a substrate for FAS and gets turned into fat.
Fatty acid synthesis - Wikipedia
"...The pyruvate produced by glycolysis is an important intermediary in the conversion of carbohydrates into fatty acids and cholesterol.[6] This occurs via the conversion of pyruvate into acetyl-CoA in the mitochondrion. However, this acetyl CoA needs to be transported into cytosol where the synthesis of fatty acids and cholesterol occurs. This cannot occur directly. To obtain cytosolic acetyl-CoA, citrate (produced by the condensation of acetyl CoA with oxaloacetate) is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol.[6] There it is cleaved by ATP citrate lyase into acetyl-CoA and oxaloacetate. The oxaloacetate can be used for gluconeogenesis (in the liver), or it can be returned into mitochondrion as malate.[7] The cytosolic acetyl-CoA is carboxylated by acetyl CoA carboxylase into malonyl CoA, the first committed step in the synthesis of fatty acids.[7][8]"

So, basically it gets converted back into acetyl-CoA once back in the cytosol. That's probably why Peat cautioned against extra citrate as an isolated supplement because in a system with Krebs cycle not working very well a good portion of the supplemental citrate will probably get converted into fat. This is also the reason I said in our past exchanges that supplementing with acetic acid directly is probably not advisable - i.e. it quite easily gets into the cytosol, forms acetyl-CoA there and is perfect substrate for much easier fatty acid synthesis than if the acetyl-CoA came from glucose through the glycolysis->PDH pathway.

 

[haidut]

should you take orlistat with every meal? also, would a combo of aspirin, niacinamide, orlistat be better? what dose of each?

I think 2g-3g aspirin should be enough for sufficient inhibition of FAS and FAO, if combined with orlistat and niacinamide. Niacinamide in doses over ~750mg actually starts to directly inhibit FAO as shown by this thread.
https://raypeatforum.com/community/threads/long-term-treatment-with-nicotinamide-induces-glucose-intolerance-and-skeletal-muscle-lipotoxicity.15393/
Since orlistat has a short half life and a good portion of its action is preventing fat absorption, I think it needs to be taken with every meal. I don't know for how long it inhibits FAS, which is its other beneficial effects for cancer.
So, 3g aspirin daily in divided doses of 1g each, 1g niacinamide in 2 divided doses of 500mg, and orlistat with each meal is what I'd try.

 

[jb116]

How does the Citrate become oxidized?

Most of it does not. A very small portion of it completes the full Krebs cycle. Most of it gets exported back to the cytosol and becomes a substrate for FAS and gets turned into fat.
Fatty acid synthesis - Wikipedia
"...The pyruvate produced by glycolysis is an important intermediary in the conversion of carbohydrates into fatty acids and cholesterol.[6] This occurs via the conversion of pyruvate into acetyl-CoA in the mitochondrion. However, this acetyl CoA needs to be transported into cytosol where the synthesis of fatty acids and cholesterol occurs. This cannot occur directly. To obtain cytosolic acetyl-CoA, citrate (produced by the condensation of acetyl CoA with oxaloacetate) is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol.[6] There it is cleaved by ATP citrate lyase into acetyl-CoA and oxaloacetate. The oxaloacetate can be used for gluconeogenesis (in the liver), or it can be returned into mitochondrion as malate.[7] The cytosolic acetyl-CoA is carboxylated by acetyl CoA carboxylase into malonyl CoA, the first committed step in the synthesis of fatty acids.[7][8]"

So, basically it gets converted back into acetyl-CoA once back in the cytosol. That's probably why Peat cautioned against extra citrate as an isolated supplement because in a system with Krebs cycle not working very well a good portion of the supplemental citrate will probably get converted into fat. This is also the reason I said in our past exchanges that supplementing with acetic acid directly is probably not advisable - i.e. it quite easily gets into the cytosol, forms acetyl-CoA there and is perfect substrate for much easier fatty acid synthesis than if the acetyl-CoA came from glucose through the glycolysis->PDH pathway.

This should be a good depiction referring to haidut's post. The orange also indicate upregulated lipogenic enzymes in cancer metabolism.

 

[haidut]

This should be a good depiction referring to haidut's post. The orange also indicate upregulated lipogenic enzymes in cancer metabolism.

View attachment 13611

Excellent, thanks! It does show a direct entry of acetate into the FAS cycle, as I suspected. It was only a suspicion before but I guess it does happen in practice too.
This picture also illustrates perfectly the vital role carnitine plays in this process and why drugs like Mildronate are so important.

 

[jb116]

Excellent, thanks! It does show a direct entry of acetate into the FAS cycle, as I suspected. It was only a suspicion before but I guess it does happen in practice too.
This picture also illustrates perfectly the vital role carnitine plays in this process and why drugs like Mildronate are so important.

Oh yes good point about carnitine. It's also evident glutamine restriction would be beneficial as you've posted about before .

 

[haidut]

Oh yes good point about carnitine. It's also evident glutamine restriction would be beneficial as you've posted about before .

It would also explain why alcohol consumption seems to speed up tumor growth in cancer patients. Even without its endotoxin and 5-HT3 effects, it is great source of citrate AND it also inhibits glucose metabolism.
Btw, correct me if I am wrong but that picture shows that the terminal point for all pathological pathways in cancer is still FAO, right? FAS can't do much damage if it does not feed into the FAO cycle, and neither can glutamine. So, depleting carnitine as much as possible while also potentially inhibiting beta oxidation directly would be the way to go if one were to choose one pathway to attack. This means high doses niacinamide and aspirin would be of primary importance in cancer therapy.
I am going to ask Peat why he does not like higher doses niacinamide. If it can inhibit beta-oxidation directly, it could be a life-saver with somebody with advanced cancer even if it risks increasing ammonia. That ammonia can easily be chelated. I mean, why else would niacinamide massive liver and pancreatic tumors disappear?
https://raypeatforum.com/community/threads/niacinamide-can-cure-liver-and-maybe-pancreatic-cancer.15021/

Btw, aspirin does all 3 - inhibit FAS, inhibit FAO, and activate PDH. If somebody can find the full study text it would be great. I need to see what concentrations of aspirin were used.
Effects of salicylate on hepatocyte lactate metabolism. - PubMed - NCBI
"...We have examined the effects of salicylate on fluxes of lactate metabolism in rat hepatocytes using a steady state model. Salicylate produces an uncoupling effect, an inhibition of gluconeogenesis, a marked activation of pyruvate dehydrogenase flux, and an inhibition of endogenous fatty acid oxidation. Agents with known functions such as dinitrophenol and dichloroacetate were also compared in this system. The in vitro inhibition of gluconeogenesis caused by salicylate is not primarily related to the uncoupling effect. The fact that octanoate, but not palmitate, overcomes the salicylate inhibition of gluconeogenesis suggests that salicylyl CoA is involved in the inhibition. To relate in vitro studies to Reye's syndrome in vivo, in which medium chain dicarboxylic acids accumulate, we have also examined the effects of monomethyl suberate on liver lactate metabolism. This half ester is taken up by the hepatocytes, and causes inhibition of lactate gluconeogenesis, and uncoupling. Both salicylate and monomethyl suberate inhibit the oxidation of 0.2 mM octanoate by hepatocytes."

 

[Mito]

How does the Citrate become oxidized?

Most of it does not. A very small portion of it completes the full Krebs cycle. Most of it gets exported back to the cytosol and becomes a substrate for FAS and gets turned into fat.

Here is a good explanation of this process even in normal cells.
In this video Chris explains how excessive ROS causes a build up citrate in the mitochondria which then moves into the cytosol where it becomes a substrate for fatty acid synthesis.

 

[jb116]

It would also explain why alcohol consumption seems to speed up tumor growth in cancer patients. Even without its endotoxin and 5-HT3 effects, it is great source of citrate AND it also inhibits glucose metabolism.
Btw, correct me if I am wrong but that picture shows that the terminal point for all pathological pathways in cancer is still FAO, right? FAS can't do much damage if it does not feed into the FAO cycle, and neither can glutamine. So, depleting carnitine as much as possible while also potentially inhibiting beta oxidation directly would be the way to go if one were to choose one pathway to attack. This means high doses niacinamide and aspirin would be of primary importance in cancer therapy.
I am going to ask Peat why he does not like higher doses niacinamide. If it can inhibit beta-oxidation directly, it could be a life-saver with somebody with advanced cancer even if it risks increasing ammonia. That ammonia can easily be chelated. I mean, why else would niacinamide massive liver and pancreatic tumors disappear?
https://raypeatforum.com/community/threads/niacinamide-can-cure-liver-and-maybe-pancreatic-cancer.15021/

Btw, aspirin does all 3 - inhibit FAS, inhibit FAO, and activate PDH. If somebody can find the full study text it would be great. I need to see what concentrations of aspirin were used.
Effects of salicylate on hepatocyte lactate metabolism. - PubMed - NCBI
"...We have examined the effects of salicylate on fluxes of lactate metabolism in rat hepatocytes using a steady state model. Salicylate produces an uncoupling effect, an inhibition of gluconeogenesis, a marked activation of pyruvate dehydrogenase flux, and an inhibition of endogenous fatty acid oxidation. Agents with known functions such as dinitrophenol and dichloroacetate were also compared in this system. The in vitro inhibition of gluconeogenesis caused by salicylate is not primarily related to the uncoupling effect. The fact that octanoate, but not palmitate, overcomes the salicylate inhibition of gluconeogenesis suggests that salicylyl CoA is involved in the inhibition. To relate in vitro studies to Reye's syndrome in vivo, in which medium chain dicarboxylic acids accumulate, we have also examined the effects of monomethyl suberate on liver lactate metabolism. This half ester is taken up by the hepatocytes, and causes inhibition of lactate gluconeogenesis, and uncoupling. Both salicylate and monomethyl suberate inhibit the oxidation of 0.2 mM octanoate by hepatocytes."

Here's my take on it, since I keep reading about imbalances of FAS and FAO leading to accumulating lipid levels, it sounds to me that when this little catabolic/anabolic dance becomes deranged, it is an epitome of cancer metabolism. Of course beta-oxidation occurs in the body all the time to a "normal" degree, and luckily it does not mean we are in a doomed or sickly state. So it seems that this crazy imbalance is the main issue. PUSHING for FAO to be dominant I think is the problem: extreme exercise, fasting, low-carbing, etc. Because it still stands that FAO is still an issue because after that damage or imbalance is said and done, cancer cells thrive on FAO. So in my interpretation, and considering normal day to day life of some degree of b-oxidation, this gross imbalance is the initiator. And to get there, I think the rapid build up of lactic acid is the primary spark or in other words, sugar metabolism is damaged. I also think that right there is why aspirin is a gem: it essentially is addressing the imbalance and the after-the-fact feast due to FAO. The metabolic activation of getting back to sugar burning is vital and so dependent on PDH as well as over-coming (re: randle cycle) FAO.

My thoughts on why Ray is maybe against very high dose niacinamide is possibly due to severely draining methyl groups and glycine in the process. Don't get me wrong, I know he's not in favor of methylation and I agree, but I think (and this might be one of those things that many folks take out of context) he is definitely not for totally zero'ing one's methyl pool. If he is for keeping gene expression at bay, this should ostensibly mean keeping status quo, in either direction. In other words, not a total methyl drain but certainly not hypermethylation either. I think because methylation was becoming such a hot topic at one point, people were misinterpreting that and over-methylating. BUT! I also think typically in a cancer case, there is most likely a situation of over methylation happening (especially so if there is methionine flooding the blood stream from muscle break-down). I think that is why it can be life-saving from cancer! So in my opinion, high-dose niacinamide with aspirin, and high-dose B1 should absolutely be in the arsenal and utilized. People without cancer should probably keep niacinamide to more reasonable levels day to day. Also niacinamide I believe inhibits lipolysis but not actual interference of b-oxidation, while helping reinstate sugar burning, so again we are seeing it is about inhibiting the imbalance.

 

[Obi-wan]

It would also explain why alcohol consumption seems to speed up tumor growth in cancer patients. Even without its endotoxin and 5-HT3 effects, it is great source of citrate AND it also inhibits glucose metabolism.
Btw, correct me if I am wrong but that picture shows that the terminal point for all pathological pathways in cancer is still FAO, right? FAS can't do much damage if it does not feed into the FAO cycle, and neither can glutamine. So, depleting carnitine as much as possible while also potentially inhibiting beta oxidation directly would be the way to go if one were to choose one pathway to attack. This means high doses niacinamide and aspirin would be of primary importance in cancer therapy.
I am going to ask Peat why he does not like higher doses niacinamide. If it can inhibit beta-oxidation directly, it could be a life-saver with somebody with advanced cancer even if it risks increasing ammonia. That ammonia can easily be chelated. I mean, why else would niacinamide massive liver and pancreatic tumors disappear?
https://raypeatforum.com/community/threads/niacinamide-can-cure-liver-and-maybe-pancreatic-cancer.15021/

Btw, aspirin does all 3 - inhibit FAS, inhibit FAO, and activate PDH. If somebody can find the full study text it would be great. I need to see what concentrations of aspirin were used.
Effects of salicylate on hepatocyte lactate metabolism. - PubMed - NCBI
"...We have examined the effects of salicylate on fluxes of lactate metabolism in rat hepatocytes using a steady state model. Salicylate produces an uncoupling effect, an inhibition of gluconeogenesis, a marked activation of pyruvate dehydrogenase flux, and an inhibition of endogenous fatty acid oxidation. Agents with known functions such as dinitrophenol and dichloroacetate were also compared in this system. The in vitro inhibition of gluconeogenesis caused by salicylate is not primarily related to the uncoupling effect. The fact that octanoate, but not palmitate, overcomes the salicylate inhibition of gluconeogenesis suggests that salicylyl CoA is involved in the inhibition. To relate in vitro studies to Reye's syndrome in vivo, in which medium chain dicarboxylic acids accumulate, we have also examined the effects of monomethyl suberate on liver lactate metabolism. This half ester is taken up by the hepatocytes, and causes inhibition of lactate gluconeogenesis, and uncoupling. Both salicylate and monomethyl suberate inhibit the oxidation of 0.2 mM octanoate by hepatocytes."

I think Mildronate would be the best source for blocking Carnitine and inhibiting beta-oxidation.

 

[Obi-wan]

Here is a good explanation of this process even in normal cells.
In this video Chris explains how excessive ROS causes a build up citrate in the mitochondria which then moves into the cytosol where it becomes a substrate for fatty acid synthesis.

This suggests that ROS creates FAS. Chemo creates high ROS...

 

[haidut]

Also niacinamide I believe inhibits lipolysis but not actual interference of b-oxidation, while helping reinstate sugar burning, so again we are seeing it is about inhibiting the imbalance.

Niacinamide does start to inhibit beta-oxidation in higher doses.
Long-term Treatment With Nicotinamide Induces Glucose Intolerance And Skeletal Muscle Lipotoxicity
"...NAM reduced exogenous FA oxidation and increased TAG esterification in skeletal muscle (Fig. 2C and D).We measured the concentration of the intracellular lipid metabolite DAG in skeletal muscle. We found that NAM led to a significant increase in skeletal muscle DAG content compared with controls (Fig. 2E) but no change in ceramide content (Fig. 2F). We also found that NAM caused a significant muscle loss in EDL (Fig. 2G). The present data demonstrate that NAM alters energy substrate preference in skeletal muscle and reduces the capacity of FA oxidation."

I will ask Peat about the methylation because my understanding is that excessive methylation is actually one of the triggers of cancer. Hypermethylation is known to be associated with many cancers, while there are almost no known cases of hypomethylation promoting cancer except possibly in the BRCA1/2 cases.
DNA methylation in cancer - Wikipedia