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

[jb116]

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

Yes I agree with you about hypermethylaytion, which is why I stated before that in a cancer state the theoretical caveat goes out the window: I am firmly for the use of high dose niacinamide in those states. i.e. derangement of FAS/FAO with hypoxia and acidosis as the primary spark. If you do ask Peat, I'd really love to know what his actual reason is as well, that would be great. That's interesting about high dose NAM inhibiting b-oxid too, thanks. What are your thoughts on FFA rebound with B3?

 

[haidut]

Yes I agree with you about hypermethylaytion, which is why I stated before that in a cancer state the theoretical caveat goes out the window: I am firmly for the use of high dose niacinamide in those states. i.e. derangement of FAS/FAO with hypoxia and acidosis as the primary spark. If you do ask Peat, I'd really love to know what his actual reason is as well, that would be great. That's interesting about high dose NAM inhibiting b-oxid too, thanks. What are your thoughts on FFA rebound with B3?

Well, he did say "up to 1g for long term use" is likely safe and the study used the HED of about 8mg/kg, so that means under 1g for most people. Since niacinamide does not inhibit excessive lipolysis by only baseline, I don't think there will be a rebound after stopping in contrast to something like niacin, which targets the receptors HCA1/HCA2 and can in theory trigger a rebound when stopped. I think this is another reason Peat likes niacinamide, in addition to the fact that niacin increases histamine/serorotonin/prostaglandin release.
I will ask him and post his response here, if he responds.

 

[jb116]

Well, he did say "up to 1g for long term use" is likely safe and the study used the HED of about 8mg/kg, so that means under 1g for most people. Since niacinamide does not inhibit excessive lipolysis by only baseline, I don't think there will be a rebound after stopping in contrast to something like niacin, which targets the receptors HCA1/HCA2 and can in theory trigger a rebound when stopped. I think this is another reason Peat likes niacinamide, in addition to the fact that niacin increases histamine/serorotonin/prostaglandin release.
I will ask him and post his response here, if he responds.

Excellent, thanks, that's what I was looking for. It's with niacin that kind of rebound becomes possible. Looking forward to his response, hopefully he responds!

 

[LucyL]

"...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]"

I'm trying to sort this out - Pyruvate converts into acetyl-CoA in the mitochondrion. Then the acetyl CoA needs to be transported into cytosol. But, citrate is required for this, however citrate is produced by condensing acetyl CoA with oxaloacetate. Where does that acetyl CoA condensed with oxaloacetate come from?

 

[SB4]

I'm trying to sort this out - Pyruvate converts into acetyl-CoA in the mitochondrion. Then the acetyl CoA needs to be transported into cytosol. But, citrate is required for this, however citrate is produced by condensing acetyl CoA with oxaloacetate. Where does that acetyl CoA condensed with oxaloacetate come from?

As far as I understand it, haidut is talking about converting glucose into fatty acids. So pyruvate in mito turns to acetyl CoA then citric acid, this usually would continue the cycle to produce energy however if the cell is signalling it has enough energy it will leave the mito and be turned into fatty acid in the cytosol.

 

[haidut]

As far as I understand it, haidut is talking about converting glucose into fatty acids. So pyruvate in mito turns to acetyl CoA then citric acid, this usually would continue the cycle to produce energy however if the cell is signalling it has enough energy it will leave the mito and be turned into fatty acid in the cytosol.

Bingo. Thanks for answering it. I think it is also not so much the cell signalling that is has enough energy but that the ETC is not functioning, usually due to blockade of cytochrome C oxidase. So, those extra electrons (citrate) from the Krebs cycle have to go somewhere and if they cannot go through the ETC and ultimately combine with oxygen then the only other alternative is fat synthesis. Since FAS also "consumes" NADPH and releases NADP, it is also an example of an emergency "oxidizing" process of sort similar to the excess pyruvate being used to oxidize excess NADH (and generate lactate) during glycolysis if the PDH is not working. So, both fatty acid synthesis and lactate generation are emergency (maldaptive) electron consuming processes when OXPHOS is not working properly due to blocks at various steps in the process. That is what both diabetes and cancer essentially are, just different degrees of severity. The rapid wasting of diabetes I, which is usually quickly fatal if not treated by insulin, and the cachexia in cancer are basically the same process - driven by excessive lipolysis and inflammation. You can think of (untreated) diabetes I as a non-organ-specific cancer. It has the same signs/symptoms and the same outcome.
@LucyL

 

[SB4]

it is also an example of an emergency "oxidizing" process of sort similar to the excess pyruvate being used to oxidize excess NADH (and generate lactate) during glycolysis if the PDH is not working.

I wonder if you can clear this up for me. If PDH isn't working, shouldn't we have a higher amount of NAD and lower NADH?

PDH takes in Pyruvate and NAD+ and spits out Acetyl-CoA and NADH+H+. If pyruvate does not enter then NAD is not converted to NADH?

Also I have heard that 2 pyruvate are required to enter the mito and operate the PDC. One gets turned into Acetyl-CoA and in turn produces NADH, the other pyruvate uses the generated NADH with LDH to turn into lactate, regenerating the NAD+ so that the 2 new Pyruvates can enter the TCA and repeat the process. Therefore the healthy ratio between pyruvate and lactate (in the mitochondria I presume) is 1:1.

I have been recently reading speculation on how a problem in PDC, specifically DHLA (Lip-SH) failing to recycle back to LA (Lip-S), can cause CFS. They say when the cell is required to produce energy in CFS PDH doesn't work and there is a spike in lactate. I would have thought this would be cytosolic lactate to try and compensate for lack of ATP but where does the LDH get all the NADH from to make Lactate.

Here is the paper if you are interested.

 

[Mito]

Bingo. Thanks for answering it. I think it is also not so much the cell signalling that is has enough energy but that the ETC is not functioning, usually due to blockade of cytochrome C oxidase. So, those extra electrons (citrate) from the Krebs cycle have to go somewhere and if they cannot go through the ETC and ultimately combine with oxygen then the only other alternative is fat synthesis.

Chris walks through the detailed biochemistry in the video class I posted above. The aconitase enzyme gets inhibited when ROS is generated in the electron transport chain via “electron leak” (oxygen didn’t get all of the electrons in should have in the ECT). The ROS inhibits aconitase by oxidizing the iron-sulfur cluster in the aconitase enzyme. Inhibiting aconitase prevents citrate from advancing in the Krebs cycle into isocitrate, so citrate builds up.

 

[haidut]

I wonder if you can clear this up for me. If PDH isn't working, shouldn't we have a higher amount of NAD and lower NADH?

No, at the end of glycolysis the output is pyruvate and NADH. So, if only glycolysis is working then you get a buildup of pyruvate and NADH in the cytosol and since glycolysis must continue at ALL COST for the organism to survive then pyruvate becomes the emergency oxidant to NADH and this oxidizes NADH back to NAD with lactate being the end product that is then shuttled to liver to be turned into pyruvate again through the Cori cycle. See this link below.
Glycolysis - Wikipedia

 

[SB4]

No, at the end of glycolysis the output is pyruvate and NADH. So, if only glycolysis is working then you get a buildup of pyruvate and NADH in the cytosol and since glycolysis must continue at ALL COST for the organism to survive then pyruvate becomes the emergency oxidant to NADH and this oxidizes NADH back to NAD with lactate being the end product that is then shuttled to liver to be turned into pyruvate again through the Cori cycle. See this link below.
Glycolysis - Wikipedia

Makes sense, thanks.

 

[Obi-wan]

Chris walks through the detailed biochemistry in the video class I posted above. The aconitase enzyme gets inhibited when ROS is generated in the electron transport chain via “electron leak” (oxygen didn’t get all of the electrons in should have in the ECT). The ROS inhibits aconitase by oxidizing the iron-sulfur cluster in the aconitase enzyme. Inhibiting aconitase prevents citrate from advancing in the Krebs cycle into isocitrate, so citrate builds up.
View attachment 13667

In normal epithelial cells of the prostate citrate is produced but not oxidized. The citrate is secreted as a component of semen. These cells also accumulate large concentrations of zinc which have an inhibitory effect on m-aconitase. By accumulating citrate, normal prostate epithelial cells appear to halt the Krebs cycle and therefore act very different to the majority of cells in the body in the production of ATP. A shift occurs in malignant prostate cells. Prostate cancer cells reverse this phenotype and adapt a zinc wasting citrate oxidizing phenotype. This shift allows these cells to utilize the Krebs Cycle and subsequent oxidative phosphorylation also shifting to a lipid producing phenotype.

 

[haidut]

oxidative phosphorylation also shifting to a lipid producing phenotype.

As I mentioned before, since their ETC is not working properly, it cannot really be called OXPHOS. I have not yet seen a cancer cell with fully functioning OXPHOS. At most, they have glycolysis and partially functioning Krebs cycle. If there was full OXPHOS there would not be much generation of fat. Those excess electrons will all make it to O2 and form water.

 

[Obi-wan]

As I mentioned before, since their ETC is not working properly, it cannot really be called OXPHOS. I have not yet seen a cancer cell with fully functioning OXPHOS. At most, they have glycolysis and partially functioning Krebs cycle. If there was full OXPHOS there would not be much generation of fat. Those excess electrons will all make it to O2 and form water.

 

[Obi-wan]

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

View attachment 13611

This chart shows only 2 entry ways into the mitochondria. Pyruvate and Acylcarnitine. Block Acylcarnitine (with Mildronate) and the cell is forced to use the Glucose pathway for fuel.

 

[haidut]

Block Acylcarnitine (with Mildronate) and the cell is forced to use the Glucose pathway for fuel.

Yes. And also increasing pyruvate/acetoacetate amount has largely the same effect as MIldronate. This is why we released Pyrucet. Both acetoacetate and pyruvate compete quite effectively with carnitine-dependent FAO. There are quotes in the Pyrucet thread from studies that expand on that.

 

[Mito]

In normal epithelial cells of the prostate citrate is produced but not oxidized. The citrate is secreted as a component of semen. These cells also accumulate large concentrations of zinc which have an inhibitory effect on m-aconitase. By accumulating citrate, normal prostate epithelial cells appear to halt the Krebs cycle and therefore act very different to the majority of cells in the body in the production of ATP. A shift occurs in malignant prostate cells. Prostate cancer cells reverse this phenotype and adapt a zinc wasting citrate oxidizing phenotype. This shift allows these cells to utilize the Krebs Cycle and subsequent oxidative phosphorylation also shifting to a lipid producing phenotype.

Interesting, if that is true then prostate epithelial cells would "normally" be ATP deficient. The bioenergetics theory would say these cell are more likely to be unable to differentiate pushing them towards a cancer metabolism.

 

[tara]

There just aren't many cases of haidut's seemingly simple approach ("Break the estrogenic vicious cycle, do NOT restrict glucose, inhibit FAO, and it should go away on its own or at the very least shrink to the point where the immune system can handle it.")

I wonder to what extent some of the approaches of eg Max Gerson worked along these lines. IIUC, his diet provided a high carb diet primarily from lots of vegetables (and vege juices). It also attended to mineral balance, that might well have influenced hormonal balance?

So, if I am reading this correctly, the study says that a commercially available baking soda product can completely control melanoma growth, prevent cancer in genetically cancer-guaranteed mice, and completely prevent metastases from such cancer(s). At the same time we are being told that nothing can really be done for metastatic melanoma, which is the second deadliest cancer (after pancreatic), and that baking soda treatment of cancer is a scam.

The product contains:
Calcium carbonate, sodium bicarbonate, magnesium carbonate, disodium phosphate, potassium bicarbonate, zinc sulfate. Not sure of proportions of all, but some clues on how much Ca, Mg, Na, Zn included. Daily dose 4g/1 tsp.
Basenpulver pH-balance Pascoe - Pascoe Natural Healthcare
If I were fighting cancer, I think I'd be paying attention to tactics that address mineral and pH buffers and balance.

 

[Obi-wan]

Interesting, if that is true then prostate epithelial cells would "normally" be ATP deficient. The bioenergetics theory would say these cell are more likely to be unable to differentiate pushing them towards a cancer metabolism.

See https://www.researchgate.net/publication/318092915_The_Metabolic_Phenotype_of_Prostate_Cancer

Also Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer. - PubMed - NCBI

This was interesting Prolactin and testosterone regulation of mitochondrial zinc in prostate epithelial cells. - PubMed - NCBI

"The results support the concept that mitochondrial zinc is an inhibitor of m-aconitase and citrate oxidation; and that prolactin and testosterone regulation of mitochondrial zinc provides a mechanism for their regulation of citrate oxidation in citrate-producing prostate epithelial cells."

Now it gets complicated Testosterone and Prolactin Regulation of Metabolic Genes and Citrate Metabolism of Prostate Epithelial Cells

"This raises the important question as to the mechanism that imparts hormone-responsiveness of the metabolic genes selectively in these prostate cells. In fact, the specificity is even more complex as represented by the opposite effects of both hormones on m-aconitase expression in ventral (increase) versus lateral (decrease) versus dorsal (no effect) prostate cells (Table 1). How does a hormone exhibit differing effects on a constitutively expressed gene in different cells of the same species? These are exciting and challenging issues that must be addressed and investigated."

"These relationships bring to focus the multifaceted and coordinated metabolic activities that must be involved in the hormonal regulation of prostate citrate production. This hormonal control requires the regulation of selective metabolic genes associated with enzyme and transport activities that are essential to the process of citrate production. How these hormone-responsive genes become selected and coordinated is a fascinating relationship awaiting resolution."

Per The mouse prostate: a basic anatomical and histological guideline"Contrary to mice, men have a prostate without exterior lobation that contains distinct glandular regions, including a peripheral zone (PZ), a central zone (CZ), a transition zone (TZ), and a non-glandular anterior fibromuscular stroma region, each with characteristic histology [26,27]. The PZ is the area that surrounds the proximal prostatic urethra. Based on anatomic [28] and interspecies comparisons of mRNA expression signatures [29], the mouse DL (Dorsal) prostate lobes are homologous to the human PZ, where 75-85% of prostate adenocarcinomas occur in patients [30-33]. The CZ, which is considered to be the human counterpart of the mouse AP lobes, is a cone-shaped region that surrounds the vas deferens, and occupies about 25% of the prostate volume. The TZ, a region that does not have a mouse homologue [34] and where most benign prostatic hyperplasia lesions develop in patients [33], is the smallest zone (5-10% of prostate volume) and surrounds the distal prostate urethra [35]. Thus, while in humans the urethra is completely encircled by the prostate, this is not the case in mice."

 

[jondoeuk]

So, if I am reading this correctly, the study says that a commercially available baking soda product can completely control melanoma growth, prevent cancer in genetically cancer-guaranteed mice, and completely prevent metastases from such cancer(s).

In mice! I know a trial took place (NCT02531919), but the data was never published.

At the same time we are being told that nothing can really be done for metastatic melanoma, which is the second deadliest cancer (after pancreatic), and that baking soda treatment of cancer is a scam.

That isn't true Five-Year Survival Observed in Longest Follow-up to Date of Advanced Melanoma Patients Treated with the Combination of Opdivo (nivolumab) and Yervoy (ipilimumab) Even if patients fail those drugs there are other treatment options Updated Results of Studies in Advanced Cervical Cancer and Melanoma Support Long-Term Efficacy of Iovance Tumor Infiltrating Lymphocyte (TIL) Therapy

 

[jondoeuk]

A new preclinical paper Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma