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

[haidut]

Cornell just finished a “trailblazing” study on the Warburg effect a few weeks ago:

Cancer’s metabolism subject of trailblazing study | Cornell Chronicle

Link to study, published December 7: Multi-scale computational study of the Warburg effect, reverse Warburg effect and glutamine addiction in solid tumors

I don’t quite understand what conclusions they drew, other than I think glutamine addiction not being relevant to cancer metabolism. I believe they’re in the camp that advocates for starving the body of glucose in order to starve the cancer.

They basically confirmed the primary role of the Warburg "effect" in cancer - i.e. in line with the study in the original post above they found that the Warburg "effect" in fact causes cancer cells to grow. It is kind of sad they call this "trailblazing" since the role of lactate as the most potent endogenous VEGF promoter has been known for decades. That why VEGF blocking drugs are one of the main therapies for cancer.

"...Using the results of FBA in models of populations of cells in the form of solid tumors, the group confirmed that the Warburg effect provides a growth advantage for the tumor, but that glutamine addiction does not benefit tumor cells’ growth. “We show that it’s not helpful [for the tumor] to be glutamine-addicted,” Stroock said. “The community will have to find other ways in which glutamine is important.” Stroock’s team also offered insights into the relationship between healthy cells and tumor cells under the reverse Warburg effect, which allows more oxygen to penetrate the cancerous mass in resource-limited microenvironments. Stroock said the group’s work, while opening doors to future study, also confirms a nearly 100-year-old theory. “It puts this ancient hypothesis on more solid footing,” he said, “and we now know more quantitatively … how cancer cells use this Warburg mechanism.”

 

[Mito]

Thanks, was not aware of his work.

He was just on a podcast ( https://peterattiamd.com/tomseyfried/) talking about cancer as a mitochondrial disease. Many of the things he talked about are very similar to Peat's view.

A few Seyfried quotes from the podcast:

(regarding cellular respiration)"...enables all the cells of our or the major of cells in our body to perform this very efficient form of energy production which then frees up the cells to do their sophisticated behaviors, liver cells do what they do, kidney cells, brain cells they all do what they do because they have this very efficient energetic system that's working called respiration."

"Pete Peterson from John's Hopkins had done a magnificent job in collating all this information and he found that in every kind of a cancer cell no matter what kind it is there was some kind of a defect in the number, structure, or function of the mitochondria and it could vary. So some cancer cells have very few mitochondria but they looked normal very, few of them, other tumor cells clearly have a lot of mitochondria but they look abnormal. So whatever it was it was something to do with an impairment of the respiratory system within the cell, and if the cell can't generate energy through normal respiration, then it has to ferment there is no other way it can get the energy."

".....everybody says respiration is normal in cancer cells, and why would they say it's normal, because they started doing cells in culture rather than looking at the tissues themselves, and once you start doing culture work your taking cells from a tissue and separating them and growing them as if they were micro-organisms in the culture dish, well this changes everything, they're no longer connected to each other there growing in some artificial fluid and there doing things that they sometime do sometimes not do in the real world so you make a lot assumptions based on a system that is artifactual.

Peter Attia asking about genetic mutations and cancer..."And is the idea that the those mutations were acquired"....."in other words the genome is unaffected in some of those cases?" Seyfried's reply: "yes we've done that, we've sequenced the entire genome of five different independently derived cancers from mouse all derived from different origins and we didn't find a single genetic abnormality what we call pathogenic where the mutation would actually have an effect on a function and we didn't find a single one."

"...so we only know that you don't get cancer if you're mitochondria remain health that's what we know so that's an important because that goes back to the prevention issue, how do you prevent cancer? You prevent cancer by keeping your mitochondria healthy. How do you do that, well you avoid if you can those risk factors mostly from the environment like viral infection, intermittent hypoxia, radiation exposure, carcinogenic exposure all these different things everyone of those things can damage respiration in a population of cells then leading to cancer because we know of no cancer that has normal respiration...."

Seyfried does however differ from Peat on how to use these ideas to fight an existing cancer. Seyfried is doing clinical studies in Turkey where they use ketogenic diets to minimize glucose and then intermittently use glutamine antagonist to starve the cancer cells and also hyperbaric oxygen. (Clinical trial in Turkey: Efficacy of Metabolically Supported Chemotherapy Combined with Ketogenic Diet, Hyperthermia, and Hyperbaric Oxygen Therapy for Stage IV Triple-Negative Breast Cancer (Iyikesici et al., 2017) [2:13:15])

 

[jondoeuk]

Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis
SAGE Journals: Your gateway to world-class journal research

 

[Mito]

Complex I and IV have been shown to be blocked in cancers, and methylene blue can help in both cases.

Why do you think some studies show blocking Complex I inhibits tumor proliferation?

“In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiaeNADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells
Highlights

• A screen identifies complex I inhibitors as highly selective against Pten-null cells
• Pten-null selectivity is unmatched by common standard of care chemotherapy agents
• Mitochondria of Pten-null cells easily switch to consuming ATP instead of producing it
• The complex I inhibitor deguelin can suppress lethal prostate cancer in RapidCaP.

https://www.cell.com/cell-reports/pdf/S2211-1247(18)30374-7.pdf

 

[jondoeuk]

Complex I and IV have been shown to be blocked in cancers, and methylene blue can help in both cases.

Using an MCT1 inhibitor increases mitochondrial metabolism MCT1 Inhibitor AZD3965 Increases Mitochondrial Metabolism, Facilitating Combination Therapy and Noninvasive Magnetic Resonance Spectroscopy

In my view you want to target that, MCT4 and at least Complex I https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31806-0 The downside is that Metformin is usually ineffective. So we need better drugs.

I know AstraZeneca has one MCT1 inhibitor in a clinical trial (NCT01791595) and they are working on a MCT4 inhibitor too. Some early data has been published for the former http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.2516

 

[haidut]

Why do you think some studies show blocking Complex I inhibits tumor proliferation?

“In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiaeNADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells
Highlights

• A screen identifies complex I inhibitors as highly selective against Pten-null cells
• Pten-null selectivity is unmatched by common standard of care chemotherapy agents
• Mitochondria of Pten-null cells easily switch to consuming ATP instead of producing it
• The complex I inhibitor deguelin can suppress lethal prostate cancer in RapidCaP.

https://www.cell.com/cell-reports/pdf/S2211-1247(18)30374-7.pdf

I don't know but on the flip side even Wikipedia talks about how deficiency of Complex I and a resulting build up of succinate is a known driver of tumor progression.
Succinic acid - Wikipedia
"...Succinate is one of three oncometabolites, metabolic intermediates whose accumulation causes metabolic and non-metabolic dysregulation implicated in tumorigenesis.[37][41] Loss-of-function mutations in the genes encoding succinate dehydrogenase, frequently found in hereditary paraganglioma and pheochromocytoma, cause pathological increase in succinate.[31] SDH mutations have also been identified in gastrointestinal stromal tumors, renal tumors, thyroid tumors, testicular seminomas and neuroblastomas.[37] The oncogenic mechanism caused by mutated SHD is thought to relate to succinate's ability to inhibit 2-oxogluterate-dependent dioxygenases."

 

[LeeLemonoil]

That's somewhat disturbing to read about succinic acid - I take it it is still a mito-beneficial supplement in moderate doses and when mito-respiration is not impaired by mutations or otherwise?

 

[Obi-wan]

According to this Pub Med Report Physiological roles of mitochondrial reactive oxygen species

"Although autophagy has been widely shown to be a survival pathway, under certain circumstances that are not completely understood at this time, autophagy can guide cell death in a process called ‘autophagic cell death.’ This method of controlled cell death is distinct from apoptosis. Some evidence suggests that mROS guide the cell fate decision to induce autophagic cell death. Autophagic cell death is induced by selective degradation of catalase, which leads to vast accumulation of H2O2 and subsequent cell death presumably by nonspecific oxidative damage (Yu et al., 2006). The source of H2O2 appears to be mitochondria, as inhibitors of complex I and complex II can directly induce autophagic cell death by increasing mROS (Chen et al., 2007). Therefore mROS may play dual functions in the context of autophagy – low levels may promote survival by inducing autophagy to allocate intracellular resources under starvation, while high levels may promote controlled autophagic cell death when survival is not possible.

 

[LeeLemonoil]

The olive leaf extract oleuropein exerts protective effects against oxidant-induced cell death, concurrently displaying pro-oxidant activity in hum... - PubMed - NCBI

The olive leaf extract oleuropein exerts protective effects against oxidant-induced cell death, concurrently displaying pro-oxidant activity in human hepatocarcinoma cells.
Katsoulieris EN1.
Author information
Abstract
OBJECTIVES:
Oleuropein (OP), the predominant natural constituent of leaves of the olive tree, exerts anti-inflammatory and antioxidant effects. The purpose of this study was to assess the protective effects of OP under the conditions of paraquat (PQ)-induced oxidative stress in vitro, using the human hepatocarcinoma cell line, HepG2.

METHODS:
Cell viability and death were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 4',6-diamidino-2-phenylindole-propidium iodide staining, respectively. Superoxide anion and lipid peroxidation levels were evaluated using nitroblue tetrazolium and thiobarbituric acid-reactive substances assays, respectively. Apoptosis was assessed by measuring poly(ADP-ribose) polymerase (PARP) and caspase-3 (Casp-3) cleavage via immunoblotting and immunofluorescence analyses.

RESULTS:
PQ induced a decrease in cellular viability by promoting necrosis through a mechanism involving superoxide generation and nuclear translocation of cleaved Casp-3. Co-treatment with OP afforded significant protection against the suppressive effects of PQ, as evident from increased cell viability, reduction of Casp-3 immunofluorescence, and normalization of β-tubulin expression levels. Unexpectedly, these OP-mediated protective effects were associated with increased superoxide and malondialdehyde generation and PARP cleavage.

DISCUSSION:
OP protects HepG2 cells against PQ-induced necrosis by suppressing Casp-3 cleavage while concomitantly acting as a pro-oxidant agent. This paradoxical mechanism of action of OP requires further investigation.

 

[Obi-wan]

I have read through this entire thread again and based upon my current knowledge have changed my opinion on cancer metabolism. Many cancers including prostate cancer develop a mutated metabolism and use the Warburg effect or the reverse Warburg effect to fuel its growth and proliferation. Major fuels are Glucose, Fatty Acids, and Proteins. The central point for all of these fuels is Acetyl CoA with entry into the Citric Acid Cycle. Blocking these fuel lines is essential in weakening the cancer. For fatty acids these lines include Acetate, SREBP-1, ACLY, FAS, FAO, Mevolonate Pathway, and SERP-2. Cancer cells have many mitochondria that are defective but also many that are working overtime. It is the hard working mitochondria that need to be stopped by "starving them of there fuels" Cancer eradication is a completely different mind set than cancer prevention. My original thought of getting the defective mitochondria to work properly is wrong IMO. I want to depolarize all mitochondria in the cancer cell and create apoptosis. In prostate cancer Citrate is oxidized and used to create Lipogenesis which creates Cholesterol/Androgens which fuels proliferation. Glutaminolysis is also involved as is later stage Glycolysis. I am now using repurposed drugs such as Metformin, Atorvastatin, Doxycycline, and Mebendazole as well as other supplements to accomplish this.

 

[haidut]

Major fuels are Glucose, Fatty Acids, and Proteins

Can you show some evidence for the first one? I have not yet seen a cancer type that properly oxidizes glucose. They just waste it into lactic acid due to blocked PDH, and whatever makes it through into the Krebs cycle gets turned into fat through citrate->FAS. Actually, the same situation applies to amino acids. Cancer cells do not really oxidize even protein properly. Cancer cells just break down tissues into amino acids and then some of them get turned into fat through transamination, then Krebs cycle then FAS, while the gluconeogenic ones get turned into glucose and that glucose is also wasted (lactate + fatty acids) as explained earlier. Basically, every cancer type that I have researched so far depends ultimately on fat oxidation. That's why they are so vulnerable to blockage of the FAO cascade.
Glycemia, starch, and sugar in context
"...When cells are stressed, they are likely to waste glucose in two ways, turning some of it into lactic acid, and turning some into fatty acids, even while fats are being oxidized, in place of the sugar that is available. Growth hormone and adrenalin, the stress-induced hormones, stimulate the oxidation of fatty acids, as well as their liberation from storage, so the correction of energy metabolism requires the minimization of the stress hormones, and of the free fatty acids. Prolactin, ACTH, and estrogen also cause the shift of metabolism toward the fatty acids."

Cancer: Disorder and Energy
"...Cancer cells use glucose and the amino acid glutamine primarily for synthetic purposes, and use fats as their energy source;the growth stimulating effect of the "essential fatty acids" (Sueyoshi and Nagao, 1962a; Holley, et al., 1974) shows that depriving a tumor of those fats retards its growth. The great energetic inefficiency of the cancer metabolism, which causes it to produce a large amount of heat and to cause systemic stress, failure of immunity, and weight loss, is because it synthesizes fat from glucose and amino acids, and then oxidizes the fat as if it were diabetic. Estrogen, which is responsible for the fact that women burn fatty acids more easily than men, is centrally involved in this metabolic inefficiency. When a tissue is exposed to estrogen, within minutes it takes up water, and begins to synthesize fat, with a tendency to produce lactic acid at the same time. The alkalizing effect of lactic acid production is apparently what accounts for the uptake of water. Since it takes longer, at least 30 minutes, to produce a significant amount of new enzymes, these early changes are explained by the activation of existing enzymes by estrogen.

"...The transhydrogenases, or the transhydrogenase function of the steroid dehydrogenases, which shift metabolic energy between glycolytic and oxidative systems, have been shown to explain these effects of estrogen, but the transhydrogenases can be activated by many stressors. The biological function of the transhydrogenases seems to be to allow cells to continue growth and repair processes in a hypoxic environment. Estrogen can start the process by creating new pathways for electrons, and will promote processes that are started by something else, and progesterone is estrogen's natural antagonist, terminating the process. Recently, a group at Johns Hopkins University (Le, et al., 2012) has been working out the implications of this ability to change the metabolism under hypoxia: Using an isotope-labeled amino acid, ". . . glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased." The implication of this is that if the tumor isn't supplied with sugar, it will increase the rate at which it consumes the host's proteins. Forty years ago the work of Shapot and Blinov was showing the same effect, except that they demonstrated the involvement of the whole organism, especially the liver, in interaction with the tumor (Blinov and Shapot, 1975)."

So, cancer is little more than extreme "diabetes" initiated by chronic stress which at some point forms a positive feedback mechanism with estrogen and at that point it becomes self-sustained. 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. Of course, it all depends on how advanced the cancer is. However, at least in terms of the pathological principle so far this energetic dysfunction seems to be present in every cancer and no adaptation around it is known to be possible or has been observed in advanced tumors, which are known to be highly adaptable and easily develop resistance to pretty much any cytotoxic chemotherapy. As such, targeting fat metabolism and stress should be the prime target of any treatment that strives to be called "curative".

 

[LucyL]

Why do you think some studies show blocking Complex I inhibits tumor proliferation?

“In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. ...
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

That is controversial -

Metformin directly acts on mitochondria to alter cellular bioenergetics

"We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle. Conflicting prior studies proposed mitochondrial complex I or various cytosolic targets for metformin action, but we show that the compound limits respiration and citric acid cycle activity in isolated mitochondria, indicating that at least for these effects, the mitochondrion is the primary target. Finally, we demonstrate that cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis than nontransformed cells, highlighting their metabolic vulnerability. Prevention of this compensatory metabolic event in cancer cells significantly impairs survival."

 

[jb116]

Just want to add, in conjunction with the lactic acid aspect from haidut's very informative post, things like metformin encourage the exact metabolism of cancer. In other words they create extracellular acidity while alkalizing the cell. Glucose as a promoter of carbon dioxide should definitely not be cut out.

 

[Inaut]

it's so hard to find out which path to choose. I tend to agree with @haidut but what do I really know.... One study says this, the other says the opposite. @Obi-wan if you are inclined in your direction, something must be guiding you that way so it will probably be the right direction for you in the end. Cancer free :)

All i can say is fruit (sugars) are probably extremely beneficial/protective in dealing with cancer. Overfeeding sugar/glucose on the other hand doesnt sound like the answer.

 

[LucyL]

it's so hard to find out which path to choose. I tend to agree with @haidut but what do I really know.... One study says this, the other says the opposite. @Obi-wan if you are inclined in your direction, something must be guiding you that way so it will probably be the right direction for you in the end. Cancer free :)

All i can say is fruit (sugars) are probably extremely beneficial/protective in dealing with cancer. Overfeeding sugar/glucose on the other hand doesnt sound like the answer.

Inaut, I would say also, "what do I really know" ? It is very difficult to decide what path is right, or what is wrong, and clinical evidence is worth a lot when you are faced with that decision. Sigh. 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.") let alone with overwhelmingly successful results. Who among us is brave enough to be the first? Obi-wan has been trying various approaches for a while, and I am just starting down that path.

Anyway, I think these drugs may act in multiple, even conflicting ways. For example, Metformin increases AMPK which suppresses SREP-1c, and according to one study "SREBP-1c in the intestine is positively regulated by insulin and negatively by AMPK, and is able to upregulate enzymes, such as acetyl-CoA carboxylase (ACC1) and fatty acid synthase (FAS), which are involved in denovo fatty acid synthesis ". The study also has this interesting chart:

Further down this article looks a mechanisms of statins, and mentions Atorvastatin may block insulin prodution... "Atorvastatin treatment of rat INS-1 β cells induced inhibition of insulin synthesis by inhibiting farnesyl pyrophosphate ester (FPP, an intermediate in mevalonate and non-mevalonate pathways), which may inhibit a chain of proteins that communicates signals from the receptor to the nucleus and is called the Ras pathway (Ras/Raf/ERK/CREB) [124]. Inhibition of this pathway leads to inhibition of promoter activity of the insulin gene and to a decrease of insulin secretion [124]. "

Perhaps some of these actions outweigh the negative increase in lactic acid etc. in cancer therapy. Surely the diet/lifestyle advice could be tailored to address some of the other aspects, like keeping PUFA super low, and the calcium/phosphorous ratio high.

 

[haidut]

That is controversial -

Metformin directly acts on mitochondria to alter cellular bioenergetics

"We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle. Conflicting prior studies proposed mitochondrial complex I or various cytosolic targets for metformin action, but we show that the compound limits respiration and citric acid cycle activity in isolated mitochondria, indicating that at least for these effects, the mitochondrion is the primary target. Finally, we demonstrate that cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis than nontransformed cells, highlighting their metabolic vulnerability. Prevention of this compensatory metabolic event in cancer cells significantly impairs survival."

I think it is pretty well-established at this point, not much controversy to it. In one of the recent threads I posted, they actually used metformin to induce cancerization, and it was precisely because of its extracellular acidifying effects - i.e. raising lactic acid by inhibiting mitochondrial ETC.
https://raypeatforum.com/community/threads/baking-soda-may-treat-cancer-metformin-may-cause-it.29266/

In fact, I think metformin is now officially listed as a known "mitochondrial toxin" (the same term they use in the study above) in several FDA/EPA databases. I will find the links and post here.

@Mito @jb116

 

[Obi-wan]

Per Wikipedia

"High blood lactic acid level is a concern if the medication is prescribed inappropriately and in overly large doses."

also

"The most serious potential side effect of metformin use is lactic acidosis; this complication is very rare, and the vast majority of these cases seem to be related to comorbid conditions, such as impaired liver or kidney function, rather than to the metformin itself.[63]"

Then we have this study at Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug? which confirms @LucyL chart above

I take 2 -500mg tablets per day. 1 in the am/1 in the pm

 

[Obi-wan]

Can you show some evidence for the first one? I have not yet seen a cancer type that properly oxidizes glucose. They just waste it into lactic acid due to blocked PDH, and whatever makes it through into the Krebs cycle gets turned into fat through citrate->FAS. Actually, the same situation applies to amino acids. Cancer cells do not really oxidize even protein properly. Cancer cells just break down tissues into amino acids and then some of them get turned into fat through transamination, then Krebs cycle then FAS, while the gluconeogenic ones get turned into glucose and that glucose is also wasted (lactate + fatty acids) as explained earlier. Basically, every cancer type that I have researched so far depends ultimately on fat oxidation. That's why they are so vulnerable to blockage of the FAO cascade.
Glycemia, starch, and sugar in context
"...When cells are stressed, they are likely to waste glucose in two ways, turning some of it into lactic acid, and turning some into fatty acids, even while fats are being oxidized, in place of the sugar that is available. Growth hormone and adrenalin, the stress-induced hormones, stimulate the oxidation of fatty acids, as well as their liberation from storage, so the correction of energy metabolism requires the minimization of the stress hormones, and of the free fatty acids. Prolactin, ACTH, and estrogen also cause the shift of metabolism toward the fatty acids."

Cancer: Disorder and Energy
"...Cancer cells use glucose and the amino acid glutamine primarily for synthetic purposes, and use fats as their energy source;the growth stimulating effect of the "essential fatty acids" (Sueyoshi and Nagao, 1962a; Holley, et al., 1974) shows that depriving a tumor of those fats retards its growth. The great energetic inefficiency of the cancer metabolism, which causes it to produce a large amount of heat and to cause systemic stress, failure of immunity, and weight loss, is because it synthesizes fat from glucose and amino acids, and then oxidizes the fat as if it were diabetic. Estrogen, which is responsible for the fact that women burn fatty acids more easily than men, is centrally involved in this metabolic inefficiency. When a tissue is exposed to estrogen, within minutes it takes up water, and begins to synthesize fat, with a tendency to produce lactic acid at the same time. The alkalizing effect of lactic acid production is apparently what accounts for the uptake of water. Since it takes longer, at least 30 minutes, to produce a significant amount of new enzymes, these early changes are explained by the activation of existing enzymes by estrogen.

"...The transhydrogenases, or the transhydrogenase function of the steroid dehydrogenases, which shift metabolic energy between glycolytic and oxidative systems, have been shown to explain these effects of estrogen, but the transhydrogenases can be activated by many stressors. The biological function of the transhydrogenases seems to be to allow cells to continue growth and repair processes in a hypoxic environment. Estrogen can start the process by creating new pathways for electrons, and will promote processes that are started by something else, and progesterone is estrogen's natural antagonist, terminating the process. Recently, a group at Johns Hopkins University (Le, et al., 2012) has been working out the implications of this ability to change the metabolism under hypoxia: Using an isotope-labeled amino acid, ". . . glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased." The implication of this is that if the tumor isn't supplied with sugar, it will increase the rate at which it consumes the host's proteins. Forty years ago the work of Shapot and Blinov was showing the same effect, except that they demonstrated the involvement of the whole organism, especially the liver, in interaction with the tumor (Blinov and Shapot, 1975)."

So, cancer is little more than extreme "diabetes" initiated by chronic stress which at some point forms a positive feedback mechanism with estrogen and at that point it becomes self-sustained. 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. Of course, it all depends on how advanced the cancer is. However, at least in terms of the pathological principle so far this energetic dysfunction seems to be present in every cancer and no adaptation around it is known to be possible or has been observed in advanced tumors, which are known to be highly adaptable and easily develop resistance to pretty much any cytotoxic chemotherapy. As such, targeting fat metabolism and stress should be the prime target of any treatment that strives to be called "curative".

I agree but Glucose (simple sugars) levels effect Insulin levels which effects fatty acid metabolism. So Insulin is a potential problem. I use Berberine and Metformin to lower insulin. @haidut what is more important to block FAS or FAO? Or both? I use Aspirin, Berberine, and Metformin to block FAS. I use Doxycycline and Mildronate to block FAO. I think Mildronate is very interesting. I know you are not a fan of Metformin. I also use Hydroycitrate which is a ATP citrate lyase inhibitor and a mild aromatase inhibitor. I would consider Tamoxifen as a stronger aromatase inhibitor. Thoughts?

 

[haidut]

I agree but Glucose (simple sugars) levels effect Insulin levels which effects fatty acid metabolism. So Insulin is a potential problem. I use Berberine and Metformin to lower insulin. @haidut what is more important to block FAS or FAO? Or both? I use Aspirin, Berberine, and Metformin to block FAS. I use Doxycycline and Mildronate to block FAO. I think Mildronate is very interesting. I know you are not a fan of Metformin. I also use Hydroycitrate which is a ATP citrate lyase inhibitor and a mild aromatase inhibitor. I would consider Tamoxifen as a stronger aromatase inhibitor. Thoughts?

I think FAO is more important as therapeutic target for cancer but FAS is also good to address as it is also overexpressed in every cancer type. Insulin is not as much of a problem as the cancer lobby is making it out to be. It is one of the most potent activators of PDH by inhibiting PDK. This is why insulin therapy for cancer was proposed as early as the 1950s but it never took off because the cancer industry made sure any attempt to treat cancer as metabolic disease was discredited before it had any chance to be proven clinically.
Low-Dose Chemotherapy with Insulin (Insulin Potentiation Therapy) in Combination with Hormone Therapy for Treatment of Castration-Resistant Prostate Cancer
Insulin Potentiation Therapy: A Treatment for Cancer?

Pyruvate is another one and this is one of the reasons we included it in Pyrucet. In general, anything that activates glucose metabolism will inhibit FAO, which insulin is also known to do. Yes, it does increase FAS but that only happens at pathological levels, and even then it is better to synthesize fat than to oxidize it, as far as keeping cancer in check goes. You can take care of keeping FAS low by simply keeping NAD/NADH ratio higher. FAS only gets activated when there is an excess of NADH, which is the case in cancer and increasing NAD/NADH both lowers lactate generation and FAS activation.
Pyruvate dehydrogenase - Wikipedia
"...Phosphorylation of E1 (PDH) by pyruvate dehydrogenase kinase (PDK) inactivates E1 and subsequently the entire complex. PDK is inhibited by dichloroacetic acid and pyruvate, resulting in a higher quantity of active, unphosphorylated PDH.[3] Phosphorylaton is reversed by pyruvate dehydrogenase phosphatase, which is stimulated by insulin, PEP, and AMP, but competitively inhibited by ATP, NADH, and Acetyl-CoA."

 

[GAF]

Gelum Drops: reducing lactic acid, increasing hemoglobin and lymphocytes - Blog: Cancer Treatments - from Research to Application

Anybody know what these are? German product. Idealabs?