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Cancer Is NOT Addicted To Glucose, As Previously Thought

Discussion in 'Scientific Studies' started by haidut, Jan 15, 2019.

  1. haidut

    haidut Member

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    Little by little, the lies about cancer told for over 100 years start to fall apart. One of the last strongholds of the "traditional" view on cancer is that it is "addicted" to glucose and eating a high-carb diet fuels tumor growth. Evidence to the contrary has actually been available for decades, and we have quite a few threads on the forum discussing the true "addiction" of cancer - fat.
    Cancer Addiction To Fat Confirmed; Niacinamide As Possible Treatment

    Now, a major cancer research center has come out with a study recognizing that sugar has little role in fueling cancer growth. In fact, when sugar was restricted, the cancer became much more aggressive and switched to oxidizing glutamine, which is also something we have discussed on the forum before.
    Melanoma Needs Glutamine To Grow And Dies Without It

    And how does the cancer get a hold of glutamine? By increasing cortisol of course, and thus stimulating muscle breakdown, which eventually leads to cachexia. That "one weird secret" most oncologists are truly desperate to hide from the public is that most cancer patients die from either cachexia or side effects of chemotherapy / radiation (especially immune suppression and resulting opportunistic infections). Very few people die directly due to their primary cancer.
    Well, the study below shows that if cachexia is the goal then restricting sugar is a "great" way to achieve it.

    Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin
    "...Finally, we examined whether Ldha-null tumor cells increase glutamine utilization from the environment as a carbon source [when glucose supply is restricted]. Glutamine is imported into the cell through the Slc1a5 transporter and can fuel the TCA cycle through glutaminase-mediated conversion to glutamate. mRNA levels of both Slc1a5 and glutaminase were upregulated in HFSC-induced SCC (Fig S1 and Fig. 7b), raising the possibility that glutamine metabolism may be increased in SCC formation35. To determine whether loss of Ldh activity promotes glutamine metabolism, we measured glutaminase activity in tumor lysate. Ldha-null tumors exhibited elevated glutaminase activity relative to wild-type tumors (n = 6) (Fig. 7c). In addition, tumor glutamine metabolism was assessed through tumor glutamine tracing with injected [U-13C5] glutamine. Metabolomics analysis of glutamine-labeled tumors indicated that Ldha-null tumors did indeed take up more glutamine than wild-type tumors (Fig. 7d). Moreover, Ldha-null tumors showed increased glutamine labeling of several TCA cycle metabolites via oxidative glutamine metabolism (Fig. 7e) and reductive glutamine metabolism (Fig. 7f), consistent with increased use of glutamine as a biosynthetic carbon source in the absence of Ldh activity."

    "...In fact, a recent study showed that only certain types of lung tumors are sensitive to inhibition of glycolysis and certain lung tumors require inhibition of both glycolysis and glutamine pathways to block tumorigenesis, suggesting that different types of tumors have different metabolic requirements."

    "...We used glutamine labeling to trace uptake and metabolism and did indeed find that Ldha-null tumors took up and used more glutamine to power their metabolism. Although there was no difference in [U-13C3] lactate labeling of TCA cycle metabolites, Ldha-null tumors increased uptake and TCA cycle metabolism of [U-13C5] glutamine, suggesting the use of glutamine as a carbon source to compensate for reduced glycolysis/glucose metabolism. These results suggest that Ldha-null tumors may be sensitized to glutaminase inhibition35. An outstanding question from this work is to understand whether this increased glutamine uptake and utilization compensates for loss of glucose metabolism in the absence of Ldh activity. It is possible that dual inhibition of both Ldh activity and glutamine uptake or glutaminase could potentially starve tumors by circumventing their metabolic flexibility, and this will be the focus of effort going forward."

    UCLA study shows tumors are not as addicted to glucose as previously thought
    "...Scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have discovered that squamous cell skin cancers do not require increased glucose to power their development and growth, contrary to a long-held belief about cancer metabolism. The findings could lead to a better understanding of the metabolic needs of many different types of cancer, and to the development of new cancer treatments. The research, led by senior authors Heather Christofk and Bill Lowry, was published in the journal Nature Communications. “These findings suggest that tumors are metabolically flexible and can use nutrients other than glucose to fuel growth,” said Christofk, a UCLA associate professor of biological chemistry and of molecular and medical pharmacology. “Understanding all of the nutrients cancers use for growth is critical to developing drugs that can successfully target cancer’s metabolism.”
     
  2. Richiebogie

    Richiebogie Member

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    I ate more fried potato chips for a few days during a period of "if its vegan it's good" madness and suddenly a brown spot appeared on my head.

    My family thought it was scary and should be looked at by a dermatologist.

    Instead I stopped the chips, stuck to fruit and boiled potatoes and a little dark chocolate and grew my hair out over the spot.

    A few weeks later I shaved my head again and the spot was gone!

    It was sort of like a nutritional magic trick!

    Not sure if it would fill a stadium though!

    People can't sit still for 3 weeks anymore!
     
  3. OP
    haidut

    haidut Member

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    So true. Ability to sit still depends a lot on GABA and good metabolism, and neither one of them is very common these days.
    Amazing story btw. Did you use any aspirin, progesterone, etc or was it just diet that fixed it?
     
  4. Mito

    Mito Member

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    Is targeting glutamine metabolism is a viable treatment approach?
    Targeting Glutamine Metabolism for Cancer Treatment
     
  5. johnwester130

    johnwester130 Member

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    Jackson's Honest and Trafo chips use coconut oil in their chips.
     
  6. ecstatichamster

    ecstatichamster Member

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    I doubt that it is.

    I think the approach worth doing is to support the body's health and its ability to get rid of cancer. High CO2, high potassium, low iron. Low PUFA. Maybe vitamin C therapy.
     
  7. Richiebogie

    Richiebogie Member

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    Just food and salt. I stopped taking aspirin when I learned fruit was already high in salicylates!

    I remember feeling the spot through my hair, as the hair grew back and being slightly worried. It was just above and behind my right ear. Yet when I shaved the hair to get a clear look at it, it was gone!

    These were cooked in sunflower and canola oils so assume issues of PUFA and acrylamide. (Boiling whole potatoes in water means no fats, less surface area exposed, less oxidation, less browning, less crisping and lower temperatures).
     
  8. OP
    haidut

    haidut Member

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    This is one of the metabolic pathways, and as the study I posted shows, combined blockade of glutamine synthesis and excessive glycolysis worked better than just glycolysis treatment. Peat wrote about glycine as "chemotherapy" for cancer and one of the main effects of glycine is the depletion of glutamine, as well as lowering excessive glycolysis.
     
  9. danielbb

    danielbb Member

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    @haidut - I really appreciate what you do here. Through Ray, your posting, and some of the people I've learned of like Otto Warburg have convinced me that chronic diseases are likely metabolism-related diseases rather than genetic diseases. I believe I have just about reversed my heart disease, for example, by fixing my metabolism (basically eating whole, non-processed food). Beyond anecdotal stories of healing however, I believe the metabolic issue is more complex than blaming sugar or fat in isolation. There are two running documentaries on Netflix right now one "Forks Over Knives" promoting low fat/high carb and the other called the Magic Pill promoting low carb/high fat. Each documentary has an aura of believability and they are almost like watching the same thing. In each case, they show all these sick people in the beginning where one documentary demonizes fat and the other documentary demonizes sugar. At the end of each, they show how all the respective sick people were healed by following the diet espoused in the respective documentary. Watch either one in isolation, and it is easy to be swayed but what appears to be cures to complex diseases. In my anecdotal experience, high carb/low fat works and low carb/high fat works to restore metabolism. I've found where problems ensue is the mixing of sugar and fat at the same time as it seems to place my body in a weird metabolic state where I retain water and I've now interpreted that as inflammation.

    I believe the Randle cycle/effect explains why this is so. It says that when we give our bodies fat, it shuts down our ability to properly process carbs. Likewise, if we've gone without food and our bodies our living off our fat stores, eating carbs will shut down the fat burning metabolism (forgive me if I have not stated things correctly). I've experimented by separating my carbs from my fat consumption and almost like magic, pounds of water came off in just about 1 week. I've found that these confused metabolic states are caused by what I call "tweaner" foods that most of us are aware can cause problems like pastries, cookies, cakes, candies, ice cream, pizza, etc. that all mix healthy doses of sugar and fat. To test my theory, I made pizza using no-fat mozzarella cheese (made from skim milk) and did not add any meat while using other vegetable toppings. Thus, I converted it into a carbohydrate-only food. Normally, I would gain 2-3 lbs the next day after consuming pizza but by making this simple tweak, there were no weight gains the next day. You can fool with the pizza mixture and use a zucchini or cauliflower-based crust to radically lower the carb content while using higher fat cheese with similar results. I've found vegetable crusts to be unsatisfactory however. I don't eat much of this, but sometimes I have a taste for it. To also support my theory about the harmful metabolic effects of mixing fat and carbs at the same meal, here is an article that has been posted on these forums before about the Randle cycle and they describe this problem near the end of the article. The following is posted for convenience:

    The Randle cycle revisited: a new head for an old hat

    "These two opposite hypotheses may be reconciled by considering a continuum in the establishment of aberrant mitochondrial function that may evolve from a partial and discreet deficiency to a progressive failure of the oxidative mitochondrial capacities. The slowly progressing pathological process could be the consequence of a continuous overabundant diet enriched in both carbohydrate and lipid, unmatched by physical activity. In the mitochondria, the redox pressure from both substrates would provoke a continuous production of ROS, resulting first in minimal damage but deteriorating with time into more extensive and irreversible lesions. This interpretation is in agreement with recent data showing that mitochondrial alterations do not precede the onset of insulin resistance and result from increased ROS production in muscle in diet-induced diabetic mice. In addition, the importance of physical activity and energy utilization is fully taken into account in our interpretation, because they are expected to protect the mitochondria by decreasing ROS production."
     
  10. Dr. C

    Dr. C Member

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    @haidut

    If this was true, than what does a PET CT (PET cat scan) show? It clearly seems that much more glucose is making it's way into cancerous cells than healthy tissue. Maybe it's not used primarily as a fuel, but it's sure being used somehow.

    There is no doubt most cancers are using glutamine to burn in their dysfunctional mitochondria for energy. But I guess those mitos are not able to burn fatty acids nor ketone bodies anymore. Just amino acids like glutamine and glutamate.

    It might seem possible to be that glucose is not primarily used as a fuel but "just" to produce lactic acid. The lactic acids is then pushed out a of tumor and leads to the formation of new blood vessels, providing the tumor with more bulding blocks and especially more gluamine/glutamate.

    The problem is, drugs blocking amino acids are highly toxic. They are just like a chemotherapeutic drug (although a little bit more targetted). Still I believe blocking glumatine from day to day while restircting glucose all the time while switiching the metabolism the ketones (which will not be burned by the tumor) might be the best strategy in theory if there wasn't this toxicity.

    What are your thoughts on this thesis?
     
  11. OP
    haidut

    haidut Member

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    Cancer cells simply waste a lot of glucose and convert it into lactate due to their highly reduced state. Diabetic cells do the same. Often, blocking fat oxidation is enough to restore balance. See the first reference I posted in the original post. It shows niacinamide made large tumors disappears so quickly the scientists thought they were delusional. The other references also talk about this, so if you go through the links I posted you will find the information you need. The one mentionign melanoma is a great one and it has links to at least 6-7 other studies on cancer, fat oxidation, and the Warburg effect.
     
  12. Kartoffel

    Kartoffel Member

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    I don't think that mixing fat and carbohydrates should be a problem. Otherwise, nature would be pretty stupid providing roughly equal amounts of energy as sugar and fat in mother's milk. Also, Ray (who always emphasizes the importance of carbohydrate oxidation) said that anything from 30-50% fat in the diet is good. Mixing fat and carbs seems to give a much more stable blood sugar (and more warmth and higher pulse rate) than just carbs alone.
     
  13. bzmazu

    bzmazu Member

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    :darts:
     
  14. Mito

    Mito Member

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    Dr. Seyfried agrees with that approach.
     
  15. Terma

    Terma Member

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    If @Travis was right that polyamines are central to cancer then it's worth noting that glutamine can raise plasma arginine and arginine is substrate for polyamine synthesis.

    Glutamine is an important precursor for de novo synthesis of arginine in humans. - PubMed - NCBI
    Yet even further he suggested that glutamate and therefore glutamine has a role in DNA methylation.

    I am not a cancer connaissoeur but some studies seem to agree with him and suggest SSAT / polyamine breakdown is compromised (Silencing of the polyamine catabolic key enzyme SSAT prevents CDK inhibitor-induced apoptosis in Caco-2 colon cancer cells), though however to stop polyamines in hyperproliferation you have to stop both the synthesis (methylation/ornithine) plus increase the breakdown (Acetyl-CoA/SSAT)... long story short, but may explain how higher NNMT is associated with worse outcomes.

    The reason it is all like this is that polyamines actually require energy (Acetyl-CoA) to break down by the body. So all a cancer cell needs to do is run low of Acetyl-CoA in its cytosol to have a serious problem, or ablate SSAT through histone methylation/acetylation or other. At the same time, however, fixing SSAT does not fix cancer alone because methylation remains high so the cell compensates and aggressively synthesizes new polyamines.

    So you need both SSAT/Acetyl-CoA working AND a polyamine synthesis methylation inhibitor.

    NNMT appears to have a crucial role in regulating this, but in cancer it correlates with worsened outcomes apparently. This may be because its end product, Nmethylnicotinamide, might actually activate SIRT1 (I have one article that stated this, but it was in liver, so unclear if true in cancer cells) or in other words survival mode - this generalization I'm more sure of.

    So in other words the cell tries to upregulate NNMT to handle the methylation but it's pointless because SSAT is still broken so local polyamine levels may remain high. (note that taking niacinamide is not necessarily the same effect as increasing NNMT even if part of it goes to NNMT, in the case of cancer, because you may achieve a higher niacinamide/n-methylnicotinamide ratio once the methyl is all mopped up)
     
  16. Terma

    Terma Member

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    If all that holds, then one theoretical cause of one kind of cancer, or maybe one state of cancer, straight outta my ass, might be "fatty acid dumping":
    https://www.sciencedirect.com/science/article/pii/S0955286300001194

    This was the authors' theory to explain some metabolic findings where it appeared as if fatty acids were being dumped into the extracellular space due to a massive carnitine overload, since it is the fat shuttle.

    Well, if you run with that idea, you have likely high methyl in cancer, meaning prime substrate floating around for carnitine synthesis, first of all.

    Second, the idea is that the fatty acids were being dumped outside the cell by carnitine, so possibly it could be bypassing the cytosol where SSAT lives.

    So you could imagine a scenario where a dysfunctional cell has loaded its mitochondria with tons of fatty acids and breaks them down to Acyl-CoA, however for whatever reason beta-oxidation and/or Krebs becomes broken and carnitine is plenty available, so the cell starts dumping both Acyl-CoA and Acetyl-CoA. In other words overproduction of Acyl-CoA takes down Acetyl groups with it, since the mito want a certain Acetyl-CoA/CoA ratio.

    Simultaneously the cell can survive fine off pure glycolysis, while high polyamines from non-working SSAT keeps it replicating. The cell tries to upregulate NNMT, but the available NAD/niacinamide might get low, so the ratio of nicotinamide/n-methylnicotinamide stays constantly poor, priming the cell (possibly through SIRT1/other) for "survival" mode instead of fixing the polyamines, backfiring.

    The only problem with this is I'm not 100% convinced the cell's cytosol should end up starved of Acetyl-CoA, but I don't know enough of the low-level details to explain how SSAT might get downregulated (histone methylation/acetylation first thing to check) to suggest an alternative at this time.

    Unlike the other above, this post is basically a thought experiment, so NaCl it up.
     
  17. Dr. C

    Dr. C Member

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    I read the Nature article (Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin)

    It says in a part: "Furthermore, transcriptome data demonstrated that transporters for lactate, pyruvate, glucose, and glutamine were all upregulated. These data suggested that despite the relatively high glycolytic rate of HFSCs under homeostatic conditions17, glycolysis may be further induced upon tumorigenesis."

    Then these guys block LDH and show that the tumor is still growing, meaning lactate is not necessary for the tumor growth. OK. But the tumor stills does a lot of glycolysis and it still seems to shuttle out the pyrovate (which by some other cell of the body would be then reconvertred).

    The authors write a lot about their other experiments (such as administering radio active marked glucose). I bet that they might have tried to breed their SCC tumor cells without glucose and that this failed. Only blocking LDH might have the tumor cells survived.

    So where is the data that shows that a tumor can be deprived of glucose and still develop and progess as fast as with lots of glucose?
     
  18. puella

    puella Member

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    I'm not sure if this supports this topic but I had my neurotransmitters tested in 2011. The results showed glutamate almost double the upper acceptable limit. At the time, the doctor wrote a "?" next to that result & said she had no idea what it indicated.
    ...6 year later discovered a brain tumor. Me thinks they could be related?
     
  19. OP
    haidut

    haidut Member

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    Of course, glutamate is excitotoxic and aside from tumors has been implicated in depression, suicide, PTSD, psychosis, Alzheimer, etc.
     
  20. OP
    haidut

    haidut Member

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    You are right, this study simply focused on LDH. I should have clarified in my post that actual glucose deprivation has been done before and it also failed. The chemical used was 2-deoxy-glucose (2-DG).
    2-Deoxy-D-glucose - Wikipedia

    The human studies I have seen with 2-DG show no more than 30% response rate (partial remission), and after a few months the tumors resume growth. There is also some preliminary evidence showing 2-DG triggers metastases even in people with previously localized tumors.
     
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