Ketogenic Diets for Cancer. I. “What makes you think that ketone bodies will help?”

Posted: October 3, 2016 in Cancer, Cell Signaling, diabetes, evolution
Tags: , , ,

Dr. Eugene Fine and I will described the problem as laid out in our campaign at Experiment.com. The campaign intends to follow-up Dr. Fine’s pilot study of ten advanced cancer patients on ketogenic diets and the in vitro projects that we are carrying out in parallel.We got good feedback and some good questions and we want to continue the scientific interaction and keep the community intact that was started on the “lab notes” at Experiment. We will recapitulate some of the points made during the  campaign and you can “ask the researchers” in comments.

“What makes you think ketone bodies will help?”

We and others have carried out experiments that show the effects of ketone bodies on cancer cells in culture, as diet for patients with advanced cancer or as adjuncts to other modalities. Most direct experimental studies, however, must be considered preliminary and it is reasonable to ask why we thought ketone bodies might help.

The evidence supporting carbohydrate restriction, or specifically ketogenic diets in cancer remains largely indirect and speculative. Our recent perspective  summarized some of the relevant evolutionary and mechanistic factors: the central theme rests with the role of the glucose-insulin axis in promoting growth and proliferation, the predominant characteristic of cancer sells. So it has been observed for some time that patients with diabetes have higher risk of cancer. Epidemiological and other kinds of studies are generally consistent with the idea although different cancers are more or less closely associated with diabetes. Drugs employed as diabetes therapy, particularly metformin, have been found to have beneficial effects in cancer as well. Metformin reduces the risk of developing cancer although the effects on mortality are not clear cut. We made the case, in our critical review that dietary carbohydrate restriction is the first line of treatment for type 2 diabetes and the best adjunct for pharmacology in type 1 diabetes.

cancer-diabetes

The association between cancer and diabetes in combination with the benefits of carbohydrate restriction in diabetes constitute one big connection. In dietary approaches, however, it is total caloric reduction that has received the most attention and, in fact, experiments show that if implemented as stated, calorie restriction represents a reliable approach to prevention and treatment of cancer, particularly in animal models. It is unknown how much of the effect is due to de facto reduction in particular macronutrients but when tested, carbohydrate reduction as the means of reducing calories prove most effective. We cited an important study by Tannenbaum. He found, in 1945 (!) that a carcinogen-induced sarcoma in mice was repressed by reduction in total calories but if  reduced by specifically lowering the carbohydrate intake, there was an enhanced response.

tannenbaum_low-carb_cr

Impressive cancer prevention with calorie restriction in animal models has been repeated many times. Oddly, the protocol is most often presented as caloric restriction.  Odd in that this appears in sophisticated scientific papers where the downstream effects of the stimulation may pinpoint twenty molecular components and where the molecular targets of the “nutrients” are characterized and may specifically be the insulin receptor and the related IGF-1 (insulin-like growth factor -1) receptor. (Insulin is probably most important in that it stimulates IGF-1 activity by reducing the levels of the associated binding proteins). In these studies, where total caloric reduction is the independent variable, the involvement of insulin and the insulin-dependent downstream pathways have been shown to be involved.

It is now appreciated that the Warburg effect, the apparent reliance of tumors on glucose for fuel, is a key observation that has been insufficiently explored. The effect provides motivation and clues for exploring the metabolic approach to cancer. Warburg thought that all cancers showed this phenotype which is not true but a large number do; of significance is that one that does not, prostate cancer, is the outlier in the figure above on relation to diabetes. The next post will start from some basic biochemistry and explain why (and how) we think that the Warburg effect points to the potential value of ketogenic diets.

 

Comments
  1. Susan Parker says:

    Dr. Feinman, I thank you deeply and personally for all you have done and are doing in these studies.

    I have three friends diagnosed with cancer this last month and will pass this over to them.

    Warm regards, Susan Parker LMT

  2. puddleg58 says:

    Not to jump the gun, but the Wikipedia entry on the Warburg effect says that glycolytic tumour cells are still capable of OXPHOS. This is contrary to the basic Warburg idea, at least as we usually come across it on the internet, but doesn’t seem incompatible to me. Tumour cells, if they are aggressive, replicate at a faster rate than the cells around them. They can’t do this without an additional energy source and glycolysis supplies this, even (or rather, especially) in the presence of normal OXPHOS. Take away glycolysis and you just have a cell with a normal energy supply. It may not drop dead in frustration, but it will at least become easier for healthy cells to compete with it, for chemo to knock it out, and for the immune system to keep it in check.

  3. Martin Levac says:

    Richard, hyperglycemia inhibits growth hormone. It’s a double-whammy with carbs. Shuts down the good (GH), increases the bad (insulin). With low-carb, surely it shuts down the bad, but maybe it doesn’t always restart the good?

  4. “”Insulin is probably most important in that it stimulates IGF-1 activity by reducing the levels of the associated binding proteins). In these studies, where total caloric reduction is the independent variable, the involvement of insulin and the insulin-dependent downstream pathways have been shown to be involved.””

    Richard is there a handy good reference for this I can use ? All the studies on IGF-1 and protein I have been able to see are confounded with a lot of carbs. Maybe in the pediatric epilepsy literature ?

  5. Philip Thackray says:

    Dr Feinman,

    Peter’s most recent article here: http://high-fat-nutrition.blogspot.com/2016/09/flow-mediated-dilation-what-does-it-mean.html while not directly related to cancer, Is a most interesting insight into the (positive) bio-chemistry of ketogenic eating. And some of his analysis may relate to ketosis and cancer.

    Phil

  6. Ken says:

    You write that lactate fermentation from glucose is not found in prostate cancer. But what about substrate-level phosphorylation from glutamine in the TCA cycle? Seyfried proposes this as a key secondary/complementary adaptation to damaged OxPhos in various tissues, and as a probable source of error in many experiments challenging Warburg’s thesis.
    There seems to be some research indicating prostate tumors consume or require abnormally high amounts of glutamine.

  7. Phyllis Mueller says:

    “Impressive cancer prevention with calorie restriction in animal models has been repeated many times.”

    Did you mean “with carbohydrate restriction”?

    • rdfeinman says:

      Sorry for the delay in answering. For some reason the app stopped notifying me of new comments. I meant calorie restriction because that is really whats been done. However, whether the effect is due to the de facto reduction in carbohydrate is not known but may be the case.

  8. puddleg58 says:

    Here’s a question – the SGLT2 inhibitor empagliflozin raises LDL, supposedly this is because of increased lipid utilization
    “Empagliflozin, via Switching Metabolism towards Lipid Utilization, Moderately Increases LDL-cholesterol Levels through Reduced LDL Catabolism”.
    http://diabetes.diabetesjournals.org/content/early/2016/03/28/db16-0049

    A drop in LDL is an early predictor of cancer. So – does this happen because of a switch AWAY from lipid utilization? i.e., towards glycolysis? Does anyone know the cause of the drop in LDL that precedes cancer?

  9. […] Ketogenic Diets for Cancer. “What makes you think that ketone bodies will help?” […]

  10. […] Ketogenic Diets for Cancer. “What makes you think that ketone bodies will help?” – is the outlier in the figure above on relation to diabetes. The next post will start from some basic biochemistry and explain why (and how) we think that the Warburg effect points to the potential value of ketogenic diets. NOTE: You can still back the … […]

  11. Leo Tat says:

    My dad had lung cancer 2 years ago. He had the aggressive form and stage 3.

    He followed the ketogenic diet (and supplements) 30% of the time for 3 months. His scans showed the tumour reduced in size very slightly at the end of that 3 months.

    However, he gave up in life so he stopped the protocols altogether, giving up on the supplements, the ketogenic diet and eating whatever he wanted. In the next 3 months his tumour doubled in size and he passed away.

    It was highly likely that the ketogenic diet was helping to reduce the growth of the tumour.

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